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Jena PK, Wakita D, Gomez AC, Carvalho TT, Atici AE, Aubuchon E, Narayanan M, Lee Y, Fishbein MC, Takasato Y, Kurashima Y, Kiyono H, Cani PD, de Vos WM, Underhill DM, Devkota S, Chen S, Shimada K, Crother TR, Arditi M, Rivas MN. Intestinal Microbiota Contributes to the Development of Cardiovascular Inflammation and Vasculitis in Mice. Circ Res 2025; 136:e53-e72. [PMID: 40026151 PMCID: PMC11985309 DOI: 10.1161/circresaha.124.325079] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/14/2024] [Revised: 02/11/2025] [Accepted: 02/13/2025] [Indexed: 03/04/2025]
Abstract
BACKGROUND Alterations in the intestinal microbiota contribute to the pathogenesis of various cardiovascular disorders, but how they affect the development of Kawasaki disease (KD) an acute pediatric vasculitis, remains unclear. METHODS We used the Lactobacillus casei cell wall extract (LCWE) murine model of KD vasculitis to assess the contribution of the intestinal microbiota to the development of vascular inflammation. We evaluated the severity of vasculitis in microbiota-depleted mice. 16S rRNA gene sequencing was used to characterize the fecal microbiome composition of LCWE-injected mice. Some groups of mice were orally treated with selected live or pasteurized bacteria, short-chain fatty acids, or Amuc_1100, the Toll-like receptor 2 signaling outer membrane protein from Akkermansia muciniphila, and their impact on vasculitis development was assessed. RESULTS We report that depleting the gut microbiota reduces the development of cardiovascular inflammation in a murine model mimicking KD vasculitis. The development of cardiovascular lesions was associated with alterations in the intestinal microbiota composition and, notably, a decreased abundance of Akkermansia muciniphila and Faecalibacterium prausnitzii. Oral supplementation with either of these live or pasteurized individual bacteria or with short-chain fatty acids produced by them attenuated cardiovascular inflammation, as reflected by decreased local immune cell infiltrations. Treatment with Amuc_1100 also reduced the severity of vascular inflammation. CONCLUSIONS This study reveals an underappreciated gut microbiota-cardiovascular inflammation axis in KD vasculitis pathogenesis and identifies specific intestinal commensals that regulate vasculitis in mice by producing metabolites or via extracellular proteins capable of enhancing and supporting gut barrier function.
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Affiliation(s)
- Prasant K. Jena
- Department of Pediatrics, Division of Infectious Diseases and Immunology, Guerin Children’s at Cedars-Sinai Medical Center, Los Angeles, CA, USA
- Infectious and Immunologic Diseases Research Center (IIDRC), Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Daiko Wakita
- Department of Pediatrics, Division of Infectious Diseases and Immunology, Guerin Children’s at Cedars-Sinai Medical Center, Los Angeles, CA, USA
- Infectious and Immunologic Diseases Research Center (IIDRC), Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Angela C. Gomez
- Department of Pediatrics, Division of Infectious Diseases and Immunology, Guerin Children’s at Cedars-Sinai Medical Center, Los Angeles, CA, USA
- Infectious and Immunologic Diseases Research Center (IIDRC), Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Thacyana T. Carvalho
- Department of Pediatrics, Division of Infectious Diseases and Immunology, Guerin Children’s at Cedars-Sinai Medical Center, Los Angeles, CA, USA
- Infectious and Immunologic Diseases Research Center (IIDRC), Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Asli E. Atici
- Department of Pediatrics, Division of Infectious Diseases and Immunology, Guerin Children’s at Cedars-Sinai Medical Center, Los Angeles, CA, USA
- Infectious and Immunologic Diseases Research Center (IIDRC), Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Emily Aubuchon
- Department of Pediatrics, Division of Infectious Diseases and Immunology, Guerin Children’s at Cedars-Sinai Medical Center, Los Angeles, CA, USA
- Infectious and Immunologic Diseases Research Center (IIDRC), Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Meena Narayanan
- Department of Pediatrics, Division of Infectious Diseases and Immunology, Guerin Children’s at Cedars-Sinai Medical Center, Los Angeles, CA, USA
- Infectious and Immunologic Diseases Research Center (IIDRC), Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Youngho Lee
- Department of Pediatrics, Division of Infectious Diseases and Immunology, Guerin Children’s at Cedars-Sinai Medical Center, Los Angeles, CA, USA
- Infectious and Immunologic Diseases Research Center (IIDRC), Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Michael C. Fishbein
- Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California Los Angeles, CA, USA
| | - Yoshihiro Takasato
- Department of Allergy, Allergy and Immunology Center, Aichi Children’s Health and Medical Center, Obu, Japan
- Division of Mucosal Immunology, IMSUT Distinguished Professor Unit, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| | - Yosuke Kurashima
- Division of Mucosal Immunology, IMSUT Distinguished Professor Unit, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
- Department of Innovative Medicine, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, Japan
| | - Hiroshi Kiyono
- Division of Mucosal Immunology, IMSUT Distinguished Professor Unit, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
- Department of Innovative Medicine, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, Japan
| | - Patrice D. Cani
- Louvain Drug Research Institute (LDRI), Metabolism and Nutrition Research Group (MNUT), UCLouvain, Université catholique de Louvain, Brussels, Belgium
- WELBIO-Walloon Excellence in Life Sciences and BIOtechnology, WELBIO department, WEL Research Institute, Wavre, Belgium
- Institute of Experimental and Clinical Research (IREC), UCLouvain, Université catholique de Louvain, Brussels, Belgium
| | - Willem M. de Vos
- Laboratory of Microbiology, Wageningen University, Wageningen, The Netherlands
- Human Microbiome Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland
| | - David M. Underhill
- Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA
- F. Widjaja Inflammatory Bowel Diseases Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Suzanne Devkota
- Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA
- F. Widjaja Inflammatory Bowel Diseases Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA
- Human Microbiome Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Shuang Chen
- Department of Pediatrics, Division of Infectious Diseases and Immunology, Guerin Children’s at Cedars-Sinai Medical Center, Los Angeles, CA, USA
- Infectious and Immunologic Diseases Research Center (IIDRC), Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA
- Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Kenichi Shimada
- Department of Pediatrics, Division of Infectious Diseases and Immunology, Guerin Children’s at Cedars-Sinai Medical Center, Los Angeles, CA, USA
- Infectious and Immunologic Diseases Research Center (IIDRC), Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA
- Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Timothy R. Crother
- Department of Pediatrics, Division of Infectious Diseases and Immunology, Guerin Children’s at Cedars-Sinai Medical Center, Los Angeles, CA, USA
- Infectious and Immunologic Diseases Research Center (IIDRC), Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA
- Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Moshe Arditi
- Department of Pediatrics, Division of Infectious Diseases and Immunology, Guerin Children’s at Cedars-Sinai Medical Center, Los Angeles, CA, USA
- Infectious and Immunologic Diseases Research Center (IIDRC), Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA
- Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA
- Smidt Heart Research Institute, Cedars Sinai Medical Center, Los Angeles, CA, USA
| | - Magali Noval Rivas
- Department of Pediatrics, Division of Infectious Diseases and Immunology, Guerin Children’s at Cedars-Sinai Medical Center, Los Angeles, CA, USA
- Infectious and Immunologic Diseases Research Center (IIDRC), Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA
- Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA
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Münte E, Viebahn G, Khurana A, Fujiki J, Nakamura T, Lang S, Demir M, Schnabl B, Hartmann P. Faecalibacterium prausnitzii Is Associated with Disease Severity in MASLD but Its Supplementation Does Not Improve Diet-Induced Steatohepatitis in Mice. Microorganisms 2025; 13:675. [PMID: 40142567 PMCID: PMC11944644 DOI: 10.3390/microorganisms13030675] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2025] [Revised: 03/13/2025] [Accepted: 03/14/2025] [Indexed: 03/28/2025] Open
Abstract
The gut microbiota plays an important role in the pathogenesis of metabolic dysfunction-associated steatotic liver disease (MASLD). In this study, we aimed to evaluate the role of the butyrate-producing bacterium Faecalibacterium prausnitzii in MASLD and whether supplementation with butyrate-producing bacteria, in particular Faecalibacterium prausnitzii, can ameliorate diet-induced steatohepatitis in mice. The relative abundance of the genus Faecalibacterium and its most abundant strain Faecalibacterium prausnitzii was determined by 16S rRNA sequencing and quantitative polymerase chain reaction (qPCR), respectively, in 95 participants with MASLD and 19 healthy control subjects. Butyrate and butyrate-producing bacteria (Faecalibacterium prausnitzii and Coprococcus comes) were gavaged to C57BL/6 mice fed a steatohepatitis-inducing diet. The fecal relative abundance of Faecalibacterium and Faecalibacterium prausnitzii was decreased in subjects with MASLD versus healthy controls and lower in individuals with MASLD and stage 3-4 fibrosis versus those with stage 0-2 fibrosis. Sodium-butyrate supplementation improved hepatic steatosis in mice on high-fat diet (HFD). Gavage of various butyrate-producing bacteria including Faecalibacterium prausnitzii and Coprococcus comes isolated from humans did not improve HFD-induced liver disease in mice. Although the abundance of Faecalibacterium prausnitzii is associated with MASLD severity in humans, its gavage to mice does not improve experimental diet-induced liver disease.
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Affiliation(s)
- Eliane Münte
- Department of Pediatrics, University of California San Diego, La Jolla, CA 92093, USA
| | - Greta Viebahn
- Department of Medicine, University of California San Diego, La Jolla, CA 92093, USA (J.F.)
| | - Amit Khurana
- Department of Pediatrics, University of California San Diego, La Jolla, CA 92093, USA
| | - Jumpei Fujiki
- Department of Medicine, University of California San Diego, La Jolla, CA 92093, USA (J.F.)
- Department of Veterinary Medicine, Rakuno Gakuen University, Ebetsu 069-8501, Hokkaido, Japan
| | - Tomohiro Nakamura
- Department of Medicine, University of California San Diego, La Jolla, CA 92093, USA (J.F.)
| | - Sonja Lang
- Department of Gastroenterology and Hepatology, University Hospital Cologne, 50937 Cologne, Germany
- Faculty of Medicine, University of Cologne, 50931 Cologne, Germany
| | - Münevver Demir
- Department of Hepatology and Gastroenterology, Campus Virchow Clinic and Campus Charité Mitte, Charité University Medicine, 13353 Berlin, Germany
| | - Bernd Schnabl
- Department of Medicine, University of California San Diego, La Jolla, CA 92093, USA (J.F.)
- Department of Medicine, VA San Diego Healthcare System, San Diego, CA 92161, USA
| | - Phillipp Hartmann
- Department of Pediatrics, University of California San Diego, La Jolla, CA 92093, USA
- Division of Gastroenterology, Hepatology & Nutrition, Rady Children’s Hospital San Diego, San Diego, CA 92123, USA
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Quan R, Decraecker L, Appeltans I, Cuende-Estévez M, Van Remoortel S, Aguilera-Lizarraga J, Wang Z, Hicks G, Wykosky J, McLean P, Denadai-Souza A, Hussein H, Boeckxstaens GE. Fecal Proteolytic Bacteria and Staphylococcal Superantigens Are Associated With Abdominal Pain Severity in Irritable Bowel Syndrome. Am J Gastroenterol 2025; 120:603-613. [PMID: 39166748 PMCID: PMC11864055 DOI: 10.14309/ajg.0000000000003042] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/04/2024] [Accepted: 07/30/2024] [Indexed: 08/23/2024]
Abstract
INTRODUCTION Changes in the composition of the gut microbiota have been associated with the development of irritable bowel syndrome (IBS). However, to what extent specific bacterial species relate to clinical symptoms remains poorly characterized. We investigated the clinical relevance of bacterial species linked with increased proteolytic activity, histamine production, and superantigen (SAg) production in patients with IBS. METHODS Fecal (n = 309) and nasal (n = 214) samples were collected from patients with IBS and healthy volunteers (HV). Clinical symptoms and gut transit time were evaluated. Bacterial abundance in feces and nasal swabs as well as fecal trypsin-like activity were assessed. RESULTS The percentage of fecal samples containing Staphylococcus aureus was significantly higher in IBS compared with HV. Forty-nine percent of S. aureus -positive fecal samples from patients with IBS were also positive for SAgs, compared with 12% of HV. Patients with IBS and positive fecal SAg-producing S. aureus reported higher pain scores than those without S. aureus . Moreover, increased fecal proteolytic activity was associated with abdominal pain. Fecal abundance of Paraprevotella clara and Alistipes putredinis was significantly decreased in IBS, particularly in samples with higher proteolytic activity. Patients with lower Alistipes putredinis or Faecalibacterium prausnitzii abundance reported more severe abdominal pain. DISCUSSION In keeping with our preclinical findings, we show that increased presence of SAg-producing S. aureus in fecal samples of patients with IBS is associated with increased levels of abdominal pain. We also show that increased fecal proteolytic activity is associated with increased abdominal pain in patients with IBS.
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Affiliation(s)
- Runze Quan
- Center for Intestinal Neuroimmune Interactions, Translational Research Center for Gastrointestinal Disorders (TARGID), KU Leuven Department of Chronic Diseases and Metabolism (CHROMETA), KU Leuven, Leuven, Belgium
| | - Lisse Decraecker
- Center for Intestinal Neuroimmune Interactions, Translational Research Center for Gastrointestinal Disorders (TARGID), KU Leuven Department of Chronic Diseases and Metabolism (CHROMETA), KU Leuven, Leuven, Belgium
| | - Iris Appeltans
- Center for Intestinal Neuroimmune Interactions, Translational Research Center for Gastrointestinal Disorders (TARGID), KU Leuven Department of Chronic Diseases and Metabolism (CHROMETA), KU Leuven, Leuven, Belgium
| | - María Cuende-Estévez
- Center for Intestinal Neuroimmune Interactions, Translational Research Center for Gastrointestinal Disorders (TARGID), KU Leuven Department of Chronic Diseases and Metabolism (CHROMETA), KU Leuven, Leuven, Belgium
| | - Samuel Van Remoortel
- Center for Intestinal Neuroimmune Interactions, Translational Research Center for Gastrointestinal Disorders (TARGID), KU Leuven Department of Chronic Diseases and Metabolism (CHROMETA), KU Leuven, Leuven, Belgium
| | - Javier Aguilera-Lizarraga
- Laboratory of Sensory Neurophysiology and Pain, Department of Pharmacology, University of Cambridge, Cambridge, UK
| | - Zheng Wang
- Center for Intestinal Neuroimmune Interactions, Translational Research Center for Gastrointestinal Disorders (TARGID), KU Leuven Department of Chronic Diseases and Metabolism (CHROMETA), KU Leuven, Leuven, Belgium
| | | | | | | | - Alexandre Denadai-Souza
- Laboratory of Mucosal Biology, Hepatology Research Unit, Department of Chronic Diseases and Metabolism (CHROMETA), KU Leuven, Leuven, Belgium
| | - Hind Hussein
- Center for Intestinal Neuroimmune Interactions, Translational Research Center for Gastrointestinal Disorders (TARGID), KU Leuven Department of Chronic Diseases and Metabolism (CHROMETA), KU Leuven, Leuven, Belgium
| | - Guy E. Boeckxstaens
- Center for Intestinal Neuroimmune Interactions, Translational Research Center for Gastrointestinal Disorders (TARGID), KU Leuven Department of Chronic Diseases and Metabolism (CHROMETA), KU Leuven, Leuven, Belgium
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Pratt ML, Plumb AN, Manjrekar A, Cardona LM, Chan CK, John JM, Sadler KE. Microbiome contributions to pain: a review of the preclinical literature. Pain 2025; 166:262-281. [PMID: 39258679 PMCID: PMC11723818 DOI: 10.1097/j.pain.0000000000003376] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2024] [Accepted: 06/28/2024] [Indexed: 09/12/2024]
Abstract
ABSTRACT Over the past 2 decades, the microbiome has received increasing attention for the role that it plays in health and disease. Historically, the gut microbiome was of particular interest to pain scientists studying nociplastic visceral pain conditions given the anatomical juxtaposition of these microorganisms and the neuroimmune networks that drive pain in such diseases. More recently, microbiomes both inside and across the surface of the body have been recognized for driving sensory symptoms in a broader set of diseases. Microbiomes have never been a more popular topic in pain research, but to date, there has not been a systematic review of the preclinical microbiome pain literature. In this article, we identified all animal studies in which both the microbiome was manipulated and pain behaviors were measured. Our analysis included 303 unique experiments across 97 articles. Microbiome manipulation methods and behavioral outcomes were recorded for each experiment so that field-wide trends could be quantified and reported. This review specifically details the animal species, injury models, behavior measures, and microbiome manipulations used in preclinical pain research. From this analysis, we were also able to conclude how manipulations of the microbiome alter pain thresholds in naïve animals and persistent pain intensity and duration in cutaneous and visceral pain models. This review summarizes by identifying existing gaps in the literature and providing recommendations for how to best plan, implement, and interpret data collected in preclinical microbiome pain experiments.
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Affiliation(s)
- McKenna L Pratt
- Department of Neuroscience, Center for Advanced Pain Studies, University of Texas at Dallas, Richardson, TX, United States
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Crucillà S, Caldart F, Michelon M, Marasco G, Costantino A. Functional Abdominal Bloating and Gut Microbiota: An Update. Microorganisms 2024; 12:1669. [PMID: 39203511 PMCID: PMC11357468 DOI: 10.3390/microorganisms12081669] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2024] [Revised: 08/02/2024] [Accepted: 08/07/2024] [Indexed: 09/03/2024] Open
Abstract
(1) Background: Functional abdominal bloating and distension (FAB/FAD) are common disorders of the gut-brain interaction. Their physiopathology is complex and not completely clarified, although gut microbiota imbalances play a central role. The treatment of FAB/FAD still represents a clinical challenge for both patients and healthcare providers. Gut microbiota modulation strategies might play a crucial role in their management. The aim of this narrative review was to update the current evidence on FAB/FAD, with a focus on gut microbiota. (2) Methods: In October 2023, a review was conducted through the Medline, PubMed, and Embase databases. Selected literature included all available English-edited studies (randomized controlled trials and cross-sectional, cohort, and case-control studies). (3) Results: Twelve studies were selected, most of which investigated the relationship between IBS and microbiota, with bloating being one of its symptoms. The studies suggest that restoring a balanced microbiome appears to be the most promising solution for better management of FAB/FAD. Targeted approaches, such as the use of probiotics, prebiotics, antibiotics such as rifaximin or dietary modifications, may hold the key to alleviating symptoms. Other therapeutic options, such as diet, neuromodulators, and brain-gut behavioral therapies (i.e., cognitive-behavioral therapy) have shown promising outcomes, but strong data are still lacking. (4) Conclusions: Targeted approaches that focus on the gut microbiota, such as the use of probiotics, prebiotics, and antibiotics, are essential in managing FAB/FAD. Understanding the complex relationship between gut microbiota and FAB/FAD is crucial for developing effective treatments. Further studies are needed to explore the specific roles of different microbial populations in patients with FAB/FAD to enhance therapeutic strategies.
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Affiliation(s)
- Salvatore Crucillà
- Gastroenterology B Unit, Pancreas Center, University of Verona, 37134 Verona, Italy;
| | - Federico Caldart
- Gastroenterology B Unit, Pancreas Center, University of Verona, 37134 Verona, Italy;
| | - Marco Michelon
- Department of Pathophysiology and Transplantation, University of Milan, 20122 Milan, Italy;
| | - Giovanni Marasco
- Department of Medical and Surgical Sciences, University of Bologna, 40138 Bologna, Italy;
- IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy
| | - Andrea Costantino
- Department of Pathophysiology and Transplantation, University of Milan, 20122 Milan, Italy;
- Unit of Gastroenterology and Endoscopy, Foundation IRCCS Ca’ Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy
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Jena PK, Wakita D, Gomez AC, Carvalho TT, Atici AE, Narayanan M, Lee Y, Fishbein MC, Cani PD, de Vos WM, Underhill DM, Devkota S, Chen S, Shimada K, Crother TR, Arditi M, Rivas MN. The intestinal microbiota contributes to the development of immune-mediated cardiovascular inflammation and vasculitis in mice. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.05.28.596258. [PMID: 38853964 PMCID: PMC11160596 DOI: 10.1101/2024.05.28.596258] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/11/2024]
Abstract
Alterations in the intestinal microbiota contribute to the pathogenesis of various cardiovascular disorders, but how they affect the development of Kawasaki disease (KD), an acute pediatric vasculitis, remains unclear. We report that depleting the gut microbiota reduces the development of cardiovascular inflammation in a murine model mimicking KD vasculitis. The development of cardiovascular lesions was associated with alterations in the intestinal microbiota composition and, notably, a decreased abundance of Akkermansia muciniphila and Faecalibacterium prausnitzii. Oral supplementation with either of these live or pasteurized individual bacteria, or with short-chain fatty acids (SCFAs) produced by them, attenuated cardiovascular inflammation. Treatment with Amuc_1100, the TLR-2 signaling outer membrane protein from A. muciniphila , also decreased the severity of vascular inflammation. This study reveals an underappreciated gut microbiota-cardiovascular inflammation axis in KD vasculitis pathogenesis and identifies specific intestinal commensals that regulate vasculitis in mice by producing metabolites or via extracellular proteins acting on gut barrier function. IN BRIEF It remains unclear whether changes in the intestinal microbiota composition are involved in the development of cardiovascular lesions associated with Kawasaki disease (KD), an immune-mediated vasculitis. Jena et al. observe alterations in the intestinal microbiota composition of mice developing vasculitis, characterized by reduced A. muciniphila and F. prausnitzii . Oral supplementation with either of these bacteria, live or pasteurized, or with bacteria-produced short-chain fatty acids (SCFAs) or Amuc_1100, the TLR-2 signaling outer membrane protein of A. muciniphila , was sufficient to alleviate the development of cardiovascular lesions in mice by promoting intestinal barrier function. HIGHLIGHTS Absence or depletion of the microbiota decreases the severity of vasculitis in a murine model mimicking KD vasculitis. Supplementation of B. wadsworthia and B. fragilis promotes murine KD vasculitis. Decreased abundances of F. prausnitzii and A. muciniphila are associated with the development of cardiovascular lesions in mice. Supplementation with either live or pasteurized A. muciniphila and F. prausnitzii, or the TLR-2 signaling Amuc_1100, reduces the severity of vasculitis by promoting gut barrier function.
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Ford AC, Vanner S, Kashyap PC, Nasser Y. Chronic Visceral Pain: New Peripheral Mechanistic Insights and Resulting Treatments. Gastroenterology 2024; 166:976-994. [PMID: 38325759 PMCID: PMC11102851 DOI: 10.1053/j.gastro.2024.01.045] [Citation(s) in RCA: 14] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/25/2023] [Revised: 11/15/2023] [Accepted: 01/05/2024] [Indexed: 02/09/2024]
Abstract
Chronic visceral pain is one of the most common reasons for patients with gastrointestinal disorders, such as inflammatory bowel disease or disorders of brain-gut interaction, to seek medical attention. It represents a substantial burden to patients and is associated with anxiety, depression, reductions in quality of life, and impaired social functioning, as well as increased direct and indirect health care costs to society. Unfortunately, the diagnosis and treatment of chronic visceral pain is difficult, in part because our understanding of the underlying pathophysiologic basis is incomplete. In this review, we highlight recent advances in peripheral pain signaling and specific physiologic and pathophysiologic preclinical mechanisms that result in the sensitization of peripheral pain pathways. We focus on preclinical mechanisms that have been translated into treatment approaches and summarize the current evidence base for directing treatment toward these mechanisms of chronic visceral pain derived from clinical trials. The effective management of chronic visceral pain remains of critical importance for the quality of life of suffers. A deeper understanding of peripheral pain mechanisms is necessary and may provide the basis for novel therapeutic interventions.
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Affiliation(s)
- Alexander C Ford
- Leeds Institute of Medical Research at St. James's, University of |Leeds, Leeds, United Kingdom; Leeds Gastroenterology Institute, Leeds Teaching Hospitals National Health Service Trust, Leeds, United Kingdom
| | - Stephen Vanner
- Gastrointestinal Diseases Research Unit, Kingston General Hospital, Queen's University, Kingston, Ontario, Canada
| | - Purna C Kashyap
- Division of Gastroenterology and Hepatology, Department of Medicine, Mayo Clinic, Rochester, Minnesota
| | - Yasmin Nasser
- Snyder Institute for Chronic Diseases, Department of Medicine, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.
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Gervason S, Meleine M, Lolignier S, Meynier M, Daugey V, Birer A, Aissouni Y, Berthon JY, Ardid D, Filaire E, Carvalho FA. Antihyperalgesic properties of gut microbiota: Parabacteroides distasonis as a new probiotic strategy to alleviate chronic abdominal pain. Pain 2024; 165:e39-e54. [PMID: 37756665 DOI: 10.1097/j.pain.0000000000003075] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2023] [Accepted: 08/08/2023] [Indexed: 09/29/2023]
Abstract
ABSTRACT The potential role of gut microbiota in pain modulation is arousing an emerging interest since recent years. This study investigated neuromodulatory properties of gut microbiota to identify next-generation probiotics to propose alternative therapies for visceral pain management. Neuromodulation ability of 10 bacterial strains isolated from a healthy donor was assessed both on ND7/23 immortalized cell line and primary neuronal cells from rat dorsal root ganglia. This screening highlighted the neuroinhibitory property of Parabacteroides distasonis (F1-2) strain, supported both by its intracellular content and membrane fraction, which was further investigated in visceral pain mouse models. Oral administration of F1-2 resulted in a significant decrease of colonic hypersensitivity (CHS) in dextran sulfate sodium (0.5%) model associated with low-grade inflammation and a significant decrease of CHS in Citrobacter rodentium postinfectious models. No effect of F1-2 oral administration on CHS was observed in a neonatal maternal separation stress model. Antihyperalgesic effect unlikely involved modulation of inflammatory processes or restoration of intestinal barrier. Exploration of direct dialogue mechanisms between this strain and nervous system, assessed by calcium imaging experiments, revealed that F1-2 interacts directly with nociceptors by reducing activation level on capsaicin, inflammatory soup, and bradykinin stimulations. Our study provides new insights about bacteria-host interaction and places P distasonis as a potential therapeutic strategy in the treatment of visceral pain observed in leaky gut-associated pathologies.
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Affiliation(s)
- Sandie Gervason
- NeuroDol, UMR 1107 INSERM, University of Clermont Auvergne, Clermont-Ferrand, France
| | - Mathieu Meleine
- NeuroDol, UMR 1107 INSERM, University of Clermont Auvergne, Clermont-Ferrand, France
| | - Stéphane Lolignier
- NeuroDol, UMR 1107 INSERM, University of Clermont Auvergne, Clermont-Ferrand, France
| | - Maëva Meynier
- NeuroDol, UMR 1107 INSERM, University of Clermont Auvergne, Clermont-Ferrand, France
- M2iSH, UMR 1071 INSERM, University of Clermont Auvergne, Clermont-Ferrand, France
| | - Valentine Daugey
- NeuroDol, UMR 1107 INSERM, University of Clermont Auvergne, Clermont-Ferrand, France
| | - Aurélien Birer
- M2iSH, UMR 1071 INSERM, University of Clermont Auvergne, Clermont-Ferrand, France
- Centre National de Référence de la Résisitance aux Antibiotiques, Service de Bactériologie, Clermont-Ferrand, France
| | - Youssef Aissouni
- NeuroDol, UMR 1107 INSERM, University of Clermont Auvergne, Clermont-Ferrand, France
| | | | - Denis Ardid
- NeuroDol, UMR 1107 INSERM, University of Clermont Auvergne, Clermont-Ferrand, France
| | - Edith Filaire
- ECREIN Team, Human Nutrition Unit (UNH), UMR 1019 INRAE-UCA, University of Clermont-Auvergne, Clermont-Ferrand, France
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9
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Pak R, Cho M, Pride K, Abd-Elsayed A. The Gut Microbiota and Chronic Pain. Curr Pain Headache Rep 2024; 28:259-269. [PMID: 38345694 DOI: 10.1007/s11916-024-01221-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/30/2024] [Indexed: 03/16/2024]
Abstract
PURPOSE OF REVIEW To examine the effects and interactions between gut microbia and chronic pain. RECENT FINDINGS The gut microbiome has been an area of interest in both the scientific and general audience due to a growing body of evidence suggesting its influence in a variety of health and disease states. Communication between the central nervous system (CNS) and gut microbiome is said to be bidirectional, in what is referred to as the gut-brain axis. Chronic pain is a prevalent costly personal and public health burden and so, there is a vested interest in devising safe and efficacious treatments. Numerous studies, many of which are animal studies, have been conducted to examine the gut microbiome's role in the pathophysiology of chronic pain states, such as neuropathy, inflammation, visceral pain, etc. As the understanding of this relationship grows, so does the potential for therapeutic targeting of the gut microbiome in chronic pain.
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Affiliation(s)
- Ray Pak
- Department of Physical Medicine and Rehabilitation, New York Medical College/Metropolitan, New York, NY, USA
| | - Michelle Cho
- Department of Physical Medicine and Rehabilitation, New York Medical College/Metropolitan, New York, NY, USA
| | - Keth Pride
- Department of Anesthesiology, University of Wisconsin School of Medicine and Public Health, 600 Highland Avenue, B6/319 CSC, Madison, WI, 53792-3272, USA
| | - Alaa Abd-Elsayed
- Department of Anesthesiology, University of Wisconsin School of Medicine and Public Health, 600 Highland Avenue, B6/319 CSC, Madison, WI, 53792-3272, USA.
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10
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Baker CC, Sessenwein JL, Wood HM, Yu Y, Tsang Q, Alward TA, Jimenez Vargas NN, Omar AA, McDonnel A, Segal JP, Sjaarda CP, Bunnett NW, Schmidt BL, Caminero A, Boev N, Bannerman CA, Ghasemlou N, Sheth PM, Vanner SJ, Reed DE, Lomax AE. Protease-Induced Excitation of Dorsal Root Ganglion Neurons in Response to Acute Perturbation of the Gut Microbiota Is Associated With Visceral and Somatic Hypersensitivity. Cell Mol Gastroenterol Hepatol 2024; 18:101334. [PMID: 38494056 PMCID: PMC11350452 DOI: 10.1016/j.jcmgh.2024.03.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/30/2023] [Revised: 03/08/2024] [Accepted: 03/11/2024] [Indexed: 03/19/2024]
Abstract
BACKGROUND & AIMS Abdominal pain is a major symptom of diseases that are associated with microbial dysbiosis, including irritable bowel syndrome and inflammatory bowel disease. Germ-free mice are more prone to abdominal pain than conventionally housed mice, and reconstitution of the microbiota in germ-free mice reduces abdominal pain sensitivity. However, the mechanisms underlying microbial modulation of pain remain elusive. We hypothesized that disruption of the intestinal microbiota modulates the excitability of peripheral nociceptive neurons. METHODS In vivo and in vitro assays of visceral sensation were performed on mice treated with the nonabsorbable antibiotic vancomycin (50 μg/mL in drinking water) for 7 days and water-treated control mice. Bacterial dysbiosis was verified by 16s rRNA analysis of stool microbial composition. RESULTS Treatment of mice with vancomycin led to an increased sensitivity to colonic distension in vivo and in vitro and hyperexcitability of dorsal root ganglion (DRG) neurons in vitro, compared with controls. Interestingly, hyperexcitability of DRG neurons was not restricted to those that innervated the gut, suggesting a widespread effect of gut dysbiosis on peripheral pain circuits. Consistent with this, mice treated with vancomycin were more sensitive than control mice to thermal stimuli applied to hind paws. Incubation of DRG neurons from naive mice in serum from vancomycin-treated mice increased DRG neuron excitability, suggesting that microbial dysbiosis alters circulating mediators that influence nociception. The cysteine protease inhibitor E64 (30 nmol/L) and the protease-activated receptor 2 (PAR-2) antagonist GB-83 (10 μmol/L) each blocked the increase in DRG neuron excitability in response to serum from vancomycin-treated mice, as did the knockout of PAR-2 in NaV1.8-expressing neurons. Stool supernatant, but not colonic supernatant, from mice treated with vancomycin increased DRG neuron excitability via cysteine protease activation of PAR-2. CONCLUSIONS Together, these data suggest that gut microbial dysbiosis alters pain sensitivity and identify cysteine proteases as a potential mediator of this effect.
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Affiliation(s)
- Corey C Baker
- Gastrointestinal Diseases Research Unit, Queen's University, Kingston, Ontario, Canada
| | - Jessica L Sessenwein
- Gastrointestinal Diseases Research Unit, Queen's University, Kingston, Ontario, Canada
| | - Hannah M Wood
- Gastrointestinal Diseases Research Unit, Queen's University, Kingston, Ontario, Canada
| | - Yang Yu
- Gastrointestinal Diseases Research Unit, Queen's University, Kingston, Ontario, Canada
| | - Quentin Tsang
- Gastrointestinal Diseases Research Unit, Queen's University, Kingston, Ontario, Canada
| | - Taylor A Alward
- Gastrointestinal Diseases Research Unit, Queen's University, Kingston, Ontario, Canada
| | | | - Amal Abu Omar
- Gastrointestinal Diseases Research Unit, Queen's University, Kingston, Ontario, Canada
| | - Abby McDonnel
- Gastrointestinal Diseases Research Unit, Queen's University, Kingston, Ontario, Canada
| | - Julia P Segal
- Department of Biomedical and Molecular Sciences, Queen's University, Kingston, Ontario, Canada
| | - Calvin P Sjaarda
- Department of Pathology and Molecular Medicine, Queen's University, Kingston, Ontario, Canada
| | - Nigel W Bunnett
- Department of Molecular Pathobiology, Neuroscience Institute, New York University, New York, New York
| | - Brian L Schmidt
- Department of Molecular Pathobiology, Neuroscience Institute, New York University, New York, New York
| | - Alberto Caminero
- Department of Medicine, Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, Ontario, Canada
| | - Nadejda Boev
- Department of Pathology and Molecular Medicine, Queen's University, Kingston, Ontario, Canada
| | - Courtney A Bannerman
- Department of Biomedical and Molecular Sciences, Queen's University, Kingston, Ontario, Canada
| | - Nader Ghasemlou
- Department of Biomedical and Molecular Sciences, Queen's University, Kingston, Ontario, Canada; Department of Anesthesiology and Perioperative Medicine, Queen's Unversity, Kingston, Ontario, Canada
| | - Prameet M Sheth
- Gastrointestinal Diseases Research Unit, Queen's University, Kingston, Ontario, Canada; Department of Biomedical and Molecular Sciences, Queen's University, Kingston, Ontario, Canada; Department of Pathology and Molecular Medicine, Queen's University, Kingston, Ontario, Canada
| | - Stephen J Vanner
- Gastrointestinal Diseases Research Unit, Queen's University, Kingston, Ontario, Canada
| | - David E Reed
- Gastrointestinal Diseases Research Unit, Queen's University, Kingston, Ontario, Canada
| | - Alan E Lomax
- Gastrointestinal Diseases Research Unit, Queen's University, Kingston, Ontario, Canada; Department of Biomedical and Molecular Sciences, Queen's University, Kingston, Ontario, Canada.
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11
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Meynier M, Daugey V, Mallaret G, Gervason S, Meleine M, Barbier J, Aissouni Y, Lolignier S, Bonnet M, Ardid D, De Vos WM, Van Hul M, Suenaert P, Brochot A, Cani PD, Carvalho FA. Pasteurized akkermansia muciniphila improves irritable bowel syndrome-like symptoms and related behavioral disorders in mice. Gut Microbes 2024; 16:2298026. [PMID: 38170633 PMCID: PMC10766393 DOI: 10.1080/19490976.2023.2298026] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/20/2023] [Accepted: 12/18/2023] [Indexed: 01/05/2024] Open
Abstract
Gut - brain communications disorders in irritable bowel syndrome (IBS) are associated with intestinal microbiota composition, increased gut permeability, and psychosocial disturbances. Symptoms of IBS are difficult to medicate, and hence much research is being made into alternative approaches. This study assesses the potential of a treatment with pasteurized Akkermansia muciniphila for alleviating IBS-like symptoms in two mouse models of IBS with different etiologies. Two clinically relevant animal models were used to mimic IBS-like symptoms in C57BL6/J mice: the neonatal maternal separation (NMS) paradigm and the Citrobacter rodentium infection model. In both models, gut permeability, colonic sensitivity, fecal microbiota composition and colonic IL-22 expression were evaluated. The cognitive performance and emotional state of the animals were also assessed by several tests in the C. rodentium infection model. The neuromodulation ability of pasteurized A. muciniphila was assessed on primary neuronal cells from mice dorsal root ganglia using a ratiometric calcium imaging approach. The administration of pasteurized A. muciniphila significantly reduced colonic hypersensitivity in both IBS mouse models, accompanied by a reinforcement of the intestinal barrier function. Beneficial effects of pasteurized A. muciniphila treatment have also been observed on anxiety-like behavior and memory defects in the C. rodentium infection model. Finally, a neuroinhibitory effect exerted by pasteurized A. muciniphila was observed on neuronal cells stimulated with two algogenic substances such as capsaicin and inflammatory soup. Our findings demonstrate novel anti-hyperalgesic and neuroinhibitory properties of pasteurized A. muciniphila, which therefore may have beneficial effects in relieving pain and anxiety in subjects with IBS.
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Affiliation(s)
- Maëva Meynier
- NeuroDol, UMR 1107 INSERM, University of Clermont Auvergne, Clermont-Ferrand, France
- M2iSH, UMR 1071 INSERM, UMR1382 INRAé, University of Clermont Auvergne, Clermont-Ferrand, France
| | - Valentine Daugey
- NeuroDol, UMR 1107 INSERM, University of Clermont Auvergne, Clermont-Ferrand, France
| | - Geoffroy Mallaret
- NeuroDol, UMR 1107 INSERM, University of Clermont Auvergne, Clermont-Ferrand, France
| | - Sandie Gervason
- NeuroDol, UMR 1107 INSERM, University of Clermont Auvergne, Clermont-Ferrand, France
| | - Mathieu Meleine
- NeuroDol, UMR 1107 INSERM, University of Clermont Auvergne, Clermont-Ferrand, France
| | - Julie Barbier
- NeuroDol, UMR 1107 INSERM, University of Clermont Auvergne, Clermont-Ferrand, France
| | - Youssef Aissouni
- NeuroDol, UMR 1107 INSERM, University of Clermont Auvergne, Clermont-Ferrand, France
| | - Stéphane Lolignier
- NeuroDol, UMR 1107 INSERM, University of Clermont Auvergne, Clermont-Ferrand, France
| | - Mathilde Bonnet
- M2iSH, UMR 1071 INSERM, UMR1382 INRAé, University of Clermont Auvergne, Clermont-Ferrand, France
| | - Denis Ardid
- NeuroDol, UMR 1107 INSERM, University of Clermont Auvergne, Clermont-Ferrand, France
| | - Willem M. De Vos
- Laboratory of Microbiology, Wageningen University, Wageningen, The Netherlands
- Human Microbiome Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland
- The Akkermansia Company™, Mont-Saint-Guibert, Belgium
| | - Matthias Van Hul
- Metabolism and Nutrition Research group, Louvain Drug Research Institute (LDRI), UCLouvain, Université Catholique de Louvain, Brussels, Belgium
- WELBIO-Walloon Excellence in Life Sciences and Biotechnology, WELBIO department, WEL Research Institute, Wavre, Belgium
| | | | | | - Patrice D. Cani
- Metabolism and Nutrition Research group, Louvain Drug Research Institute (LDRI), UCLouvain, Université Catholique de Louvain, Brussels, Belgium
- WELBIO-Walloon Excellence in Life Sciences and Biotechnology, WELBIO department, WEL Research Institute, Wavre, Belgium
- Institute of Experimental and Clinical Research (IREC), UCLouvain, Université catholique de Louvain, Brussels, Belgium
| | - Frédéric A. Carvalho
- NeuroDol, UMR 1107 INSERM, University of Clermont Auvergne, Clermont-Ferrand, France
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12
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Wang Y, Ma W, Mehta R, Nguyen LH, Song M, Drew DA, Asnicar F, Huttenhower C, Segata N, Wolf J, Spector T, Berry S, Staller K, Chan AT. Diet and gut microbial associations in irritable bowel syndrome according to disease subtype. Gut Microbes 2023; 15:2262130. [PMID: 37786251 PMCID: PMC10549191 DOI: 10.1080/19490976.2023.2262130] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/30/2023] [Accepted: 09/15/2023] [Indexed: 10/04/2023] Open
Abstract
The role of diet and the gut microbiome in the etiopathogenesis of irritable bowel syndrome (IBS) is not fully understood. Therefore, we investigated the interplay between dietary risk factors and gut microbiota in IBS subtypes using a food frequency questionnaire and stool metagenome data from 969 participants aged 18-65 years in the ZOE PREDICT 1 study, an intervention study designed to predict postprandial metabolic responses. We identified individuals with IBS subtype according to the Rome III criteria based on predominant bowel habits during symptom onset: diarrhea (i.e. looser), constipation (i.e. harder), and mixed. Participants with IBS-D (n = 59) consumed more healthy plant-based foods (e.g. whole grains, leafy vegetables) and fiber, while those with IBS-C (n = 49) tended to consume more unhealthy plant-based foods (e.g. refined grains, fruit juice) than participants without IBS (n = 797). Microbial diversity was nominally lower in patients with IBS-D than in participants without IBS or with IBS-C. Using multivariable-adjusted linear regression, we identified specific microbiota variations in IBS subtypes, including slight increases in pro-inflammatory taxa in IBS-C (e.g. Escherichia coli) and loss of strict anaerobes in IBS-D (e.g. Faecalibacterium prausnitzii). Our analysis also revealed intriguing evidence of interactions between diet and Faecalibacterium prausnitzii. The positive associations between fiber and iron intake and IBS-diarrhea were stronger among individuals with a higher relative abundance of Faecalibacterium prausnitzii, potentially driven by carbohydrate metabolic pathways, including the superpathway of β-D-glucuronide and D-glucuronate degradation. In conclusion, our findings suggest subtype-specific variations in dietary habits, gut microbial composition and function, and diet-microbiota interactions in IBS, providing insights into potential microbiome-informed dietary interventions.
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Affiliation(s)
- Yiqing Wang
- Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
- Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Wenjie Ma
- Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
- Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Raaj Mehta
- Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
- Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Long H. Nguyen
- Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
- Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
- Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, USA
| | - Mingyang Song
- Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
- Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA
- Department of Nutrition, Harvard T.H. Chan School of Public Health, 677 Huntington Avenue, Boston, MA, USA
| | - David A. Drew
- Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
- Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Francesco Asnicar
- Department of Cellular, Computational and Integrative Biology, University of Trento, Trento, Italy
| | - Curtis Huttenhower
- Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, USA
- Broad Institute of MIT and Harvard, Cambridge, MA, USA
| | - Nicola Segata
- Department of Cellular, Computational and Integrative Biology, University of Trento, Trento, Italy
- European Institute of Oncology Scientific Institute for Research, Hospitalization and Healthcare, Milan, Italy
| | | | - Tim Spector
- Department of Twin Research, King’s College London, London, UK
| | - Sarah Berry
- Department of Nutritional Sciences, King’s College London, London, UK
| | - Kyle Staller
- Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
- Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Andrew T. Chan
- Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
- Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
- Department of Nutrition, Harvard T.H. Chan School of Public Health, 677 Huntington Avenue, Boston, MA, USA
- Channing Division of Network Medicine, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, USA
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13
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Fyntanidou B, Amaniti A, Soulioti E, Zagalioti SC, Gkarmiri S, Chorti A, Loukipoudi L, Ioannidis A, Dalakakis I, Menni AE, Shrewsbury AD, Kotzampassi K. Probiotics in Postoperative Pain Management. J Pers Med 2023; 13:1645. [PMID: 38138872 PMCID: PMC10745134 DOI: 10.3390/jpm13121645] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2023] [Revised: 11/20/2023] [Accepted: 11/23/2023] [Indexed: 12/24/2023] Open
Abstract
Postoperative pain is the unpleasant sensory and emotional experience after surgery, its origin being both the inflammatory reaction induced by the surgical trauma on the abdominal wall and the splanchnic pain induced by the activation of nociceptors of the viscera, which are highly sensitive to distension, ischemia, and inflammation. Nowadays, it is well recognized that there is a close relationship between the gut microbiome and pain perception, and that microbiome is highly affected by both anesthesia and surgical manipulation. Thus, efforts to restore the disturbed microbiome via supplementation with beneficial bacteria, namely probiotics, seem to be effective. In this article, the knowledge gained mainly from experimental research on this topic is analyzed, the concluding message being that each probiotic strain works in its own way towards pain relief.
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Affiliation(s)
- Barbara Fyntanidou
- Department of Emergency Medicine, Aristotle University of Thessaloniki, 54636 Thessaloniki, Greece; (B.F.); (S.-C.Z.); (S.G.)
| | - Aikaterini Amaniti
- Department of Anesthesia & Intensive Care, Aristotle University of Thessaloniki, 54636 Thessaloniki, Greece; (A.A.); (L.L.); (I.D.)
| | - Eleftheria Soulioti
- Second Department of Anesthesiology, National and Kapodistrian University of Athens, Attikon University Hospital, 12462 Athens, Greece;
| | - Sofia-Chrysovalantou Zagalioti
- Department of Emergency Medicine, Aristotle University of Thessaloniki, 54636 Thessaloniki, Greece; (B.F.); (S.-C.Z.); (S.G.)
| | - Sofia Gkarmiri
- Department of Emergency Medicine, Aristotle University of Thessaloniki, 54636 Thessaloniki, Greece; (B.F.); (S.-C.Z.); (S.G.)
| | - Angeliki Chorti
- Department of Surgery, Aristotle University of Thessaloniki, 54636 Thessaloniki, Greece; (A.C.); (A.I.); (A.-E.M.); (A.D.S.)
| | - Lamprini Loukipoudi
- Department of Anesthesia & Intensive Care, Aristotle University of Thessaloniki, 54636 Thessaloniki, Greece; (A.A.); (L.L.); (I.D.)
| | - Aris Ioannidis
- Department of Surgery, Aristotle University of Thessaloniki, 54636 Thessaloniki, Greece; (A.C.); (A.I.); (A.-E.M.); (A.D.S.)
| | - Ioannis Dalakakis
- Department of Anesthesia & Intensive Care, Aristotle University of Thessaloniki, 54636 Thessaloniki, Greece; (A.A.); (L.L.); (I.D.)
| | - Alexandra-Eleftheria Menni
- Department of Surgery, Aristotle University of Thessaloniki, 54636 Thessaloniki, Greece; (A.C.); (A.I.); (A.-E.M.); (A.D.S.)
| | - Anne D. Shrewsbury
- Department of Surgery, Aristotle University of Thessaloniki, 54636 Thessaloniki, Greece; (A.C.); (A.I.); (A.-E.M.); (A.D.S.)
| | - Katerina Kotzampassi
- Department of Surgery, Aristotle University of Thessaloniki, 54636 Thessaloniki, Greece; (A.C.); (A.I.); (A.-E.M.); (A.D.S.)
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14
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Álvarez-Herms J, González A, Corbi F, Odriozola I, Odriozola A. Possible relationship between the gut leaky syndrome and musculoskeletal injuries: the important role of gut microbiota as indirect modulator. AIMS Public Health 2023; 10:710-738. [PMID: 37842270 PMCID: PMC10567981 DOI: 10.3934/publichealth.2023049] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2023] [Revised: 08/03/2023] [Accepted: 08/07/2023] [Indexed: 10/17/2023] Open
Abstract
This article aims to examine the evidence on the relationship between gut microbiota (GM), leaky gut syndrome and musculoskeletal injuries. Musculoskeletal injuries can significantly impair athletic performance, overall health, and quality of life. Emerging evidence suggests that the state of the gut microbiota and the functional intestinal permeability may contribute to injury recovery. Since 2007, a growing field of research has supported the idea that GM exerts an essential role maintaining intestinal homeostasis and organic and systemic health. Leaky gut syndrome is an acquired condition where the intestinal permeability is impaired, and different bacteria and/or toxins enter in the bloodstream, thereby promoting systemic endotoxemia and chronic low-grade inflammation. This systemic condition could indirectly contribute to increased local musculoskeletal inflammation and chronificate injuries and pain, thereby reducing recovery-time and limiting sport performance. Different strategies, including a healthy diet and the intake of pre/probiotics, may contribute to improving and/or restoring gut health, thereby modulating both systemically as local inflammation and pain. Here, we sought to identify critical factors and potential strategies that could positively improve gut microbiota and intestinal health, and reduce the risk of musculoskeletal injuries and its recovery-time and pain. In conclusion, recent evidences indicate that improving gut health has indirect consequences on the musculoskeletal tissue homeostasis and recovery through the direct modulation of systemic inflammation, the immune response and the nociceptive pain.
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Affiliation(s)
- Jesús Álvarez-Herms
- Department of Genetics, Physical Anthropology and Animal Physiology, University of the Basque Country UPV/EHU, 48080 Leioa, Spain
- Phymo Lab, Physiology, and Molecular laboratory, Spain
| | - Adriana González
- Department of Genetics, Physical Anthropology and Animal Physiology, University of the Basque Country UPV/EHU, 48080 Leioa, Spain
| | - Francisco Corbi
- Institut Nacional d'Educació Física de Catalunya (INEFC), Centre de Lleida, Universitat de Lleida (UdL), Lleida, Spain
| | - Iñaki Odriozola
- Health Department of Basque Government, Donostia-San Sebastián, Spain
| | - Adrian Odriozola
- Department of Genetics, Physical Anthropology and Animal Physiology, University of the Basque Country UPV/EHU, 48080 Leioa, Spain
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15
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Martín R, Rios-Covian D, Huillet E, Auger S, Khazaal S, Bermúdez-Humarán LG, Sokol H, Chatel JM, Langella P. Faecalibacterium: a bacterial genus with promising human health applications. FEMS Microbiol Rev 2023; 47:fuad039. [PMID: 37451743 PMCID: PMC10410495 DOI: 10.1093/femsre/fuad039] [Citation(s) in RCA: 130] [Impact Index Per Article: 65.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2023] [Revised: 06/08/2023] [Accepted: 07/12/2023] [Indexed: 07/18/2023] Open
Abstract
In humans, many diseases are associated with alterations in gut microbiota, namely increases or decreases in the abundance of specific bacterial groups. One example is the genus Faecalibacterium. Numerous studies have underscored that low levels of Faecalibacterium are correlated with inflammatory conditions, with inflammatory bowel disease (IBD) in the forefront. Its representation is also diminished in the case of several diseases, including colorectal cancer (CRC), dermatitis, and depression. Additionally, the relative presence of this genus is considered to reflect, at least in part, intestinal health status because Faecalibacterium is frequently present at reduced levels in individuals with gastrointestinal diseases or disorders. In this review, we first thoroughly describe updates to the taxonomy of Faecalibacterium, which has transformed a single-species taxon to a multispecies taxon over the last decade. We then explore the links discovered between Faecalibacterium abundance and various diseases since the first IBD-focused studies were published. Next, we examine current available strategies for modulating Faecalibacterium levels in the gut. Finally, we summarize the mechanisms underlying the beneficial effects that have been attributed to this genus. Together, epidemiological and experimental data strongly support the use of Faecalibacterium as a next-generation probiotic (NGP) or live biotherapeutic product (LBP).
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Affiliation(s)
- Rebeca Martín
- Paris-Saclay University, INRAE, AgroParisTech, Micalis Institute, 78350, Jouy-en-Josas, France
| | - David Rios-Covian
- Paris-Saclay University, INRAE, AgroParisTech, Micalis Institute, 78350, Jouy-en-Josas, France
| | - Eugénie Huillet
- Paris-Saclay University, INRAE, AgroParisTech, Micalis Institute, 78350, Jouy-en-Josas, France
| | - Sandrine Auger
- Paris-Saclay University, INRAE, AgroParisTech, Micalis Institute, 78350, Jouy-en-Josas, France
| | - Sarah Khazaal
- Paris-Saclay University, INRAE, AgroParisTech, Micalis Institute, 78350, Jouy-en-Josas, France
| | - Luis G Bermúdez-Humarán
- Paris-Saclay University, INRAE, AgroParisTech, Micalis Institute, 78350, Jouy-en-Josas, France
| | - Harry Sokol
- Paris-Saclay University, INRAE, AgroParisTech, Micalis Institute, 78350, Jouy-en-Josas, France
- Sorbonne Université, INSERM, Centre de Recherche Saint-Antoine, CRSA, AP-HP, Saint Antoine Hospital, Gastroenterology Department, F-75012 Paris, France
- Paris Centre for Microbiome Medicine (PaCeMM) FHU, F-75012, Paris, France
| | - Jean-Marc Chatel
- Paris-Saclay University, INRAE, AgroParisTech, Micalis Institute, 78350, Jouy-en-Josas, France
| | - Philippe Langella
- Paris-Saclay University, INRAE, AgroParisTech, Micalis Institute, 78350, Jouy-en-Josas, France
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16
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Garofalo C, Cristiani CM, Ilari S, Passacatini LC, Malafoglia V, Viglietto G, Maiuolo J, Oppedisano F, Palma E, Tomino C, Raffaeli W, Mollace V, Muscoli C. Fibromyalgia and Irritable Bowel Syndrome Interaction: A Possible Role for Gut Microbiota and Gut-Brain Axis. Biomedicines 2023; 11:1701. [PMID: 37371796 DOI: 10.3390/biomedicines11061701] [Citation(s) in RCA: 19] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2023] [Revised: 06/06/2023] [Accepted: 06/09/2023] [Indexed: 06/29/2023] Open
Abstract
Fibromyalgia (FM) is a serious chronic pain syndrome, characterised by muscle and joint stiffness, insomnia, fatigue, mood disorders, cognitive dysfunction, anxiety, depression and intestinal irritability. Irritable Bowel Syndrome (IBS) shares many of these symptoms, and FM and IBS frequently co-exist, which suggests a common aetiology for the two diseases. The exact physiopathological mechanisms underlying both FM and IBS onset are unknown. Researchers have investigated many possible causes, including alterations in gut microbiota, which contain billions of microorganisms in the human digestive tract. The gut-brain axis has been proven to be the link between the gut microbiota and the central nervous system, which can then control the gut microbiota composition. In this review, we will discuss the similarities between FM and IBS. Particularly, we will focus our attention on symptomatology overlap between FM and IBS as well as the similarities in microbiota composition between FM and IBS patients. We will also briefly discuss the potential therapeutic approaches based on microbiota manipulations that are successfully used in IBS and could be employed also in FM patients to relieve pain, ameliorate the rehabilitation outcome, psychological distress and intestinal symptoms.
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Affiliation(s)
- Cinzia Garofalo
- Department of Experimental and Clinical Medicine, "Magna Græcia" University of Catanzaro, 88100 Catanzaro, Italy
| | - Costanza Maria Cristiani
- Department of Medical and Surgical Sciences, Neuroscience Research Center, "Magna Græcia" University of Catanzaro, 88100 Catanzaro, Italy
| | - Sara Ilari
- Physiology and Pharmacology of Pain, IRCCS San Raffaele Roma, 00166 Rome, Italy
| | - Lucia Carmela Passacatini
- Department of Health Science, Institute of Research for Food Safety & Health (IRC-FSH), "Magna Græcia" University of Catanzaro, 88100 Catanzaro, Italy
| | | | - Giuseppe Viglietto
- Department of Experimental and Clinical Medicine, "Magna Græcia" University of Catanzaro, 88100 Catanzaro, Italy
| | - Jessica Maiuolo
- Department of Health Science, Institute of Research for Food Safety & Health (IRC-FSH), "Magna Græcia" University of Catanzaro, 88100 Catanzaro, Italy
| | - Francesca Oppedisano
- Department of Health Science, Institute of Research for Food Safety & Health (IRC-FSH), "Magna Græcia" University of Catanzaro, 88100 Catanzaro, Italy
| | - Ernesto Palma
- Department of Health Science, Institute of Research for Food Safety & Health (IRC-FSH), "Magna Græcia" University of Catanzaro, 88100 Catanzaro, Italy
| | - Carlo Tomino
- Scientific Direction, IRCCS San Raffaele Roma, 00166 Rome, Italy
| | - William Raffaeli
- Institute for Research on Pain, ISAL Foundation, Torre Pedrera, 47922 Rimini, Italy
| | - Vincenzo Mollace
- Department of Health Science, Institute of Research for Food Safety & Health (IRC-FSH), "Magna Græcia" University of Catanzaro, 88100 Catanzaro, Italy
| | - Carolina Muscoli
- Department of Health Science, Institute of Research for Food Safety & Health (IRC-FSH), "Magna Græcia" University of Catanzaro, 88100 Catanzaro, Italy
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17
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Understanding the Connection between Gut Homeostasis and Psychological Stress. J Nutr 2023; 153:924-939. [PMID: 36806451 DOI: 10.1016/j.tjnut.2023.01.026] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2022] [Revised: 12/24/2022] [Accepted: 01/17/2023] [Indexed: 02/03/2023] Open
Abstract
Long-term exposure to adverse life events that provoke acute or chronic psychological stress (hereinafter "stress") can negatively affect physical health and even increase susceptibility to psychological illnesses, such as anxiety and depression. As a part of the hypothalamic-pituitary-adrenal axis, corticotropin-releasing factor (CRF) released from the hypothalamus is primarily responsible for the stress response. Typically, CRF disrupts the gastrointestinal system and leads to gut microbiota dysbiosis, thereby increasing risk of functional gastrointestinal diseases, such as irritable bowel syndrome. Furthermore, CRF increases oxidative damage to the colon and triggers immune responses involving mast cells, neutrophils, and monocytes. CRF even affects the differentiation of intestinal stem cells (ISCs), causing enterochromaffin cells to secrete excessive amounts of 5-hydroxytryptamine (5-HT). Therefore, stress is often accompanied by damage to the intestinal epithelial barrier function, followed by increased intestinal permeability and bacterial translocation. There are multi-network interactions between the gut microbiota and stress, and gut microbiota may relieve the effects of stress on the body. Dietary intake of probiotics can provide energy for ISCs through glycolysis, thereby alleviating the disruption to homeostasis caused by stress, and it significantly bolsters the intestinal barrier, alleviates intestinal inflammation, and maintains endocrine homeostasis. Gut microbiota also directly affect the synthesis of hormones and neurotransmitters, such as CRF, 5-HT, dopamine, and norepinephrine. Moreover, the Mediterranean diet enhances the stress resistance to some extent by regulating the intestinal flora. This article reviews recent research on how stress damages the gut and microbiota, how the gut microbiota can improve gut health by modulating injury due to stress, and how the diet relieves stress injury by interfering with intestinal microflora. This review gives insight into the potential role of the gut and its microbiota in relieving the effects of stress via the gut-brain axis.
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18
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Complete Genome Sequences of Eight Faecalibacterium sp. Strains Isolated from Healthy Human Stool. Microbiol Resour Announc 2023; 12:e0082422. [PMID: 36511692 PMCID: PMC9872689 DOI: 10.1128/mra.00824-22] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Eight Faecalibacterium sp. strains were isolated from feces of healthy human volunteers. Here, we describe their genome sequences. The genome sizes ranged from 2.78 Mbp to 3.23 Mbp, with an average GC content of 56.6% and encoding 2,795 protein-coding genes on average.
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Bai Z, Zhang N, Jin Y, Chen L, Mao Y, Sun L, Fang F, Liu Y, Han M, Li G. Comprehensive analysis of 84 Faecalibacterium prausnitzii strains uncovers their genetic diversity, functional characteristics, and potential risks. Front Cell Infect Microbiol 2023; 12:919701. [PMID: 36683686 PMCID: PMC9846645 DOI: 10.3389/fcimb.2022.919701] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2022] [Accepted: 12/09/2022] [Indexed: 01/06/2023] Open
Abstract
Faecalibacterium prausnitzii is a beneficial human gut microbe and a candidate for next-generation probiotics. With probiotics now being used in clinical treatments, concerns about their safety and side effects need to be considered. Therefore, it is essential to obtain a comprehensive understanding of the genetic diversity, functional characteristics, and potential risks of different F. prausnitzii strains. In this study, we collected the genetic information of 84 F . prausnitzii strains to conduct a pan-genome analysis with multiple perspectives. Based on single-copy genes and the sequences of 16S rRNA and the compositions of the pan-genome, different phylogenetic analyses of F. prausnitzii strains were performed, which showed the genetic diversity among them. Among the proteins of the pan-genome, we found that the accessory clusters made a greater contribution to the primary genetic functions of F. prausnitzii strains than the core and specific clusters. The functional annotations of F. prausnitzii showed that only a very small number of proteins were related to human diseases and there were no secondary metabolic gene clusters encoding harmful products. At the same time, complete fatty acid metabolism was detected in F. prausnitzii. In addition, we detected harmful elements, including antibiotic resistance genes, virulence factors, and pathogenic genes, and proposed the probiotic potential risk index (PPRI) and probiotic potential risk score (PPRS) to classify these 84 strains into low-, medium-, and high-risk groups. Finally, 15 strains were identified as low-risk strains and prioritized for clinical application. Undoubtedly, our results provide a comprehensive understanding and insight into F. prausnitzii, and PPRI and PPRS can be applied to evaluate the potential risks of probiotics in general and to guide the application of probiotics in clinical application.
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Affiliation(s)
- Zipeng Bai
- School of Life Sciences, Anhui Medical University, Hefei, Anhui, China
| | - Na Zhang
- School of Life Sciences, Anhui Medical University, Hefei, Anhui, China
| | - Yu Jin
- Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Long Chen
- School of Life Sciences, Anhui Medical University, Hefei, Anhui, China
| | - Yujie Mao
- School of Life Sciences, Anhui Medical University, Hefei, Anhui, China
| | - Lingna Sun
- School of Life Sciences, Anhui Medical University, Hefei, Anhui, China
| | - Feifei Fang
- Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Ying Liu
- Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Maozhen Han
- School of Life Sciences, Anhui Medical University, Hefei, Anhui, China
| | - Gangping Li
- Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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20
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Mázala-de-Oliveira T, Jannini de Sá YAP, Carvalho VDF. Impact of gut-peripheral nervous system axis on the development of diabetic neuropathy. Mem Inst Oswaldo Cruz 2023; 118:e220197. [PMID: 36946851 PMCID: PMC10027071 DOI: 10.1590/0074-02760220197] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2022] [Accepted: 02/14/2023] [Indexed: 03/22/2023] Open
Abstract
Diabetes is a chronic metabolic disease caused by a reduction in the production and/or action of insulin, with consequent development of hyperglycemia. Diabetic patients, especially those who develop neuropathy, presented dysbiosis, with an increase in the proportion of pathogenic bacteria and a decrease in the butyrate-producing bacteria. Due to this dysbiosis, diabetic patients presented a weakness of the intestinal permeability barrier and high bacterial product translocation to the bloodstream, in parallel to a high circulating levels of pro-inflammatory cytokines such as TNF-α. In this context, we propose here that dysbiosis-induced increased systemic levels of bacterial products, like lipopolysaccharide (LPS), leads to an increase in the production of pro-inflammatory cytokines, including TNF-α, by Schwann cells and spinal cord of diabetics, being crucial for the development of neuropathy.
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Affiliation(s)
| | | | - Vinicius de Frias Carvalho
- Fundação Oswaldo Cruz-Fiocruz, Instituto Oswaldo Cruz, Rio de Janeiro, RJ, Brasil
- Instituto Nacional de Ciência e Tecnologia em Neuroimunomodulação, Rio de Janeiro, RJ, Brasil
- + Corresponding author:
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21
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Abstract
Proteases are an evolutionarily conserved family of enzymes that degrade peptide bonds and have been implicated in several common gastrointestinal (GI) diseases. Although luminal proteolytic activity is important for maintenance of homeostasis and health, the current review describes recent advances in our understanding of how overactivity of luminal proteases contributes to the pathophysiology of celiac disease, irritable bowel syndrome, inflammatory bowel disease and GI infections. Luminal proteases, many of which are produced by the microbiota, can modulate the immunogenicity of dietary antigens, reduce mucosal barrier function and activate pro-inflammatory and pro-nociceptive host signaling. Increased proteolytic activity has been ascribed to both increases in protease production and decreases in inhibitors of luminal proteases. With the identification of strains of bacteria that are important sources of proteases and their inhibitors, the stage is set to develop drug or microbial therapies to restore protease balance and alleviate disease.
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Affiliation(s)
- Alberto Caminero
- Department of Medicine, Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, Ontario, Canada
| | - Mabel Guzman
- Gastrointestinal Diseases Research Unit, Kingston General Hospital, Queen’s University, Kingston, Ontario, Canada
| | - Josie Libertucci
- Department of Medicine, Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, Ontario, Canada
| | - Alan E. Lomax
- Gastrointestinal Diseases Research Unit, Kingston General Hospital, Queen’s University, Kingston, Ontario, Canada,CONTACT Alan E. Lomax Gastrointestinal Diseases Research Unit, Kingston General Hospital, Kingston, ON, K7L 2V7, Canada
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22
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Pujo J, De Palma G, Lu J, Galipeau HJ, Surette MG, Collins SM, Bercik P. Gut microbiota modulates visceral sensitivity through calcitonin gene-related peptide (CGRP) production. Gut Microbes 2023; 15:2188874. [PMID: 36939195 PMCID: PMC10038053 DOI: 10.1080/19490976.2023.2188874] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 03/21/2023] Open
Abstract
Abdominal pain is common in patients with gastrointestinal disorders, but its pathophysiology is unclear, in part due to poor understanding of basic mechanisms underlying visceral sensitivity. Accumulating evidence suggests that gut microbiota is an important determinant of visceral sensitivity. Clinical and basic research studies also show that sex plays a role in pain perception, although the precise pathways are not elucidated. We investigated pain responses in germ-free and conventionally raised mice of both sexes, and assessed visceral sensitivity to colorectal distension, neuronal excitability of dorsal root ganglia (DRG) neurons and the production of substance P and calcitonin gene-related peptide (CGRP) in response to capsaicin or a mixture of G-protein coupled receptor (GPCR) agonists. Germ-free mice displayed greater in vivo responses to colonic distention than conventional mice, with no differences between males and females. Pretreatment with intracolonic capsaicin or GPCR agonists increased responses in conventional, but not in germ-free mice. In DRG neurons, gut microbiota and sex had no effect on neuronal activation by capsaicin or GPCR agonists. While stimulated production of substance P by DRG neurons was similar in germ-free and conventional mice, with no additional effect of sex, the CGRP production was higher in germ-free mice, mainly in females. Absence of gut microbiota increases visceral sensitivity to colorectal distention in both male and female mice. This is, at least in part, due to increased production of CGRP by DRG neurons, which is mainly evident in female mice. However, central mechanisms are also likely involved in this process.
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Affiliation(s)
- Julien Pujo
- Farncombe Family Digestive Health Research Institute, Department of Medicine, McMaster University, Hamilton, Canada
| | - Giada De Palma
- Farncombe Family Digestive Health Research Institute, Department of Medicine, McMaster University, Hamilton, Canada
| | - Jun Lu
- Farncombe Family Digestive Health Research Institute, Department of Medicine, McMaster University, Hamilton, Canada
| | - Heather J Galipeau
- Farncombe Family Digestive Health Research Institute, Department of Medicine, McMaster University, Hamilton, Canada
| | - Michael G Surette
- Farncombe Family Digestive Health Research Institute, Department of Medicine, McMaster University, Hamilton, Canada
| | - Stephen M Collins
- Farncombe Family Digestive Health Research Institute, Department of Medicine, McMaster University, Hamilton, Canada
| | - Premysl Bercik
- Farncombe Family Digestive Health Research Institute, Department of Medicine, McMaster University, Hamilton, Canada
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23
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Tonelli Enrico V, Vo N, Methe B, Morris A, Sowa G. An unexpected connection: A narrative review of the associations between Gut Microbiome and Musculoskeletal Pain. EUROPEAN SPINE JOURNAL : OFFICIAL PUBLICATION OF THE EUROPEAN SPINE SOCIETY, THE EUROPEAN SPINAL DEFORMITY SOCIETY, AND THE EUROPEAN SECTION OF THE CERVICAL SPINE RESEARCH SOCIETY 2022; 31:3603-3615. [PMID: 36308543 PMCID: PMC9617047 DOI: 10.1007/s00586-022-07429-y] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 10/12/2022] [Revised: 10/12/2022] [Accepted: 10/14/2022] [Indexed: 11/06/2022]
Abstract
PURPOSE Multiple diverse factors contribute to musculoskeletal pain, a major cause of physical dysfunction and health-related costs worldwide. Rapidly growing evidence demonstrates that the gut microbiome has overarching influences on human health and the body's homeostasis and resilience to internal and external perturbations. This broad role of the gut microbiome is potentially relevant and connected to musculoskeletal pain, though the literature on the topic is limited. Thus, the literature on the topic of musculoskeletal pain and gut microbiome was explored. METHODS This narrative review explores the vast array of reported metabolites associated with inflammation and immune-metabolic response, which are known contributors to musculoskeletal pain. Moreover, it covers known modifiable (e.g., diet, lifestyle choices, exposure to prescription drugs, pollutants, and chemicals) and non-modifiable factors (e.g., gut architecture, genetics, age, birth history, and early feeding patterns) that are known to contribute to changes to the gut microbiome. Particular attention is devoted to modifiable factors, as the ultimate goal of researching this topic is to implement gut microbiome health interventions into clinical practice. RESULTS Overall, numerous associations exist in the literature that could converge on the gut microbiome's pivotal role in musculoskeletal health. Particularly, a variety of metabolites that are either directly produced or indirectly modulated by the gut microbiome have been highlighted. CONCLUSION The review highlights noticeable connections between the gut and musculoskeletal health, thus warranting future research to focus on the gut microbiome's role in musculoskeletal conditions.
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Affiliation(s)
- Valerio Tonelli Enrico
- Ferguson Laboratory for Orthopaedic and Spine Research, Department of Orthopaedic Surgery, University of Pittsburgh Medical Center, University of Pittsburgh, 200 Lothrop Street, Room E1612, BST, Pittsburgh, PA, 15261, USA.
- Department of Physical Therapy, University of Pittsburgh, 100 Technology Dr, Pittsburgh, PA, 15219, USA.
| | - Nam Vo
- Ferguson Laboratory for Orthopaedic and Spine Research, Department of Orthopaedic Surgery, University of Pittsburgh Medical Center, University of Pittsburgh, 200 Lothrop Street, Room E1612, BST, Pittsburgh, PA, 15261, USA
| | - Barbara Methe
- Department of Medicine, Division of Pulmonary, Allergy and Critical Care Medicine, School of Medicine, University of Pittsburgh, 1218 Scaife Hall 3550 Terrace Street, Pittsburgh, PA, 15261, USA
| | - Alison Morris
- Department of Medicine, Division of Pulmonary, Allergy and Critical Care Medicine, School of Medicine, University of Pittsburgh, 1218 Scaife Hall 3550 Terrace Street, Pittsburgh, PA, 15261, USA
| | - Gwendolyn Sowa
- Ferguson Laboratory for Orthopaedic and Spine Research, Department of Orthopaedic Surgery, University of Pittsburgh Medical Center, University of Pittsburgh, 200 Lothrop Street, Room E1612, BST, Pittsburgh, PA, 15261, USA
- Department of Physical Medicine and Rehabilitation, School of Medicine, University of Pittsburgh, Kaufmann Medical Building, Suite 910, 3471 Fifth Avenue, Pittsburgh, PA, 15213, USA
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24
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Torres-Maravilla E, Holowacz S, Delannoy J, Lenoir L, Jacouton E, Gervason S, Meynier M, Boucard AS, Carvalho FA, Barbut F, Bermúdez-Humarán LG, Langella P, Waligora-Dupriet AJ. Serpin-positive Bifidobacterium breve CNCM I-5644 improves intestinal permeability in two models of irritable bowel syndrome. Sci Rep 2022; 12:19776. [PMID: 36396717 PMCID: PMC9672316 DOI: 10.1038/s41598-022-21746-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2022] [Accepted: 09/30/2022] [Indexed: 11/19/2022] Open
Abstract
Probiotic supplementation can help to mitigate the pathogenesis of irritable bowel syndrome (IBS) by reinforcing the intestinal barrier, and reducing both inflammation and proteolytic activity. Here, a combination of in vitro tests was performed on 33 Bifidobacterium strains as probiotic candidates for IBS. In addition to the classical tests performed, the detection of the serine protease inhibitor (serpin) enzyme capable of decreasing the high proteolytic activity found in IBS patients was included. Three serpin-positive strains were selected: Bifidobacterium breve CNCM I-5644, Bifidobacterium longum subsp. infantis CNCM I-5645 and B. longum CNCM I-5646 for their immunomodulation properties and protection of intestinal epithelial integrity in vitro. Furthermore, we found that B. breve CNCM I-5644 strain prevented intestinal hyperpermeability by upregulating Cingulin and Tight Junction Protein 1 mRNA levels and reducing pro-inflammatory markers. The ability of CNCM I-5644 strain to restore intestinal hyperpermeability (FITC-dextran) was shown in the murine model of low-grade inflammation induced by dinitrobenzene sulfonic acid (DNBS). This effect of this strain was corroborated in a second model of IBS, the neonatal maternal separation model in mice. Altogether, these data suggest that serpin-positive B. breve CNCM I-5644 may partially prevent disorders associated with increased barrier permeability such as IBS.
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Affiliation(s)
- Edgar Torres-Maravilla
- grid.460789.40000 0004 4910 6535INRAE, AgroParisTech, Micalis Institute, Université Paris-Saclay, 78350 Jouy-en-Josas, France ,grid.7429.80000000121866389Université Paris Cité, INSERM, 3PHM, F-75006 Paris, France
| | - Sophie Holowacz
- PiLeJe Laboratoire, 37 Quai de Grenelle, 75015 Paris Cedex 15, France
| | - Johanne Delannoy
- grid.7429.80000000121866389Université Paris Cité, INSERM, 3PHM, F-75006 Paris, France
| | - Loïc Lenoir
- PiLeJe Laboratoire, 37 Quai de Grenelle, 75015 Paris Cedex 15, France
| | - Elsa Jacouton
- PiLeJe Laboratoire, 37 Quai de Grenelle, 75015 Paris Cedex 15, France
| | - Sandie Gervason
- grid.494717.80000000115480420INSERM UMR 1107 NeuroDol, University of Clermont Auvergne, 63001 Clermont-Ferrand, France
| | - Maëva Meynier
- grid.494717.80000000115480420INSERM UMR 1107 NeuroDol, University of Clermont Auvergne, 63001 Clermont-Ferrand, France
| | - Anne-Sophie Boucard
- grid.460789.40000 0004 4910 6535INRAE, AgroParisTech, Micalis Institute, Université Paris-Saclay, 78350 Jouy-en-Josas, France
| | - Frédéric A. Carvalho
- grid.494717.80000000115480420INSERM UMR 1107 NeuroDol, University of Clermont Auvergne, 63001 Clermont-Ferrand, France
| | - Frédéric Barbut
- grid.7429.80000000121866389Université Paris Cité, INSERM, 3PHM, F-75006 Paris, France ,grid.50550.350000 0001 2175 4109National Reference Laboratory for C. Difficile, Hôpital Saint-Antoine, Assistance Publique-Hôpitaux de Paris, 75012 Paris, France
| | - Luis G. Bermúdez-Humarán
- grid.460789.40000 0004 4910 6535INRAE, AgroParisTech, Micalis Institute, Université Paris-Saclay, 78350 Jouy-en-Josas, France
| | - Philippe Langella
- grid.460789.40000 0004 4910 6535INRAE, AgroParisTech, Micalis Institute, Université Paris-Saclay, 78350 Jouy-en-Josas, France
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25
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Xu QY, Zhang HL, Du H, Li YC, Ji FH, Li R, Xu GY. Identification of a Glutamatergic Claustrum-Anterior Cingulate Cortex Circuit for Visceral Pain Processing. J Neurosci 2022; 42:8154-8168. [PMID: 36100399 PMCID: PMC9637003 DOI: 10.1523/jneurosci.0779-22.2022] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2022] [Revised: 08/30/2022] [Accepted: 09/04/2022] [Indexed: 11/21/2022] Open
Abstract
Chronic visceral pain is a major challenge for both patients and health providers. Although the central sensitization of the brain is thought to play an important role in the development of visceral pain, the detailed neural circuits remain largely unknown. Using a well-established chronic visceral hypersensitivity model induced by neonatal maternal deprivation (NMD) in male mice, we identified a distinct pathway whereby the claustrum (CL) glutamatergic neuron projecting to the anterior cingulate cortex (ACC) is critical for visceral pain but not for CFA-evoked inflammatory pain. By a combination of in vivo circuit-dissecting extracellular electrophysiological approaches and visceral pain related electromyographic (EMG) recordings, we demonstrated that optogenetic inhibition of CL glutamatergic activity suppressed the ACC neural activity and visceral hypersensitivity of NMD mice whereas selective activation of CL glutamatergic activity enhanced the ACC neural activity and evoked visceral pain of control mice. Further, optogenetic studies demonstrate a causal link between such neuronal activity and visceral pain behaviors. Chemogenetic activation or inhibition of ACC neural activities reversed the effects of optogenetic manipulation of CL neural activities on visceral pain responses. Importantly, molecular detection showed that NMD significantly enhances the expression of NMDA receptors and activated CaMKIIα in the ACC postsynaptic density (PSD) region. Together, our data establish a functional role for CL→ACC glutamatergic neurons in gating visceral pain, thus providing a potential treatment strategy for visceral pain.SIGNIFICANCE STATEMENT Studies have shown that sensitization of anterior cingulate cortex (ACC) plays an important role in chronic pain. However, it is as yet unknown whether there is a specific brain region and a distinct neural circuit that helps the ACC to distinguish visceral and somatic pain. The present study demonstrates that claustrum (CL) glutamatergic neurons maybe responding to colorectal distention (CRD) rather than somatic stimulation and that a CL glutamatergic projection to ACC glutamatergic neuron regulates visceral pain in mice. Furthermore, excessive NMDA receptors and overactive CaMKIIα in the ACC postsynaptic density (PSD) region were observed in mice with chronic visceral pain. Together, these findings reveal a novel neural circuity underlying the central sensitization of chronic visceral pain.
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Affiliation(s)
- Qi-Ya Xu
- Jiangsu Key Laboratory of Neuropsychiatric Diseases, Institute of Neuroscience, Soochow University, Suzhou 215123, People's Republic of China
| | - Hai-Long Zhang
- Jiangsu Key Laboratory of Neuropsychiatric Diseases, Institute of Neuroscience, Soochow University, Suzhou 215123, People's Republic of China
| | - Han Du
- Jiangsu Key Laboratory of Neuropsychiatric Diseases, Institute of Neuroscience, Soochow University, Suzhou 215123, People's Republic of China
| | - Yong-Chang Li
- Jiangsu Key Laboratory of Neuropsychiatric Diseases, Institute of Neuroscience, Soochow University, Suzhou 215123, People's Republic of China
| | - Fu-Hai Ji
- Department of Anesthesiology, The First Affiliated Hospital of Soochow University, Suzhou 215006, People's Republic of China
| | - Rui Li
- Department of Gastroenterology, The First Affiliated Hospital of Soochow University, Suzhou 215006, People's Republic of China
| | - Guang-Yin Xu
- Jiangsu Key Laboratory of Neuropsychiatric Diseases, Institute of Neuroscience, Soochow University, Suzhou 215123, People's Republic of China
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Mallaret G, Lashermes A, Meleine M, Boudieu L, Barbier J, Aissouni Y, Gelot A, Chassaing B, Gewirtz AT, Ardid D, Carvalho FA. Involvement of toll-like receptor 5 in mouse model of colonic hypersensitivity induced by neonatal maternal separation. World J Gastroenterol 2022; 28:3903-3916. [PMID: 36157543 PMCID: PMC9367235 DOI: 10.3748/wjg.v28.i29.3903] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/15/2022] [Revised: 06/09/2022] [Accepted: 07/06/2022] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Chronic abdominal pain is the most common cause for gastroenterology consultation and is frequently associated with functional gastrointestinal disorders including irritable bowel syndrome and inflammatory bowel disease. These disorders present similar brain/gut/microbiota trialogue alterations, associated with abnormal intestinal permeability, intestinal dysbiosis and colonic hypersensitivity (CHS). Intestinal dysbiosis can alter colon homeostasis leading to abnormal activation of the innate immunity that promotes CHS, perhaps involving the toll-like receptors (TLRs), which play a central role in innate immunity.
AIM To understand the mechanisms between early life event paradigm on intestinal permeability, fecal microbiota composition and CHS development in mice with TLRs expression in colonocytes.
METHODS Maternal separation model (NMS) CHS model, which mimics deleterious events in childhood that can induce a wide range of chronic disorders during adulthood were used. Colonic sensitivity of NMS mice was evaluated by colorectal distension (CRD) coupled with intracolonic pressure variation (IPV) measurement. Fecal microbiota composition was analyzed by 16S rRNA sequencing from weaning to CRD periods. TLR mRNA expression was evaluated in colonocytes. Additionally, the effect of acute intrarectal instillation of the TLR5 agonist flagellin (FliC) on CHS in adult naive wildtype mice was analyzed.
RESULTS Around 50% of NMS mice exhibited increased intestinal permeability and CHS associated with intestinal dysbiosis, characterized by a significant decrease of species richness, an alteration of the core fecal microbiota and a specific increased relative abundance of flagellated bacteria. Only TLR5 mRNA expression was increased in colonocytes of NMS mice with CHS. Acute intrarectal instillation of FliC induced transient increase of IPV, reflecting transient CHS appearance.
CONCLUSION Altogether, these data suggest a pathophysiological continuum between intestinal dysbiosis and CHS, with a role for TLR5.
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Affiliation(s)
- Geoffroy Mallaret
- Department of Pharmacology, UMR 1107 NeuroDol, University of Clermont Auvergne, Clermont-Ferrand 63000, France
| | - Amandine Lashermes
- Department of Microbiology, Université Paris-Saclay, National Research Institute for Agriculture, Food and the Environment, AgroParisTech, Micalis Institute, Jouy-en-Josas 78350, France
| | - Mathieu Meleine
- Department of Pharmacology, UMR 1107 NeuroDol, University of Clermont Auvergne, Clermont-Ferrand 63000, France
| | - Ludivine Boudieu
- Department of Pharmacology, UMR 1107 NeuroDol, University of Clermont Auvergne, Clermont-Ferrand 63000, France
| | - Julie Barbier
- Department of Pharmacology, UMR 1107 NeuroDol, University of Clermont Auvergne, Clermont-Ferrand 63000, France
| | - Youssef Aissouni
- Department of Pharmacology, UMR 1107 NeuroDol, University of Clermont Auvergne, Clermont-Ferrand 63000, France
| | - Agathe Gelot
- Department of Pharmacology, UMR 1107 NeuroDol, University of Clermont Auvergne, Clermont-Ferrand 63000, France
| | - Benoit Chassaing
- Team “Mucosal Microbiota in Chronic Inflammatory Diseases”, INSERM U1016, CNRS UMR 8104, Université Paris Cité, Paris 75014, France
| | - Andrew T Gewirtz
- Center for Inflammation, Institute for Biomedical Sciences, Georgia State University, Atlanta, GA30033, United States
| | - Denis Ardid
- Department of Pharmacology, UMR 1107 NeuroDol, University of Clermont Auvergne, Clermont-Ferrand 63000, France
| | - Frederic Antonio Carvalho
- Department of Pharmacology, INSERM 1107 NeuroDOL/University of Clermont Auvergne, Clermont-Ferrand 63000, France
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27
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Li Y, Cao W, Gao NL, Zhao XM, Chen WH. Consistent Alterations of Human Fecal Microbes After Transplantation into Germ-free Mice. GENOMICS, PROTEOMICS & BIOINFORMATICS 2022; 20:382-393. [PMID: 34118462 PMCID: PMC9684084 DOI: 10.1016/j.gpb.2020.06.024] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/03/2019] [Revised: 04/21/2020] [Accepted: 09/08/2020] [Indexed: 01/05/2023]
Abstract
Fecal microbiota transplantation (FMT) of human fecal samples into germ-free (GF) mice is useful for establishing causal relationships between the gut microbiota and human phenotypes. However, due to the intrinsic differences between human and mouse intestines and the different diets of the two organisms, it may not be possible to replicate human phenotypes in mice through FMT; similarly, treatments that are effective in mouse models may not be effective in humans. In this study, we aimed to identify human gut microbes that undergo significant and consistent changes (i.e., in relative abundances) after transplantation into GF mice in multiple experimental settings. We collected 16S rDNA-seq data from four published studies and analyzed the gut microbiota profiles from 1713 human-mouse pairs. Strikingly, on average, we found that only 47% of the human gut microbes could be re-established in mice at the species level, among which more than 1/3 underwent significant changes (referred to as "variable taxa"). Most of the human gut microbes that underwent significant changes were consistent across multiple human-mouse pairs and experimental settings. Consequently, about 1/3 of human samples changed their enterotypes, i.e., significant changes in their leading species after FMT. Mice fed with a controlled diet showed a lower enterotype change rate (23.5%) than those fed with a noncontrolled diet (49.0%), suggesting a possible solution for rescue. Most of the variable taxa have been reported to be implicated in human diseases, with some recognized as the causative species. Our results highlight the challenges of using a mouse model to replicate human gut microbiota-associated phenotypes, provide useful information for researchers using mice in gut microbiota studies, and call for additional validations after FMT. An online database named FMT-DB is publicly available at http://fmt2mice.humangut.info/#/.
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Affiliation(s)
- Yanze Li
- MOE Key Laboratory of Molecular Biophysics, Hubei Key Laboratory of Bioinformatics and Molecular-imaging, Department of Bioinformatics and Systems Biology, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan 430074, China
| | - Wenming Cao
- MOE Key Laboratory of Molecular Biophysics, Hubei Key Laboratory of Bioinformatics and Molecular-imaging, Department of Bioinformatics and Systems Biology, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan 430074, China
| | - Na L Gao
- MOE Key Laboratory of Molecular Biophysics, Hubei Key Laboratory of Bioinformatics and Molecular-imaging, Department of Bioinformatics and Systems Biology, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan 430074, China
| | - Xing-Ming Zhao
- Institute of Science and Technology for Brain-Inspired Intelligence (ISTBI), Fudan University, Shanghai 200433, China,Corresponding authors.
| | - Wei-Hua Chen
- MOE Key Laboratory of Molecular Biophysics, Hubei Key Laboratory of Bioinformatics and Molecular-imaging, Department of Bioinformatics and Systems Biology, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan 430074, China,College of Life Science, Henan Normal University, Xinxiang 453007, China,Corresponding authors.
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28
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Hu W, Gao W, Liu Z, Fang Z, Zhao J, Zhang H, Lu W, Chen W. Biodiversity and Physiological Characteristics of Novel Faecalibacterium prausnitzii Strains Isolated from Human Feces. Microorganisms 2022; 10:microorganisms10020297. [PMID: 35208752 PMCID: PMC8876097 DOI: 10.3390/microorganisms10020297] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2021] [Revised: 01/15/2022] [Accepted: 01/16/2022] [Indexed: 01/27/2023] Open
Abstract
Faecalibacterium prausnitzii is prevalent in the human gut and is a potential candidate for next-generation probiotics (NGPs) or biotherapeutics. However, the biodiversity and physiological characteristics of Faecalibacterium prausnitzii remain unclear. This study isolated 26 novel F. prausnitzii strains from human feces using a combination of negative screening and prime-specific PCR amplification (NSPA). Based on a 16S rRNA gene analysis, F. prausnitzii strains can be classified into two main phylogroups (phylogroups I and II), which were further clustered into five subgroups (I-A, II-B, II-C, II-D, and II-E). The ultrastructure, colony morphology, growth performance, and short-chain fatty acids (SCFAs)-producing ability were found to be variable among these F. prausnitzii isolates. The optimal pH for the isolates growth ranged between 6.0 and 7.0, while most isolates were inhibited by 0.1% of bile salts. Antimicrobial resistance profiles showed that all F. prausnitzii isolates were susceptible to vancomycin, whereas >80% were kanamycin and gentamicin resistant. Additionally, all strains can utilize maltose, cellulose, and fructose but not xylose, sorbose, and 2′-FL. Overall, our work provides new insights into the biodiversity and physiological characteristics of F. prausnitzii, as well as the choices of strains suitable for NGPs.
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Affiliation(s)
- Wenbing Hu
- State Key Laboratory of Food Science and Technology, Jiangnan University, Wuxi 214122, China; (W.H.); (W.G.); (Z.L.); (Z.F.); (J.Z.); (H.Z.); (W.C.)
- School of Food Science and Technology, Jiangnan University, Wuxi 214122, China
| | - Wenyu Gao
- State Key Laboratory of Food Science and Technology, Jiangnan University, Wuxi 214122, China; (W.H.); (W.G.); (Z.L.); (Z.F.); (J.Z.); (H.Z.); (W.C.)
- School of Food Science and Technology, Jiangnan University, Wuxi 214122, China
| | - Zongmin Liu
- State Key Laboratory of Food Science and Technology, Jiangnan University, Wuxi 214122, China; (W.H.); (W.G.); (Z.L.); (Z.F.); (J.Z.); (H.Z.); (W.C.)
- School of Food Science and Technology, Jiangnan University, Wuxi 214122, China
| | - Zhifeng Fang
- State Key Laboratory of Food Science and Technology, Jiangnan University, Wuxi 214122, China; (W.H.); (W.G.); (Z.L.); (Z.F.); (J.Z.); (H.Z.); (W.C.)
- School of Food Science and Technology, Jiangnan University, Wuxi 214122, China
| | - Jianxin Zhao
- State Key Laboratory of Food Science and Technology, Jiangnan University, Wuxi 214122, China; (W.H.); (W.G.); (Z.L.); (Z.F.); (J.Z.); (H.Z.); (W.C.)
- School of Food Science and Technology, Jiangnan University, Wuxi 214122, China
- National Engineering Research Center for Functional Food, Jiangnan University, Wuxi 214122, China
| | - Hao Zhang
- State Key Laboratory of Food Science and Technology, Jiangnan University, Wuxi 214122, China; (W.H.); (W.G.); (Z.L.); (Z.F.); (J.Z.); (H.Z.); (W.C.)
- School of Food Science and Technology, Jiangnan University, Wuxi 214122, China
- National Engineering Research Center for Functional Food, Jiangnan University, Wuxi 214122, China
- (Yangzhou) Institute of Food Biotechnology, Jiangnan University, Yangzhou 225004, China
- Wuxi Translational Medicine Research Center and Jiangsu Translational Medicine Research Institute Wuxi Branch, Wuxi 214122, China
| | - Wenwei Lu
- State Key Laboratory of Food Science and Technology, Jiangnan University, Wuxi 214122, China; (W.H.); (W.G.); (Z.L.); (Z.F.); (J.Z.); (H.Z.); (W.C.)
- School of Food Science and Technology, Jiangnan University, Wuxi 214122, China
- National Engineering Research Center for Functional Food, Jiangnan University, Wuxi 214122, China
- Correspondence: ; Tel./Fax: +86-510-85197302
| | - Wei Chen
- State Key Laboratory of Food Science and Technology, Jiangnan University, Wuxi 214122, China; (W.H.); (W.G.); (Z.L.); (Z.F.); (J.Z.); (H.Z.); (W.C.)
- School of Food Science and Technology, Jiangnan University, Wuxi 214122, China
- National Engineering Research Center for Functional Food, Jiangnan University, Wuxi 214122, China
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29
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Meynier M, Baudu E, Rolhion N, Defaye M, Straube M, Daugey V, Modoux M, Wawrzyniak I, Delbac F, Villéger R, Méleine M, Borras Nogues E, Godfraind C, Barnich N, Ardid D, Poirier P, Sokol H, Chatel JM, Langella P, Livrelli V, Bonnet M, Carvalho FA. AhR/IL-22 pathway as new target for the treatment of post-infectious irritable bowel syndrome symptoms. Gut Microbes 2022; 14:2022997. [PMID: 35090380 PMCID: PMC8803069 DOI: 10.1080/19490976.2021.2022997] [Citation(s) in RCA: 32] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/20/2021] [Revised: 11/12/2021] [Accepted: 12/10/2021] [Indexed: 02/04/2023] Open
Abstract
Alterations in brain/gut/microbiota axis are linked to Irritable Bowel Syndrome (IBS) physiopathology. Upon gastrointestinal infection, chronic abdominal pain and anxio-depressive comorbidities may persist despite pathogen clearance leading to Post-Infectious IBS (PI-IBS). This study assesses the influence of tryptophan metabolism, and particularly the microbiota-induced AhR expression, on intestinal homeostasis disturbance following gastroenteritis resolution, and evaluates the efficacy of IL-22 cytokine vectorization on PI-IBS symptoms. The Citrobacter rodentium infection model in C57BL6/J mice was used to mimic Enterobacteria gastroenteritis. Intestinal homeostasis was evaluated as low-grade inflammation, permeability, mucosa-associated microbiota composition, and colonic sensitivity. Cognitive performances and emotional state of animals were assessed using several tests. Tryptophan metabolism was analyzed by targeted metabolomics. AhR activity was evaluated using a luciferase reporter assay method. One Lactococcus lactis strain carrying an eukaryotic expression plasmid for murine IL-22 (L. lactisIL-22) was used to induce IL-22 production in mouse colonic mucosa. C. rodentium-infected mice exhibited persistent colonic hypersensitivity and cognitive impairments and anxiety-like behaviors after pathogen clearance. These post-infectious disorders were associated with low-grade inflammation, increased intestinal permeability, decrease of Lactobacillaceae abundance associated with the colonic layer, and increase of short-chain fatty acids (SCFAs). During post-infection period, the indole pathway and AhR activity were decreased due to a reduction of tryptophol production. Treatment with L. lactisIL-22 restored gut permeability and normalized colonic sensitivity, restored cognitive performances and decreased anxiety-like behaviors. Data from the video-tracking system suggested an upgrade of welfare for mice receiving the L.lactisIL-22 strain. Our findings revealed that AhR/IL-22 signaling pathway is altered in a preclinical PI-IBS model. IL-22 delivering alleviate PI-IBS symptoms as colonic hypersensitivity, cognitive impairments, and anxiety-like behaviors by acting on intestinal mucosa integrity. Thus, therapeutic strategies targeting this pathway could be developed to treat IBS patients suffering from chronic abdominal pain and associated well-being disorders.
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Affiliation(s)
- Maëva Meynier
- M2iSH, UMR 1071 INSERM, University of Clermont Auvergne, INRAE USC 2018, Clermont-Ferrand63001, France
- NeuroDol, UMR 1107 INSERM, University of Clermont Auvergne, Clermont-Ferrand63001, France
| | - Elodie Baudu
- M2iSH, UMR 1071 INSERM, University of Clermont Auvergne, INRAE USC 2018, Clermont-Ferrand63001, France
- NeuroDol, UMR 1107 INSERM, University of Clermont Auvergne, Clermont-Ferrand63001, France
| | - Nathalie Rolhion
- Sorbonne University, INSERM, Centre de Recherche Saint-Antoine, CRSA, AP-HP, Saint Antoine Hospital, Gastroenterology Department, F-75012Paris, France
- Paris Centre for Microbiome Medicine FHU, Paris, France
| | - Manon Defaye
- NeuroDol, UMR 1107 INSERM, University of Clermont Auvergne, Clermont-Ferrand63001, France
- Department of Physiology and Pharmacology, Inflammation Research Network, Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, AB, T2N 4N1, Canada
- LMGE, CNRS 6023, University of Clermont Auvergne, Clermont-Ferrand63001, France
| | - Marjolène Straube
- Sorbonne University, INSERM, Centre de Recherche Saint-Antoine, CRSA, AP-HP, Saint Antoine Hospital, Gastroenterology Department, F-75012Paris, France
| | - Valentine Daugey
- NeuroDol, UMR 1107 INSERM, University of Clermont Auvergne, Clermont-Ferrand63001, France
| | - Morgane Modoux
- Sorbonne University, INSERM, Centre de Recherche Saint-Antoine, CRSA, AP-HP, Saint Antoine Hospital, Gastroenterology Department, F-75012Paris, France
| | - Ivan Wawrzyniak
- LMGE, CNRS 6023, University of Clermont Auvergne, Clermont-Ferrand63001, France
| | - Frédéric Delbac
- LMGE, CNRS 6023, University of Clermont Auvergne, Clermont-Ferrand63001, France
| | - Romain Villéger
- M2iSH, UMR 1071 INSERM, University of Clermont Auvergne, INRAE USC 2018, Clermont-Ferrand63001, France
| | - Mathieu Méleine
- NeuroDol, UMR 1107 INSERM, University of Clermont Auvergne, Clermont-Ferrand63001, France
| | - Esther Borras Nogues
- Université Paris-Saclay, Institut National de la Recherche Agronomique et Environnementale (INRAE), AgroParisTech UMR 1319 MICALIS, Jouy-en-Josas, France
| | - Catherine Godfraind
- M2iSH, UMR 1071 INSERM, University of Clermont Auvergne, INRAE USC 2018, Clermont-Ferrand63001, France
- CHU Clermont-Ferrand, Neuropathology Unit, Clermont-Ferrand, France
| | - Nicolas Barnich
- M2iSH, UMR 1071 INSERM, University of Clermont Auvergne, INRAE USC 2018, Clermont-Ferrand63001, France
| | - Denis Ardid
- NeuroDol, UMR 1107 INSERM, University of Clermont Auvergne, Clermont-Ferrand63001, France
| | - Philippe Poirier
- M2iSH, UMR 1071 INSERM, University of Clermont Auvergne, INRAE USC 2018, Clermont-Ferrand63001, France
- CHU Clermont-Ferrand, Laboratoire de Parasitologie et de Mycologie, Clermont-Ferrand, France
| | - Harry Sokol
- Sorbonne University, INSERM, Centre de Recherche Saint-Antoine, CRSA, AP-HP, Saint Antoine Hospital, Gastroenterology Department, F-75012Paris, France
- Paris Centre for Microbiome Medicine FHU, Paris, France
- Université Paris-Saclay, Institut National de la Recherche Agronomique et Environnementale (INRAE), AgroParisTech UMR 1319 MICALIS, Jouy-en-Josas, France
| | - Jean-Marc Chatel
- Université Paris-Saclay, Institut National de la Recherche Agronomique et Environnementale (INRAE), AgroParisTech UMR 1319 MICALIS, Jouy-en-Josas, France
| | - Philippe Langella
- Université Paris-Saclay, Institut National de la Recherche Agronomique et Environnementale (INRAE), AgroParisTech UMR 1319 MICALIS, Jouy-en-Josas, France
| | - Valérie Livrelli
- M2iSH, UMR 1071 INSERM, University of Clermont Auvergne, INRAE USC 2018, Clermont-Ferrand63001, France
- CHU Clermont-Ferrand, Laboratoire de Parasitologie et de Mycologie, Clermont-Ferrand, France
| | - Mathilde Bonnet
- M2iSH, UMR 1071 INSERM, University of Clermont Auvergne, INRAE USC 2018, Clermont-Ferrand63001, France
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30
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Tramullas M, Collins JM, Fitzgerald P, Dinan TG, O' Mahony SM, Cryan JF. Estrous cycle and ovariectomy-induced changes in visceral pain are microbiota-dependent. iScience 2021; 24:102850. [PMID: 34381975 PMCID: PMC8333168 DOI: 10.1016/j.isci.2021.102850] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2021] [Revised: 06/07/2021] [Accepted: 07/09/2021] [Indexed: 12/11/2022] Open
Abstract
Visceral hypersensitivity (VH) is a hallmark of many functional gastrointestinal disorders including irritable bowel syndrome and is categorized by a dull, diffuse sensation of abdominal pain. Recently, the gut microbiota has been implicated in VH in male mice, but the effects in females have yet to be explored fully. To this end, we now show that somewhat surprisingly, female germ-free mice have similar visceral pain responses to colorectal distension (CRD) as their conventional controls. However, we show that although sensitivity to CRD is estrous cycle stage-dependent in conventional mice, it is not in germ-free mice. Further, ovariectomy (OVX) induced VH in conventional but not germ-free mice, and induced weight gain regardless of microbiota status. Finally, we show that estrogen-replacement ameliorated OVX-induced VH. Taken together, this study provides evidence for a major role of female sex hormones and the gut microbiota in sensation of visceral pain in females.
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Affiliation(s)
| | - James M Collins
- APC Microbiome Ireland, University College Cork, Cork, Ireland.,Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland
| | | | - Timothy G Dinan
- APC Microbiome Ireland, University College Cork, Cork, Ireland.,Department of Psychiatry and Behavioural Science, University College Cork, Cork, Ireland
| | - Siobhain M O' Mahony
- APC Microbiome Ireland, University College Cork, Cork, Ireland.,Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland
| | - John F Cryan
- APC Microbiome Ireland, University College Cork, Cork, Ireland.,Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland
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31
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Bioactive Compounds in Food as a Current Therapeutic Approach to Maintain a Healthy Intestinal Epithelium. Microorganisms 2021; 9:microorganisms9081634. [PMID: 34442713 PMCID: PMC8401766 DOI: 10.3390/microorganisms9081634] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2021] [Revised: 07/08/2021] [Accepted: 07/28/2021] [Indexed: 12/12/2022] Open
Abstract
The intestinal epithelium serves as an effective barrier against the external environment, hampering the passage of potentially harmful substances (such as pathogenic microbes) that could trigger an exacerbated host immune response. The integrity of this barrier is thus essential for the maintenance of proper intestinal homeostasis and efficient protective reactions against chemical and microbial challenges. The principal consequence of intestinal barrier defects is an increase in intestinal permeability, which leads to an increased influx of luminal stressors, such as pathogens, toxins, and allergens, which in turn trigger inflammation and immune response. The fine and fragile balance of intestinal homeostasis can be altered by multiple factors that regulate barrier function, many of which are poorly understood. This review will address the role of gut microbiota as well as food supplements (such as probiotics, prebiotics, and synbiotics) in modulating gut health and regulating intestinal barrier function. In particular, we will focus on three human pathologies: inflammatory bowel disease, irritable bowel syndrome, and food allergy.
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32
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Luck B, Horvath TD, Engevik KA, Ruan W, Haidacher SJ, Hoch KM, Oezguen N, Spinler JK, Haag AM, Versalovic J, Engevik MA. Neurotransmitter Profiles Are Altered in the Gut and Brain of Mice Mono-Associated with Bifidobacterium dentium. Biomolecules 2021; 11:1091. [PMID: 34439760 PMCID: PMC8392031 DOI: 10.3390/biom11081091] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2021] [Revised: 06/29/2021] [Accepted: 07/18/2021] [Indexed: 12/16/2022] Open
Abstract
BACKGROUND Accumulating evidence indicates that the gut microbiota can synthesize neurotransmitters as well as impact host-derived neurotransmitter levels. In the past, it has been challenging to decipher which microbes influence neurotransmitters due to the complexity of the gut microbiota. METHODS To address whether a single microbe, Bifidobacterium dentium, could regulate important neurotransmitters, we examined Bifidobacteria genomes and explored neurotransmitter pathways in secreted cell-free supernatant using LC-MS/MS. To determine if B. dentium could impact neurotransmitters in vivo, we mono-associated germ-free mice with B. dentium ATCC 27678 and examined fecal and brain neurotransmitter concentrations. RESULTS We found that B. dentium possessed the enzymatic machinery to generate γ-aminobutyric acid (GABA) from glutamate, glutamine, and succinate. Consistent with the genome analysis, we found that B. dentium secreted GABA in a fully defined microbial media and elevated fecal GABA in B. dentium mono-associated mice compared to germ-free controls. We also examined the tyrosine/dopamine pathway and found that B. dentium could synthesize tyrosine, but could not generate L-dopa, dopamine, norepinephrine, or epinephrine. In vivo, we found that B. dentium mono-associated mice had elevated levels of tyrosine in the feces and brain. CONCLUSIONS These data indicate that B. dentium can contribute to in vivo neurotransmitter regulation.
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Affiliation(s)
- Berkley Luck
- Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX 77030, USA; (B.L.); (T.D.H.); (S.J.H.); (K.M.H.); (N.O.); (J.K.S.); (A.M.H.); (J.V.)
- Department of Pathology, Texas Children’s Hospital, Houston, TX 77030, USA
| | - Thomas D. Horvath
- Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX 77030, USA; (B.L.); (T.D.H.); (S.J.H.); (K.M.H.); (N.O.); (J.K.S.); (A.M.H.); (J.V.)
- Department of Pathology, Texas Children’s Hospital, Houston, TX 77030, USA
| | - Kristen A. Engevik
- Department of Virology and Microbiology, Baylor College of Medicine, Houston, TX 77030, USA;
| | - Wenly Ruan
- Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA;
- Section of Gastroenterology, Hepatology, and Nutrition, Texas Children’s Hospital, Houston, TX 77030, USA
| | - Sigmund J. Haidacher
- Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX 77030, USA; (B.L.); (T.D.H.); (S.J.H.); (K.M.H.); (N.O.); (J.K.S.); (A.M.H.); (J.V.)
- Department of Pathology, Texas Children’s Hospital, Houston, TX 77030, USA
| | - Kathleen M. Hoch
- Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX 77030, USA; (B.L.); (T.D.H.); (S.J.H.); (K.M.H.); (N.O.); (J.K.S.); (A.M.H.); (J.V.)
- Department of Pathology, Texas Children’s Hospital, Houston, TX 77030, USA
| | - Numan Oezguen
- Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX 77030, USA; (B.L.); (T.D.H.); (S.J.H.); (K.M.H.); (N.O.); (J.K.S.); (A.M.H.); (J.V.)
- Department of Pathology, Texas Children’s Hospital, Houston, TX 77030, USA
| | - Jennifer K. Spinler
- Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX 77030, USA; (B.L.); (T.D.H.); (S.J.H.); (K.M.H.); (N.O.); (J.K.S.); (A.M.H.); (J.V.)
- Department of Pathology, Texas Children’s Hospital, Houston, TX 77030, USA
| | - Anthony M. Haag
- Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX 77030, USA; (B.L.); (T.D.H.); (S.J.H.); (K.M.H.); (N.O.); (J.K.S.); (A.M.H.); (J.V.)
- Department of Pathology, Texas Children’s Hospital, Houston, TX 77030, USA
| | - James Versalovic
- Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX 77030, USA; (B.L.); (T.D.H.); (S.J.H.); (K.M.H.); (N.O.); (J.K.S.); (A.M.H.); (J.V.)
- Department of Pathology, Texas Children’s Hospital, Houston, TX 77030, USA
| | - Melinda A. Engevik
- Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX 77030, USA; (B.L.); (T.D.H.); (S.J.H.); (K.M.H.); (N.O.); (J.K.S.); (A.M.H.); (J.V.)
- Department of Regenerative Medicine & Cell Biology, Medical University of South Carolina, Charleston, SC 29425, USA
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Impact of 2'-Fucosyllactose on Gut Microbiota Composition in Adults with Chronic Gastrointestinal Conditions: Batch Culture Fermentation Model and Pilot Clinical Trial Findings. Nutrients 2021; 13:nu13030938. [PMID: 33799455 PMCID: PMC7998190 DOI: 10.3390/nu13030938] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2021] [Revised: 03/06/2021] [Accepted: 03/11/2021] [Indexed: 02/07/2023] Open
Abstract
Intestinal dysbiosis has been described in patients with certain gastrointestinal conditions including irritable bowel syndrome (IBS) and ulcerative colitis. 2′-fucosyllactose (2′-FL), a prebiotic human milk oligosaccharide, is considered bifidogenic and butyrogenic. To assess prebiotic effects of 2′-FL, alone or in combination with probiotic strains (potential synbiotics), in vitro experiments were conducted on stool from healthy, IBS, and ulcerative colitis adult donors. In anaerobic batch culture fermenters, Bifidobacterium and Eubacterium rectale-Clostridium coccoides counts, and short-chain fatty acids (SCFAs) including butyrate increased during fermentation with 2′-FL and some of the 2′-FL/probiotic combinations. In a subsequent open-label pilot trial, the effect of a 2′-FL-containing nutritional formula was evaluated in twelve adults with IBS or ulcerative colitis. Gastrointestinal Quality of Life Index (GIQLI) total and gastrointestinal symptoms domain scores, stool counts of Bifidobacterium and Faecalibacterium prausnitzii, and stool SCFAs including butyrate, increased after six weeks of intervention. Consistent with documented effects of 2′-FL, the batch culture fermentation experiments demonstrated bifidogenic and butyrogenic effects of 2′-FL during fermentation with human stool samples. Consumption of the 2′-FL-containing nutritional formula by adults with IBS or ulcerative colitis was associated with improvements in intra- and extra-intestinal symptoms, and bifidogenic and butyrogenic effects.
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Ryan JJ, Patno NM. Short-Term Tolerability, Safety, and Gut Microbial Composition Responses to a Multi-Strain Probiotic Supplement: An Open-Label Study in Healthy Adults. Integr Med (Encinitas) 2021; 20:24-34. [PMID: 34393673 PMCID: PMC8352413] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/13/2023]
Abstract
BACKGROUND Probiotics are among the most commonly used dietary supplements and evidence of their efficacy is increasing. Despite the long historical use of probiotics, some experts suggest that additional research is necessary to understand their potential risks. OBJECTIVES Main aims of this study were to assess short-term tolerability and safety of a new, high colony-forming unit count, multi-strain probiotic supplement. Exploratory objectives included evaluating effects on gut microbial composition. METHODS Ten healthy adults were enrolled in a single-arm, open-label study. Over a 10-day period, participants consumed a once daily probiotic capsule (2.1 x 1011 CFU) containing Lactobacillus acidophilus NCFM, Lactobacillus paracasei Lpc-37, Lactobacillus plantarum Lp-115, Lactobacillus rhamnosus GG, Lactobacillus rhamnosus HN001, Bifidobacterium lactis Bi-07, Bifidobacterium lactis Bl-04, and Bifidobacterium lactis HN019. The primary measure of tolerability pertained to whether or not participants completed the study. Secondary safety measures included clinical biomarkers from a routine metabolic panel and a complete blood count. Exploratory measures included stool microbiota counts. RESULTS All participants completed the study and there were no serious adverse events. All documented adverse events were prompted by the investigators and the most commonly reported symptoms were gastrointestinal. There was a single instance of a biomarker abnormality in one individual. Overall, decreases in total bilirubin and aspartate aminotransferase, and increases in stool levels of Lactobacillus species, Faecalibacterium prausnitzii, and Akkermansia muciniphila (P < .05) were observed over the course of the study. CONCLUSIONS The findings of this study suggest the multi-strain probiotic supplement was well-tolerated and most likely safe. Changes in liver function measures suggest the probiotics could potentially impact liver health. Stool microbiota changes suggest the probiotic could potentially impact gut health by affecting levels of intestinal microbiota that have been described as bioindicators of health and potential keystone species. However, additional research is necessary to follow up on the exploratory findings of this preliminary work.
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Affiliation(s)
- Jennifer Joan Ryan
- investigator and adjunct faculty at the Helfgott Research Institute, National University of Natural Medicine, Portland, OR, USA
| | - Noelle M. Patno
- Digestive Health Therapeutic Platform Lead at Metagenics, Inc in Aliso Viejo, CA, USA
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Leylabadlo HE, Ghotaslou R, Feizabadi MM, Farajnia S, Moaddab SY, Ganbarov K, Khodadadi E, Tanomand A, Sheykhsaran E, Yousefi B, Kafil HS. The critical role of Faecalibacterium prausnitzii in human health: An overview. Microb Pathog 2020; 149:104344. [PMID: 32534182 DOI: 10.1016/j.micpath.2020.104344] [Citation(s) in RCA: 133] [Impact Index Per Article: 26.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2020] [Revised: 06/05/2020] [Accepted: 06/08/2020] [Indexed: 12/12/2022]
Abstract
Faecalibacterium prausnitzii (F. prausnitzii) is one of the most abundant bacterial species in the colon of healthy human adults and representing more than 5% of the total bacterial population. Recently, it has been known as a major actor in human intestinal health and a biosensor. Changes in this species population richness and quantity have been observed in many illnesses and several investigations have reported that abundance of F. prausnitzii is reduced in different intestinal disorders. In the current review, we aim to consider literature from various library databases and electronic searches (Science Direct, PubMed, and Google Scholar) which were randomly collected and serve as an overview of different features of F. prausnitzii including metabolites, anti-inflammatory action, and correlation of dysbiosis of this bacterium with various complications in human.
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Affiliation(s)
- Hamed Ebrahimzadeh Leylabadlo
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Department of Bacteriology and Virology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran; Students' Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran.
| | - Reza Ghotaslou
- Department of Bacteriology and Virology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran; Liver and Gastrointestinal Diseases Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
| | - Mohammad Mehdi Feizabadi
- Department of Microbiology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
| | - Safar Farajnia
- Biotechnology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
| | - Seyed Yaghoub Moaddab
- Liver and Gastrointestinal Diseases Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
| | | | - Ehsaneh Khodadadi
- Hematology and Oncology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
| | - Asghar Tanomand
- Department of Microbiology, Maragheh University of Medical Sciences, Maragheh, Iran.
| | - Elham Sheykhsaran
- Department of Bacteriology and Virology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran.
| | - Bahman Yousefi
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
| | - Hossein Samadi Kafil
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
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Lactobacillus rhamnosus GG soluble mediators ameliorate early life stress-induced visceral hypersensitivity and changes in spinal cord gene expression. Neuronal Signal 2020; 4:NS20200007. [PMID: 33343931 PMCID: PMC7726314 DOI: 10.1042/ns20200007] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2020] [Revised: 10/26/2020] [Accepted: 11/10/2020] [Indexed: 02/06/2023] Open
Abstract
Visceral hypersensitivity is a hallmark of many functional and stress-related gastrointestinal disorders, and there is growing evidence that the gut microbiota may play a role in its pathophysiology. It has previously been shown that early life stress-induced visceral sensitivity is reduced by various probiotic strains of bacteria (including Lactobacillus rhamnosus GG (LGG)) alone or in combination with prebiotic fibres in rat models. However, the exact mechanisms underpinning such effects remain unresolved. Here, we investigated if soluble mediators derived from LGG can mimic the bacteria's effects on visceral hypersensitivity and the microbiota-gut-brain axis. Rats were exposed to maternal separation (MS) from postnatal days 2-12. From weaning onwards both non-separated (NS) and MS offspring were provided drinking water with or without supplementation of standardized preparations of the LGG soluble mediators (LSM). Our results show that MS led to increased visceral sensitivity and exaggerated corticosterone plasma levels following restraint stress in adulthood, and both of these effects were ameliorated through LSM supplementation. Differential regulation of various genes in the spinal cord of MS versus NS rats was observed, 41 of which were reversed by LSM supplementation. At the microbiota composition level MS led to changes in beta diversity and abundance of specific bacteria including parabacteroides, which were ameliorated by LSM. These findings support probiotic soluble mediators as potential interventions in the reduction of symptoms of visceral hypersensitivity.
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Abboud C, Duveau A, Bouali-Benazzouz R, Massé K, Mattar J, Brochoire L, Fossat P, Boué-Grabot E, Hleihel W, Landry M. Animal models of pain: Diversity and benefits. J Neurosci Methods 2020; 348:108997. [PMID: 33188801 DOI: 10.1016/j.jneumeth.2020.108997] [Citation(s) in RCA: 58] [Impact Index Per Article: 11.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2020] [Revised: 11/03/2020] [Accepted: 11/08/2020] [Indexed: 12/15/2022]
Abstract
Chronic pain is a maladaptive neurological disease that remains a major health problem. A deepening of our knowledge on mechanisms that cause pain is a prerequisite to developing novel treatments. A large variety of animal models of pain has been developed that recapitulate the diverse symptoms of different pain pathologies. These models reproduce different pain phenotypes and remain necessary to examine the multidimensional aspects of pain and understand the cellular and molecular basis underlying pain conditions. In this review, we propose an overview of animal models, from simple organisms to rodents and non-human primates and the specific traits of pain pathologies they model. We present the main behavioral tests for assessing pain and investing the underpinning mechanisms of chronic pathological pain. The validity of animal models is analysed based on their ability to mimic human clinical diseases and to predict treatment outcomes. Refine characterization of pathological phenotypes also requires to consider pain globally using specific procedures dedicated to study emotional comorbidities of pain. We discuss the limitations of pain models when research findings fail to be translated from animal models to human clinics. But we also point to some recent successes in analgesic drug development that highlight strategies for improving the predictive validity of animal models of pain. Finally, we emphasize the importance of using assortments of preclinical pain models to identify pain subtype mechanisms, and to foster the development of better analgesics.
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Affiliation(s)
- Cynthia Abboud
- Univ. Bordeaux, CNRS, Interdisciplinary Institute for Neuroscience, IINS, UMR 5297, F-33000 Bordeaux, France; Univ. Bordeaux, CNRS, Institute for Neurodegenerative Diseases, IMN, UMR 5293, F-33000 Bordeaux, France; Faculty of Arts and Sciences, Holy Spirit University of Kaslik (USEK), Lebanon
| | - Alexia Duveau
- Univ. Bordeaux, CNRS, Institute for Neurodegenerative Diseases, IMN, UMR 5293, F-33000 Bordeaux, France
| | - Rabia Bouali-Benazzouz
- Univ. Bordeaux, CNRS, Institute for Neurodegenerative Diseases, IMN, UMR 5293, F-33000 Bordeaux, France
| | - Karine Massé
- Univ. Bordeaux, CNRS, Institute for Neurodegenerative Diseases, IMN, UMR 5293, F-33000 Bordeaux, France
| | - Joseph Mattar
- School of Medicine and Medical Sciences, Holy Spirit University of Kaslik (USEK), Lebanon
| | - Louison Brochoire
- Univ. Bordeaux, CNRS, Institute for Neurodegenerative Diseases, IMN, UMR 5293, F-33000 Bordeaux, France
| | - Pascal Fossat
- Univ. Bordeaux, CNRS, Institute for Neurodegenerative Diseases, IMN, UMR 5293, F-33000 Bordeaux, France
| | - Eric Boué-Grabot
- Univ. Bordeaux, CNRS, Institute for Neurodegenerative Diseases, IMN, UMR 5293, F-33000 Bordeaux, France
| | - Walid Hleihel
- School of Medicine and Medical Sciences, Holy Spirit University of Kaslik (USEK), Lebanon; Faculty of Arts and Sciences, Holy Spirit University of Kaslik (USEK), Lebanon
| | - Marc Landry
- Univ. Bordeaux, CNRS, Institute for Neurodegenerative Diseases, IMN, UMR 5293, F-33000 Bordeaux, France.
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Andrade JC, Almeida D, Domingos M, Seabra CL, Machado D, Freitas AC, Gomes AM. Commensal Obligate Anaerobic Bacteria and Health: Production, Storage, and Delivery Strategies. Front Bioeng Biotechnol 2020; 8:550. [PMID: 32582673 PMCID: PMC7291883 DOI: 10.3389/fbioe.2020.00550] [Citation(s) in RCA: 36] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2020] [Accepted: 05/07/2020] [Indexed: 12/12/2022] Open
Abstract
In the last years several human commensals have emerged from the gut microbiota studies as potential probiotics or therapeutic agents. Strains of human gut inhabitants such as Akkermansia, Bacteroides, or Faecalibacterium have shown several interesting bioactivities and are thus currently being considered as food supplements or as live biotherapeutics, as is already the case with other human commensals such as bifidobacteria. The large-scale use of these bacteria will pose many challenges and drawbacks mainly because they are quite sensitive to oxygen and/or very difficult to cultivate. This review highlights the properties of some of the most promising human commensals bacteria and summarizes the most up-to-date knowledge on their potential health effects. A comprehensive outlook on the potential strategies currently employed and/or available to produce, stabilize, and deliver these microorganisms is also presented.
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Affiliation(s)
- José Carlos Andrade
- CESPU, Instituto de Investigação e Formação Avançada em Ciências e Tecnologias da Saúde, Gandra, Portugal
| | - Diana Almeida
- CBQF - Centro de Biotecnologia e Química Fina - Laboratório Associado, Escola Superior de Biotecnologia, Universidade Católica Portuguesa, Porto, Portugal
| | - Melany Domingos
- CBQF - Centro de Biotecnologia e Química Fina - Laboratório Associado, Escola Superior de Biotecnologia, Universidade Católica Portuguesa, Porto, Portugal
| | - Catarina Leal Seabra
- CBQF - Centro de Biotecnologia e Química Fina - Laboratório Associado, Escola Superior de Biotecnologia, Universidade Católica Portuguesa, Porto, Portugal
| | - Daniela Machado
- CBQF - Centro de Biotecnologia e Química Fina - Laboratório Associado, Escola Superior de Biotecnologia, Universidade Católica Portuguesa, Porto, Portugal
| | - Ana Cristina Freitas
- CBQF - Centro de Biotecnologia e Química Fina - Laboratório Associado, Escola Superior de Biotecnologia, Universidade Católica Portuguesa, Porto, Portugal
| | - Ana Maria Gomes
- CBQF - Centro de Biotecnologia e Química Fina - Laboratório Associado, Escola Superior de Biotecnologia, Universidade Católica Portuguesa, Porto, Portugal
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Co-Culture with Bifidobacterium catenulatum Improves the Growth, Gut Colonization, and Butyrate Production of Faecalibacterium prausnitzii: In Vitro and In Vivo Studies. Microorganisms 2020; 8:microorganisms8050788. [PMID: 32466189 PMCID: PMC7285360 DOI: 10.3390/microorganisms8050788] [Citation(s) in RCA: 58] [Impact Index Per Article: 11.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2020] [Revised: 05/22/2020] [Accepted: 05/23/2020] [Indexed: 12/19/2022] Open
Abstract
Faecalibacterium prausnitzii is a major commensal bacterium in the human gut. It produces short-chain fatty acids that promote intestinal health. However, the bacterium is extremely oxygen-sensitive, making it difficult to develop as a probiotic. To facilitate practical application of F. prausnitzii, we investigated factors that affect its growth and mammalian gut colonization. We evaluated cross-feeding interactions between F. prausnitzii and seven Bifidobacterium strains, and the anti-inflammatory properties of bacterial metabolites produced in co-culture, in vitro and in vivo. Co-culture of F. prausnitzii and Bifidobacterium catenulatum, with fructooligosaccharides as an energy source, resulted in the greatest viable cell-count and butyrate production increases. Further, the co-culture supernatant reduced the amount of proinflammatory cytokines produced by HT-29 cells and RAW 264.7 macrophages, an effect that was similar to that of butyrate. Furthermore, feeding mice both Faecalibacterium and Bifidobacterium enhanced F. prausnitzii gut colonization. Finally, feeding the co-culture supernatant decreased interleukin 8 levels in the colon and increased butyrate levels in the cecum in the dextran sodium sulfate-induced colitis mouse model. These observations indicate that the Faecalibacterium-Bifidobacterium co-culture exerts an anti-inflammatory effect by promoting F. prausnitzii survival and short-chain fatty acid production, with possible implications for the treatment of inflammatory bowel disease.
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Lewis ED, Antony JM, Crowley DC, Piano A, Bhardwaj R, Tompkins TA, Evans M. Efficacy of Lactobacillus paracasei HA-196 and Bifidobacterium longum R0175 in Alleviating Symptoms of Irritable Bowel Syndrome (IBS): A Randomized, Placebo-Controlled Study. Nutrients 2020; 12:nu12041159. [PMID: 32326347 PMCID: PMC7230591 DOI: 10.3390/nu12041159] [Citation(s) in RCA: 49] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2020] [Revised: 03/19/2020] [Accepted: 04/16/2020] [Indexed: 12/12/2022] Open
Abstract
Specific probiotic strains can alleviate the gastrointestinal (GI) symptoms and psychiatric comorbidities of irritable bowel syndrome (IBS). In this randomized, double-blind, placebo-controlled study, the efficacy of Lactobacillus paracasei HA-196 (L. paracasei) and Bifidobacterium longum R0175 (B. longum) in reducing the GI and psychological symptoms of IBS was evaluated in 251 adults with either constipation (IBS-C), diarrhea (IBS-D), or mixed-pattern (IBS-M). Following a 2-week run-in period, participants were randomized to one of three interventions: L. paracasei (n = 84), B. longum (n = 83) or placebo (n = 81). IBS symptoms, stool frequency and consistency and quality of life were assessed by questionnaires. The differences from baseline in the severity of IBS symptoms at 4 and 8 weeks were similar between groups. Participants in this study were classified, after randomization, into subtypes according to Rome III. Within the L. paracasei group, complete spontaneous and spontaneous bowel movement frequency increased in participants with IBS-C (n = 10) after 8 weeks of supplementation (both p < 0.05) and decreased in participants with IBS-D (n = 10, p = 0.013). Both L. paracasei and B. longum supplementation improved the quality of life in emotional well-being and social functioning compared with baseline (all p < 0.05). In conclusion, L. paracasei and B. longum may reduce GI symptom severity and improve the psychological well-being of individuals with certain IBS subtypes.
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Affiliation(s)
- Erin D. Lewis
- KGK Science Inc., London, ON N6A 5R8, Canada; (E.D.L.); (J.M.A.); (D.C.C.)
| | - Joseph M. Antony
- KGK Science Inc., London, ON N6A 5R8, Canada; (E.D.L.); (J.M.A.); (D.C.C.)
| | - David C. Crowley
- KGK Science Inc., London, ON N6A 5R8, Canada; (E.D.L.); (J.M.A.); (D.C.C.)
| | - Amanda Piano
- Lallemand Health Solutions, Montreal, QC H4P 2R2, Canada; (A.P.); (R.B.); (T.A.T.)
| | - Renu Bhardwaj
- Lallemand Health Solutions, Montreal, QC H4P 2R2, Canada; (A.P.); (R.B.); (T.A.T.)
| | - Thomas A. Tompkins
- Lallemand Health Solutions, Montreal, QC H4P 2R2, Canada; (A.P.); (R.B.); (T.A.T.)
| | - Malkanthi Evans
- KGK Science Inc., London, ON N6A 5R8, Canada; (E.D.L.); (J.M.A.); (D.C.C.)
- Correspondence:
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Bahlouli W, Breton J, Lelouard M, L'Huillier C, Tirelle P, Salameh E, Amamou A, Atmani K, Goichon A, Bôle-Feysot C, Ducrotté P, Ribet D, Déchelotte P, Coëffier M. Stress-induced intestinal barrier dysfunction is exacerbated during diet-induced obesity. J Nutr Biochem 2020; 81:108382. [PMID: 32417626 DOI: 10.1016/j.jnutbio.2020.108382] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2019] [Revised: 02/21/2020] [Accepted: 03/13/2020] [Indexed: 02/06/2023]
Abstract
Obesity and irritable bowel syndrome (IBS) are two major public health issues. Interestingly previous data report a marked increase of IBS prevalence in morbid obese subjects compared with non-obese subjects but underlying mechanisms remain unknown. Obesity and IBS share common intestinal pathophysiological mechanisms such as gut dysbiosis, intestinal hyperpermeability and low-grade inflammatory response. We thus aimed to evaluate the link between obesity and IBS using different animal models. Male C57Bl/6 mice received high fat diet (HFD) for 12 weeks and were then submitted to water avoidance stress (WAS). In response to WAS, HFD mice exhibited higher intestinal permeability and plasma corticosterone concentration than non-obese mice. We were not able to reproduce a similar response both in ob/ob mice and in leptin-treated non-obese mice. In addition, metformin, a hypoglycemic agent, limited fasting glycaemia both in unstressed and WAS diet-induced obese mice but only partially restored colonic permeability in unstressed HFD mice. Metformin failed to improve intestinal permeability in WAS HFD mice. Finally, cecal microbiota transplantation from HFD mice in antibiotics-treated recipient mice did not reproduce the effects observed in stressed HFD mice. In conclusion, stress induced a more marked intestinal barrier dysfunction in diet-induced obese mice compared with non-obese mice that seems to be independent of leptin, glycaemia and gut microbiota. These data should be further confirmed and the role of the dietary composition should be studied.
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Affiliation(s)
- Wafa Bahlouli
- Normandie University, UNIROUEN, INSERM UMR 1073 "Nutrition, inflammation and gut-brain axis", 76183 Rouen, France; Institute of Research and Innovation in Biomedicine (IRIB), UNIROUEN, 76183 Rouen, France
| | - Jonathan Breton
- Normandie University, UNIROUEN, INSERM UMR 1073 "Nutrition, inflammation and gut-brain axis", 76183 Rouen, France; Institute of Research and Innovation in Biomedicine (IRIB), UNIROUEN, 76183 Rouen, France
| | - Mauranne Lelouard
- Normandie University, UNIROUEN, INSERM UMR 1073 "Nutrition, inflammation and gut-brain axis", 76183 Rouen, France; Institute of Research and Innovation in Biomedicine (IRIB), UNIROUEN, 76183 Rouen, France
| | - Clément L'Huillier
- Normandie University, UNIROUEN, INSERM UMR 1073 "Nutrition, inflammation and gut-brain axis", 76183 Rouen, France; Institute of Research and Innovation in Biomedicine (IRIB), UNIROUEN, 76183 Rouen, France
| | - Pauline Tirelle
- Normandie University, UNIROUEN, INSERM UMR 1073 "Nutrition, inflammation and gut-brain axis", 76183 Rouen, France; Institute of Research and Innovation in Biomedicine (IRIB), UNIROUEN, 76183 Rouen, France
| | - Emmeline Salameh
- Normandie University, UNIROUEN, INSERM UMR 1073 "Nutrition, inflammation and gut-brain axis", 76183 Rouen, France; Institute of Research and Innovation in Biomedicine (IRIB), UNIROUEN, 76183 Rouen, France
| | - Asma Amamou
- Normandie University, UNIROUEN, INSERM UMR 1073 "Nutrition, inflammation and gut-brain axis", 76183 Rouen, France; Institute of Research and Innovation in Biomedicine (IRIB), UNIROUEN, 76183 Rouen, France
| | - Karim Atmani
- Normandie University, UNIROUEN, INSERM UMR 1073 "Nutrition, inflammation and gut-brain axis", 76183 Rouen, France; Institute of Research and Innovation in Biomedicine (IRIB), UNIROUEN, 76183 Rouen, France
| | - Alexis Goichon
- Normandie University, UNIROUEN, INSERM UMR 1073 "Nutrition, inflammation and gut-brain axis", 76183 Rouen, France; Institute of Research and Innovation in Biomedicine (IRIB), UNIROUEN, 76183 Rouen, France
| | - Christine Bôle-Feysot
- Normandie University, UNIROUEN, INSERM UMR 1073 "Nutrition, inflammation and gut-brain axis", 76183 Rouen, France; Institute of Research and Innovation in Biomedicine (IRIB), UNIROUEN, 76183 Rouen, France
| | - Philippe Ducrotté
- Normandie University, UNIROUEN, INSERM UMR 1073 "Nutrition, inflammation and gut-brain axis", 76183 Rouen, France; Institute of Research and Innovation in Biomedicine (IRIB), UNIROUEN, 76183 Rouen, France; Department of Gastroenterology, Rouen University Hospital, 76183 Rouen, France
| | - David Ribet
- Normandie University, UNIROUEN, INSERM UMR 1073 "Nutrition, inflammation and gut-brain axis", 76183 Rouen, France; Institute of Research and Innovation in Biomedicine (IRIB), UNIROUEN, 76183 Rouen, France
| | - Pierre Déchelotte
- Normandie University, UNIROUEN, INSERM UMR 1073 "Nutrition, inflammation and gut-brain axis", 76183 Rouen, France; Institute of Research and Innovation in Biomedicine (IRIB), UNIROUEN, 76183 Rouen, France; Department of Nutrition, Rouen University Hospital, 76183 Rouen, France
| | - Moïse Coëffier
- Normandie University, UNIROUEN, INSERM UMR 1073 "Nutrition, inflammation and gut-brain axis", 76183 Rouen, France; Institute of Research and Innovation in Biomedicine (IRIB), UNIROUEN, 76183 Rouen, France; Department of Nutrition, Rouen University Hospital, 76183 Rouen, France.
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Massacci FR, Berri M, Lemonnier G, Guettier E, Blanc F, Jardet D, Rossignol MN, Mercat MJ, Doré J, Lepage P, Rogel-Gaillard C, Estellé J. Late weaning is associated with increased microbial diversity and Faecalibacterium prausnitzii abundance in the fecal microbiota of piglets. Anim Microbiome 2020; 2:2. [PMID: 33499995 PMCID: PMC7807523 DOI: 10.1186/s42523-020-0020-4] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2019] [Accepted: 01/09/2020] [Indexed: 12/12/2022] Open
Abstract
Background In pig production systems, weaning is a crucial period characterized by nutritional, environmental, and social stresses. Piglets transition from a milk-based diet to a solid, more complex plant-based diet, and their gut physiology must adapt accordingly. It is well established that piglets weaned later display improved health, better wean-to-finish growth performance, and lower mortality rates. The aim of this study was to evaluate the impact of weaning age on fecal microbiota diversity and composition in piglets. Forty-eight Large White piglets were divided into 4 groups of 12 animals that were weaned at different ages: 14 days (early weaning), 21 days (a common weaning age in intensive pig farming), 28 days (idem), and 42 days (late weaning). Microbiota composition was assessed in each group by sequencing the 16S rRNA gene using fecal samples taken on the day of weaning, 7 days later, and at 60 days of age. Results In each group, there were significant differences in fecal microbiota composition before and after weaning (p < 0.05), confirming that weaning can drastically change the gut microbiota. Microbiota diversity was positively correlated with weaning age: microbial alpha diversity and richness were higher in piglets weaned at 42 days of age both on the day of weaning and 7 days later. The abundance of Faecalibacterium prausnitzii operational taxonomic units (OTUs) was also higher in piglets weaned at 42 days of age. Conclusions Overall, these results show that late weaning increased gut microbiota diversity and the abundance of F. prausnitzii, a microorganism with positive effects in humans. Piglets might thus derive a competitive advantage from later weaning because they have more time to accumulate a higher diversity of potentially beneficial microbes prior to the stressful and risky weaning period.
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Affiliation(s)
- Francesca Romana Massacci
- GABI, INRA, AgroParisTech, Université Paris-Saclay, 78350, Jouy-en-Josas, France. .,Department of Agricultural and Food Sciences, University of Bologna, Bologna, Italy. .,Istituto Zooprofilattico Sperimentale dell'Umbria e delle Marche 'Togo Rosati', Perugia, Italy.
| | | | - Gaetan Lemonnier
- GABI, INRA, AgroParisTech, Université Paris-Saclay, 78350, Jouy-en-Josas, France
| | | | - Fany Blanc
- GABI, INRA, AgroParisTech, Université Paris-Saclay, 78350, Jouy-en-Josas, France
| | - Deborah Jardet
- GABI, INRA, AgroParisTech, Université Paris-Saclay, 78350, Jouy-en-Josas, France
| | | | | | - Joël Doré
- MICALIS, INRA, AgroParisTech, Université Paris-Saclay, Jouy-en-Josas, France.,MetaGenoPolis, INRA, Université Paris-Saclay, Jouy-en-Josas, France
| | - Patricia Lepage
- MICALIS, INRA, AgroParisTech, Université Paris-Saclay, Jouy-en-Josas, France
| | | | - Jordi Estellé
- GABI, INRA, AgroParisTech, Université Paris-Saclay, 78350, Jouy-en-Josas, France.
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Wieërs G, Belkhir L, Enaud R, Leclercq S, Philippart de Foy JM, Dequenne I, de Timary P, Cani PD. How Probiotics Affect the Microbiota. Front Cell Infect Microbiol 2020; 9:454. [PMID: 32010640 PMCID: PMC6974441 DOI: 10.3389/fcimb.2019.00454] [Citation(s) in RCA: 293] [Impact Index Per Article: 58.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2019] [Accepted: 12/13/2019] [Indexed: 12/15/2022] Open
Abstract
Probiotics have been used to treat a variety of diseases for decades; however, what is the rationale for their application? Such a treatment was first proposed in the early nineteenth century based on observations of decreased bifidobacterial populations in children suffering from diarrhea, suggesting that oral intake of bifidobacteria could replete this subpopulation of the microbiota and improve health. Since then, studies have shown modifications in the gut or skin microbiota in the course of a variety of diseases and suggested positive effects of certain probiotics. Most studies failed to report any impact on the microbiota. The impact of probiotics as well as of bacteria colonizing food does not reside in their ability to graft in the microbiota but rather in sharing genes and metabolites, supporting challenged microbiota, and directly influencing epithelial and immune cells. Such observations argue that probiotics could be associated with conventional drugs for insulin resistance, infectious diseases, inflammatory diseases, and psychiatric disorders and could also interfere with drug metabolism. Nevertheless, in the context of a plethora of probiotic strains and associations produced in conditions that do not allow direct comparisons, it remains difficult to know whether a patient would benefit from taking a particular probiotic. In other words, although several mechanisms are observed when studying a single probiotic strain, not all individual strains are expected to share the same effects. To clarify the role of probiotics in the clinic, we explored the relation between probiotics and the gut and skin microbiota.
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Affiliation(s)
- Grégoire Wieërs
- Service de Médecine Interne Générale, Clinique Saint Pierre, Ottignies, Belgium
| | - Leila Belkhir
- Service de Médecine Interne et Maladies Infectieuses, Cliniques Universitaires Saint Luc, UCLouvain, Université Catholique de Louvain, Brussels, Belgium
| | - Raphaël Enaud
- CHU Bordeaux, CRCM Pédiatrique, CIC 1401, Université de Bordeaux, INSERM, CRCTB, U1045, CHU Bordeaux, Bordeaux, France
| | - Sophie Leclercq
- Institute of Neuroscience and Louvain Drug Research Institute, UCLouvain, Université Catholique de Louvain, Brussels, Belgium
| | | | | | - Philippe de Timary
- Service de Psychiatrie, Cliniques Universitaires Saint Luc, UCLouvain, Université Catholique de Louvain, Brussels, Belgium
| | - Patrice D. Cani
- Walloon Excellence in Life Sciences and BIOtechnology, Metabolism and Nutrition Research Group, Louvain Drug Research Institute, UCLouvain, Université Catholique de Louvain, Brussels, Belgium
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Massacci FR, Lovito C, Tofani S, Tentellini M, Genovese DA, De Leo AAP, Papa P, Magistrali CF, Manuali E, Trabalza-Marinucci M, Moscati L, Forte C. Dietary Saccharomyces cerevisiae boulardii CNCM I-1079 Positively Affects Performance and Intestinal Ecosystem in Broilers during a Campylobacter jejuni Infection. Microorganisms 2019; 7:E596. [PMID: 31766507 PMCID: PMC6956328 DOI: 10.3390/microorganisms7120596] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2019] [Revised: 11/19/2019] [Accepted: 11/20/2019] [Indexed: 01/30/2023] Open
Abstract
In poultry production, probiotics have shown promise to limit campylobacteriosis at the farm level, the most commonly reported zoonosis in Europe. The aim of this trial was to evaluate the effects of Saccharomyces supplementation in Campylobacter jejuni challenged chickens on performance and intestinal ecosystem. A total of 156 day old male Ross 308 chicks were assigned to a basal control diet (C) or to a Saccharomyces cerevisiae boulardii CNCM I-1079 supplemented diet (S). All the birds were orally challenged with C. jejuni on day (d) 21. Live weight and growth performance were evaluated on days 1, 21, 28 and 40. The histology of intestinal mucosa was analyzed and the gut microbiota composition was assessed by 16S rRNA. Performance throughout the trial as well as villi length and crypt depth were positively influenced by yeast supplementation. A higher abundance of operational taxonomic units (OTUs) annotated as Lactobacillus reuteri and Faecalibacterium prausnitzii and a lower abundance of Campylobacter in fecal samples from S compared to the C group were reported. Supplementation with Saccharomyces cerevisiae boulardii can effectively modulate the intestinal ecosystem, leading to a higher abundance of beneficial microorganisms and modifying the intestinal mucosa architecture, with a subsequent improvement of the broilers' growth performance.
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Affiliation(s)
- Francesca Romana Massacci
- Istituto Zooprofilattico Sperimentale dell’Umbria e delle Marche ‘Togo Rosati’, 06126 Perugia, Italy; (F.R.M.); (C.L.); (S.T.); (M.T.); (D.A.G.); (A.A.P.D.L.); (P.P.); (C.F.M.); (E.M.); (L.M.)
- Department of Agricultural and Food Sciences, University of Bologna, 40127 Bologna, Italy
- GABI, INRA, AgroParisTech, Université Paris-Saclay, 78350 Jouy-en-Josas, France
| | - Carmela Lovito
- Istituto Zooprofilattico Sperimentale dell’Umbria e delle Marche ‘Togo Rosati’, 06126 Perugia, Italy; (F.R.M.); (C.L.); (S.T.); (M.T.); (D.A.G.); (A.A.P.D.L.); (P.P.); (C.F.M.); (E.M.); (L.M.)
| | - Silvia Tofani
- Istituto Zooprofilattico Sperimentale dell’Umbria e delle Marche ‘Togo Rosati’, 06126 Perugia, Italy; (F.R.M.); (C.L.); (S.T.); (M.T.); (D.A.G.); (A.A.P.D.L.); (P.P.); (C.F.M.); (E.M.); (L.M.)
- Istituto Zooprofilattico Sperimentale del Lazio e della Toscana ‘M. Aleandri’, 00178 Roma, Italy
| | - Michele Tentellini
- Istituto Zooprofilattico Sperimentale dell’Umbria e delle Marche ‘Togo Rosati’, 06126 Perugia, Italy; (F.R.M.); (C.L.); (S.T.); (M.T.); (D.A.G.); (A.A.P.D.L.); (P.P.); (C.F.M.); (E.M.); (L.M.)
| | - Domenica Anna Genovese
- Istituto Zooprofilattico Sperimentale dell’Umbria e delle Marche ‘Togo Rosati’, 06126 Perugia, Italy; (F.R.M.); (C.L.); (S.T.); (M.T.); (D.A.G.); (A.A.P.D.L.); (P.P.); (C.F.M.); (E.M.); (L.M.)
| | - Alessia Arcangela Pia De Leo
- Istituto Zooprofilattico Sperimentale dell’Umbria e delle Marche ‘Togo Rosati’, 06126 Perugia, Italy; (F.R.M.); (C.L.); (S.T.); (M.T.); (D.A.G.); (A.A.P.D.L.); (P.P.); (C.F.M.); (E.M.); (L.M.)
| | - Paola Papa
- Istituto Zooprofilattico Sperimentale dell’Umbria e delle Marche ‘Togo Rosati’, 06126 Perugia, Italy; (F.R.M.); (C.L.); (S.T.); (M.T.); (D.A.G.); (A.A.P.D.L.); (P.P.); (C.F.M.); (E.M.); (L.M.)
| | - Chiara Francesca Magistrali
- Istituto Zooprofilattico Sperimentale dell’Umbria e delle Marche ‘Togo Rosati’, 06126 Perugia, Italy; (F.R.M.); (C.L.); (S.T.); (M.T.); (D.A.G.); (A.A.P.D.L.); (P.P.); (C.F.M.); (E.M.); (L.M.)
| | - Elisabetta Manuali
- Istituto Zooprofilattico Sperimentale dell’Umbria e delle Marche ‘Togo Rosati’, 06126 Perugia, Italy; (F.R.M.); (C.L.); (S.T.); (M.T.); (D.A.G.); (A.A.P.D.L.); (P.P.); (C.F.M.); (E.M.); (L.M.)
| | | | - Livia Moscati
- Istituto Zooprofilattico Sperimentale dell’Umbria e delle Marche ‘Togo Rosati’, 06126 Perugia, Italy; (F.R.M.); (C.L.); (S.T.); (M.T.); (D.A.G.); (A.A.P.D.L.); (P.P.); (C.F.M.); (E.M.); (L.M.)
| | - Claudio Forte
- Istituto Zooprofilattico Sperimentale dell’Umbria e delle Marche ‘Togo Rosati’, 06126 Perugia, Italy; (F.R.M.); (C.L.); (S.T.); (M.T.); (D.A.G.); (A.A.P.D.L.); (P.P.); (C.F.M.); (E.M.); (L.M.)
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Microbiota: a novel regulator of pain. J Neural Transm (Vienna) 2019; 127:445-465. [PMID: 31552496 DOI: 10.1007/s00702-019-02083-z] [Citation(s) in RCA: 43] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2019] [Accepted: 09/16/2019] [Indexed: 02/07/2023]
Abstract
Among the various regulators of the nervous system, the gut microbiota has been recently described to have the potential to modulate neuronal cells activation. While bacteria-derived products can induce aversive responses and influence pain perception, recent work suggests that "abnormal" microbiota is associated with neurological diseases such as Alzheimer's, Parkinson's disease or autism spectrum disorder (ASD). Here we review how the gut microbiota modulates afferent sensory neurons function and pain, highlighting the role of the microbiota/gut/brain axis in the control of behaviors and neurological diseases. We outline the changes in gut microbiota, known as dysbiosis, and their influence on painful gastrointestinal disorders. Furthermore, both direct host/microbiota interaction that implicates activation of "pain-sensing" neurons by metabolites, or indirect communication via immune activation is discussed. Finally, treatment options targeting the gut microbiota, including pre- or probiotics, will be proposed. Further studies on microbiota/nervous system interaction should lead to the identification of novel microbial ligands and host receptor-targeted drugs, which could ultimately improve chronic pain management and well-being.
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Pain regulation by gut microbiota: molecular mechanisms and therapeutic potential. Br J Anaesth 2019; 123:637-654. [PMID: 31551115 DOI: 10.1016/j.bja.2019.07.026] [Citation(s) in RCA: 225] [Impact Index Per Article: 37.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2019] [Revised: 07/15/2019] [Accepted: 07/16/2019] [Indexed: 12/14/2022] Open
Abstract
The relationship between gut microbiota and neurological diseases, including chronic pain, has received increasing attention. The gut microbiome is a crucial modulator of visceral pain, whereas recent evidence suggests that gut microbiota may also play a critical role in many other types of chronic pain, including inflammatory pain, headache, neuropathic pain, and opioid tolerance. We present a narrative review of the current understanding on the role of gut microbiota in pain regulation and discuss the possibility of targeting gut microbiota for the management of chronic pain. Numerous signalling molecules derived from gut microbiota, such as by-products of microbiota, metabolites, neurotransmitters, and neuromodulators, act on their receptors and remarkably regulate the peripheral and central sensitisation, which in turn mediate the development of chronic pain. Gut microbiota-derived mediators serve as critical modulators for the induction of peripheral sensitisation, directly or indirectly regulating the excitability of primary nociceptive neurones. In the central nervous system, gut microbiota-derived mediators may regulate neuroinflammation, which involves the activation of cells in the blood-brain barrier, microglia, and infiltrating immune cells, to modulate induction and maintenance of central sensitisation. Thus, we propose that gut microbiota regulates pain in the peripheral and central nervous system, and targeting gut microbiota by diet and pharmabiotic intervention may represent a new therapeutic strategy for the management of chronic pain.
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Lomax AE, Pradhananga S, Sessenwein JL, O'Malley D. Bacterial modulation of visceral sensation: mediators and mechanisms. Am J Physiol Gastrointest Liver Physiol 2019; 317:G363-G372. [PMID: 31290688 DOI: 10.1152/ajpgi.00052.2019] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
The potential role of the intestinal microbiota in modulating visceral pain has received increasing attention during recent years. This has led to the identification of signaling pathways that have been implicated in communication between gut bacteria and peripheral pain pathways. In addition to the well-characterized impact of the microbiota on the immune system, which in turn affects nociceptor excitability, bacteria can modulate visceral afferent pathways by effects on enterocytes, enteroendocrine cells, and the neurons themselves. Proteases produced by bacteria, or by host cells in response to bacteria, can increase or decrease the excitability of nociceptive dorsal root ganglion (DRG) neurons depending on the receptor activated. Short-chain fatty acids generated by colonic bacteria are involved in gut-brain communication, and intracolonic short-chain fatty acids have pronociceptive effects in rodents but may be antinociceptive in humans. Gut bacteria modulate the synthesis and release of enteroendocrine cell mediators, including serotonin and glucagon-like peptide-1, which activate extrinsic afferent neurons. Deciphering the complex interactions between visceral afferent neurons and the gut microbiota may lead to the development of improved probiotic therapies for visceral pain.
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Affiliation(s)
- Alan E Lomax
- Gastrointestinal Diseases Research Unit, Queen's University, Kingston, Ontario, Canada
| | - Sabindra Pradhananga
- Gastrointestinal Diseases Research Unit, Queen's University, Kingston, Ontario, Canada
| | - Jessica L Sessenwein
- Gastrointestinal Diseases Research Unit, Queen's University, Kingston, Ontario, Canada
| | - Dervla O'Malley
- APC Microbiome Ireland, University College Cork, Cork, Ireland.,Department of Physiology, University College Cork, Cork, Ireland
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Abstract
The developmental period constitutes a critical window of sensitivity to stress. Indeed, early-life adversity increases the risk to develop psychiatric diseases, but also gastrointestinal disorders such as the irritable bowel syndrome at adulthood. In the past decade, there has been huge interest in the gut-brain axis, especially as regards stress-related emotional behaviours. Animal models of early-life adversity, in particular, maternal separation (MS) in rodents, demonstrate lasting deleterious effects on both the gut and the brain. Here, we review the effects of MS on both systems with a focus on stress-related behaviours. In addition, we discuss more recent findings showing the impact of gut-directed interventions, including nutrition with pre- and probiotics, illustrating the role played by gut microbiota in mediating the long-term effects of MS. Overall, preclinical studies suggest that nutritional approaches with pro- and prebiotics may constitute safe and efficient strategies to attenuate the effects of early-life stress on the gut-brain axis. Further research is required to understand the complex mechanisms underlying gut-brain interaction dysfunctions after early-life stress as well as to determine the beneficial impact of gut-directed strategies in a context of early-life adversity in human subjects.
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50
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Cherbuy C, Bellet D, Robert V, Mayeur C, Schwiertz A, Langella P. Modulation of the Caecal Gut Microbiota of Mice by Dietary Supplement Containing Resistant Starch: Impact Is Donor-Dependent. Front Microbiol 2019; 10:1234. [PMID: 31244792 PMCID: PMC6563722 DOI: 10.3389/fmicb.2019.01234] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2019] [Accepted: 05/17/2019] [Indexed: 12/27/2022] Open
Abstract
Alterations in the gut microbiota have been associated with a wide range of pathologies and conditions. Maintaining a well-balanced microbiota is a key factor in sustaining good health. Our aim was to investigate the impact of a resistant starch-containing dietary supplement (SymbioIntest®) on the composition of the human gut microbiota and on intestinal short chain fatty acid (SCFA) concentration. Human microbiota-associated mice were used. Ex-germ-free mice were inoculated with fecal suspensions from four different donors. Three weeks later, the mice were orally gavaged for 1 month with either a daily dose of 10 mg of SymbioIntest® or the vehicle (water) for the negative control group. The composition of the microbiota and SCFA levels were analyzed by 16S rRNA gene sequencing and gas chromatography, respectively. In three groups of mice, SymbioIntest® supplementation increased the concentration of caecal butyrate. This was in conjunction with a remodeling of the gut microbiota. OTUs belonging to the Bacteroidaceae, Porphyromonadaceae, Lachnospiraceae and Ruminococcaceae families were affected. In two groups of mice the greatest changes in OTUs were seen in the Faecalibacterium genus. The supplementation’s highest impact was observed in mice inoculated with gut microbiota containing a lower number of Ruminococcaceae and Faecalibacterium and a higher number of Prevotellaceae. SymbioIntest® supplementation elicited a beneficial effect on the healthy adult gut microbiota by increasing caecal butyrate production and health-promoting taxa. We highlight the fact that screening the gut microbiota may be used for predicting individualized responses to dietary interventions and thus developing personalized nutritional strategies.
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Affiliation(s)
- Claire Cherbuy
- Micalis Institute, INRA, AgroParisTech, Université Paris-Saclay, Jouy-en-Josas, France
| | - Déborah Bellet
- Micalis Institute, INRA, AgroParisTech, Université Paris-Saclay, Jouy-en-Josas, France
| | - Véronique Robert
- Micalis Institute, INRA, AgroParisTech, Université Paris-Saclay, Jouy-en-Josas, France
| | - Camille Mayeur
- Micalis Institute, INRA, AgroParisTech, Université Paris-Saclay, Jouy-en-Josas, France
| | | | - Philippe Langella
- Micalis Institute, INRA, AgroParisTech, Université Paris-Saclay, Jouy-en-Josas, France
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