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Hauser G, Benjak Horvat I, Rajilić-Stojanović M, Krznarić-Zrnić I, Kukla M, Aljinović-Vučić V, Mikolašević I. Intestinal Microbiota Modulation by Fecal Microbiota Transplantation in Nonalcoholic Fatty Liver Disease. Biomedicines 2025; 13:779. [PMID: 40299326 PMCID: PMC12024620 DOI: 10.3390/biomedicines13040779] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2025] [Revised: 03/14/2025] [Accepted: 03/20/2025] [Indexed: 04/30/2025] Open
Abstract
Numerous factors are involved in the pathogenesis of nonalcoholic fatty liver disease (NAFLD), which are responsible for its development and progression as an independent entity, but also thanks to their simultaneous action. This is explained by the hypothesis of multiple parallel hits. These factors are insulin resistance, lipid metabolism alteration, oxidative stress, endoplasmic reticulum stress, inflammatory cytokine liberation, gut microbiota dysbiosis or gut-liver axis activation. This is a systematic review which has an aim to show the connection between intestinal microbiota and the role of its disbalance in the development of NAFLD. The gut microbiota is made from a wide spectrum of microorganisms that has a systemic impact on human health, with a well-documented role in digestion, energy metabolism, the stimulation of the immune system, synthesis of essential nutrients, etc. It has been shown that dysbiosis is associated with all three stages of chronic liver disease. Thus, the modulation of the gut microbiota has attracted research interest as a novel therapeutic approach for the management of NAFLD patients. The modification of microbiota can be achieved by substantial diet modification and the application of probiotics or prebiotics, while the most radical effects are observed by fecal microbiota transplantation (FMT). Given the results of FMT in the context of metabolic syndrome (MetS) and NAFLD in animal models and scarce pilot studies on humans, FMT seems to be a promising treatment option that could reverse intestinal dysbiosis and thereby influence the course of NAFLD.
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Affiliation(s)
- Goran Hauser
- Department of Gastroenterology, Clinical Hospital Center Rijeka, 51000 Rijeka, Croatia; (G.H.); (I.K.-Z.); (I.M.)
- Faculty of Medicine, University of Rijeka, 51000 Rijeka, Croatia;
| | - Indira Benjak Horvat
- Faculty of Medicine, University of Rijeka, 51000 Rijeka, Croatia;
- County Hospital Varaždin, 42000 Varaždin, Croatia
| | - Mirjana Rajilić-Stojanović
- Department of Biochemical Engineering & Biotechnology, Faculty of Technology and Metallurgy, University of Belgrade, 11000 Belgrade, Serbia;
| | - Irena Krznarić-Zrnić
- Department of Gastroenterology, Clinical Hospital Center Rijeka, 51000 Rijeka, Croatia; (G.H.); (I.K.-Z.); (I.M.)
| | - Michail Kukla
- Department of Internal Medicine and Geriatrics, Jagiellonian University Medical College, 31-121 Cracow, Poland;
- Department of Endoscopy, University Hospital in Cracow, 30-688 Cracow, Poland
- 1st Infectious Diseases Ward, Gromkowski Regional Specialist Hospital, Wroclaw, 5 Koszarowa St., 50-149 Wroclaw, Poland
| | - Vedrana Aljinović-Vučić
- Faculty of Medicine, University of Rijeka, 51000 Rijeka, Croatia;
- Medical Affairs Department, Jadran Galenski Laboratorij d.d., 51000 Rijeka, Croatia
| | - Ivana Mikolašević
- Department of Gastroenterology, Clinical Hospital Center Rijeka, 51000 Rijeka, Croatia; (G.H.); (I.K.-Z.); (I.M.)
- Faculty of Medicine, University of Rijeka, 51000 Rijeka, Croatia;
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Mamun AA, Geng P, Wang S, Shao C, Xiao J. IUPHAR review: Targeted therapies of signaling pathways based on the gut microbiome in autism spectrum disorders: Mechanistic and therapeutic applications. Pharmacol Res 2025; 211:107559. [PMID: 39733842 DOI: 10.1016/j.phrs.2024.107559] [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: 07/11/2024] [Revised: 12/22/2024] [Accepted: 12/23/2024] [Indexed: 12/31/2024]
Abstract
Autism spectrum disorders (ASD) are complex neurodevelopmental disorders characterized by impairments in social interaction, communication and repetitive activities. Gut microbiota significantly influences behavior and neurodevelopment by regulating the gut-brain axis. This review explores gut microbiota-influenced treatments for ASD, focusing on their therapeutic applications and mechanistic insights. In addition, this review discusses the interactions between gut microbiota and the immune, metabolic and neuroendocrine systems, focusing on crucial microbial metabolites including short-chain fatty acids (SCFAs) and several neurotransmitters. Furthermore, the review explores various therapy methods including fecal microbiota transplantation, dietary modifications, probiotics and prebiotics and evaluates their safety and efficacy in reducing ASD symptoms. The discussion shows the potential of customized microbiome-based therapeutics and the integration of multi-omics methods to understand the underlying mechanisms. Moreover, the review explores the intricate relationship between gut microbiota and ASD, aiming to develop innovative therapies that utilize the gut microbiome to improve the clinical outcomes of ASD patients. Microbial metabolites such as neurotransmitter precursors, tryptophan metabolites and SCFAs affect brain development and behavior. Symptoms of ASD are linked to changes in these metabolites. Dysbiosis in the gut microbiome may impact neuroinflammatory processes linked to autism, negatively affecting immune signaling pathways. Research indicates that probiotics and prebiotics can improve gut microbiota and alleviate symptoms in ASD patients. Fecal microbiota transplantation may also improve behavioral symptoms and restore gut microbiota balance. The review emphasizes the need for further research on gut microbiota modification as a potential therapeutic approach for ASD, highlighting its potential in clinical settings.
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Affiliation(s)
- Abdullah Al Mamun
- Central Laboratory of The Lishui Hospital of Wenzhou Medical University, The First Affiliated Hospital of Lishui University, Lishui People's Hospital, Lishui, Zhejiang 323000, China; Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325000, China
| | - Peiwu Geng
- Central Laboratory of The Lishui Hospital of Wenzhou Medical University, The First Affiliated Hospital of Lishui University, Lishui People's Hospital, Lishui, Zhejiang 323000, China
| | - Shuanghu Wang
- Central Laboratory of The Lishui Hospital of Wenzhou Medical University, The First Affiliated Hospital of Lishui University, Lishui People's Hospital, Lishui, Zhejiang 323000, China
| | - Chuxiao Shao
- Central Laboratory of The Lishui Hospital of Wenzhou Medical University, The First Affiliated Hospital of Lishui University, Lishui People's Hospital, Lishui, Zhejiang 323000, China.
| | - Jian Xiao
- Central Laboratory of The Lishui Hospital of Wenzhou Medical University, The First Affiliated Hospital of Lishui University, Lishui People's Hospital, Lishui, Zhejiang 323000, China; Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325000, China; Department of Wound Healing, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, China.
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De Salvo C, Osme A, Ghannoum M, Cominelli F, Di Martino L. A New Probiotic Formulation Promotes Resolution of Inflammation in a Crohn's Disease Mouse Model by Inducing Apoptosis in Mucosal Innate Immune Cells. Int J Mol Sci 2024; 25:12066. [PMID: 39596135 PMCID: PMC11593709 DOI: 10.3390/ijms252212066] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2024] [Revised: 11/02/2024] [Accepted: 11/07/2024] [Indexed: 11/28/2024] Open
Abstract
The interaction between gut-residing microorganisms plays a critical role in the pathogenesis of Crohn's disease (CD), where microbiome dysregulation can alter immune responses, leading to unresolved local inflammation. The aim of this study is to analyze the immunomodulatory properties of a recently developed probiotic + amylase blend in the SAMP1/YitFc (SAMP) mouse model of CD-like ileitis. Four groups of SAMP mice were gavaged for 56 days with the following treatments: 1) probiotic strains + amylase (0.25 mg/100 µL PBS); 2) only probiotics; 3) only amylase; PBS-treated controls. Ilea were collected for GeoMx Digital Spatial Profiler (DSP) analysis and histological evaluation. Histology assessment for inflammation indicated a significantly reduced level of ileitis in mice administered the probiotics + amylase blend. DSP analysis showed decreased abundance of neutrophils and increased abundance of dendritic cells, regulatory T cells, and macrophages, with a significant enrichment of five intracellular pathways related to apoptosis, in probiotics + amylase-treated mice. Increased apoptosis occurrence was confirmed by (TdT)- deoxyuridine triphosphate (dUTP)-biotin nick end labeling assay. Our data demonstrate a beneficial role of the probiotic and amylase blend, highlighting an increased apoptosis of innate immunity-associated cell subsets, thus promoting the resolution of inflammation. Hence, we suggest that the developed probiotic enzyme blend may be a therapeutic tool to manage CD and therefore is a candidate formulation to be tested in clinical trials.
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Affiliation(s)
- Carlo De Salvo
- Department of Pathology, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA; (C.D.S.); (F.C.)
| | - Abdullah Osme
- Department of Anatomic Pathology, University of Alabama at Birmingham, Birmingham, AL 35294, USA;
| | - Mahmoud Ghannoum
- Center for Medical Mycology and Integrated Microbiome Core, Department of Dermatology, University Hospitals Cleveland Medical Center, Case Western Reserve University, Cleveland, OH 44106, USA;
| | - Fabio Cominelli
- Department of Pathology, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA; (C.D.S.); (F.C.)
- Case Digestive Health Research Institute, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA
- Department of Medicine, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA
| | - Luca Di Martino
- Case Digestive Health Research Institute, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA
- Department of Medicine, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA
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Ahmadi S, Hasani A, Khabbaz A, Poortahmasbe V, Hosseini S, Yasdchi M, Mehdizadehfar E, Mousavi Z, Hasani R, Nabizadeh E, Nezhadi J. Dysbiosis and fecal microbiota transplant: Contemplating progress in health, neurodegeneration and longevity. Biogerontology 2024; 25:957-983. [PMID: 39317918 DOI: 10.1007/s10522-024-10136-4] [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] [Received: 05/21/2024] [Accepted: 08/30/2024] [Indexed: 09/26/2024]
Abstract
The gut-brain axis plays an important role in mental health. The intestinal epithelial surface is colonized by billions of commensal and transitory bacteria, known as the Gut Microbiota (GM). However, potential pathogens continuously stimulate intestinal immunity when they find the place. The last two decades have witnessed several studies revealing intestinal bacteria as a key factor in the health-disease balance of the gut, as well as disease-emergent in other parts of the body. Various neurological processes, such as cognition, learning, and memory, could be affected by dysbiosis in GM. Additionally, the aging process and longevity are related to systemic inflammation caused by dysbiosis. Commensal GM affects brain development, behavior, and healthy aging suggesting that building changes in GM might be a potential therapeutic method. The innovation in GM dysbiosis is intervention by Fecal Microbiota Transplantation (FMT), which has been confirmed as a therapy for recurrent Clostridium difficile infections and is promising for other clinical disorders, such as Parkinson's disease, Multiple Sclerosis (MS), Alzheimer's disease, and depression. Additionally, FMT may be possible to promote healthy aging, and extend longevity. This review aims to connect dysbiosis, neurological disorders, and aging and the potential of FMT as a therapeutic strategy to treat these disorders, and to enhance the quality of life in the elderly.
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Affiliation(s)
- Somayeh Ahmadi
- Infectious and Tropical Diseases Research Center, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
- Students Research Committee, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Alka Hasani
- Infectious and Tropical Diseases Research Center, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran.
- Clinical Research Development Unit, Sina Educational, Research and Treatment Center, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran.
| | - Aytak Khabbaz
- Neurosciences Research Center, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Vahdat Poortahmasbe
- Infectious and Tropical Diseases Research Center, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Samaneh Hosseini
- Neurosciences Research Center, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mohammad Yasdchi
- Neurosciences Research Center, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Elham Mehdizadehfar
- Neurosciences Research Center, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Zahra Mousavi
- Department of Psychology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Roqaiyeh Hasani
- School of Medicine, Istanbul Okan University, Tuzla, 34959, Istanbul, Turkey
| | - Edris Nabizadeh
- Infectious and Tropical Diseases Research Center, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Javad Nezhadi
- Infectious and Tropical Diseases Research Center, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
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Shi H, Newton DP, Nguyen TH, Estrela S, Sanchez J, Tu M, Ho PY, Zeng Q, DeFelice B, Sonnenburg J, Huang KC. Nutrient competition predicts gut microbiome restructuring under drug perturbations. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.08.06.606863. [PMID: 39211277 PMCID: PMC11360974 DOI: 10.1101/2024.08.06.606863] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/04/2024]
Abstract
Human gut commensal bacteria are routinely exposed to various stresses, including therapeutic drugs, and collateral effects are difficult to predict. To systematically interrogate community-level effects of drug perturbations, we screened stool-derived in vitro communities with 707 clinically relevant small molecules. Across ∼5,000 community-drug interaction conditions, compositional and metabolomic responses were predictably impacted by nutrient competition, with certain species exhibiting improved growth due to adverse impacts on competitors. Changes to community composition were generally reversed by reseeding with the original community, although occasionally species promotion was long-lasting, due to higher-order interactions, even when the competitor was reseeded. Despite strong selection pressures, emergence of resistance within communities was infrequent. Finally, while qualitative species responses to drug perturbations were conserved across community contexts, nutrient competition quantitatively affected their abundances, consistent with predictions of consumer-resource models. Our study reveals that quantitative understanding of the interaction landscape, particularly nutrient competition, can be used to anticipate and potentially mitigate side effects of drug treatment on the gut microbiota.
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Di Bella S, Sanson G, Monticelli J, Zerbato V, Principe L, Giuffrè M, Pipitone G, Luzzati R. Clostridioides difficile infection: history, epidemiology, risk factors, prevention, clinical manifestations, treatment, and future options. Clin Microbiol Rev 2024; 37:e0013523. [PMID: 38421181 PMCID: PMC11324037 DOI: 10.1128/cmr.00135-23] [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] [Indexed: 03/02/2024] Open
Abstract
SUMMARYClostridioides difficile infection (CDI) is one of the major issues in nosocomial infections. This bacterium is constantly evolving and poses complex challenges for clinicians, often encountered in real-life scenarios. In the face of CDI, we are increasingly equipped with new therapeutic strategies, such as monoclonal antibodies and live biotherapeutic products, which need to be thoroughly understood to fully harness their benefits. Moreover, interesting options are currently under study for the future, including bacteriophages, vaccines, and antibiotic inhibitors. Surveillance and prevention strategies continue to play a pivotal role in limiting the spread of the infection. In this review, we aim to provide the reader with a comprehensive overview of epidemiological aspects, predisposing factors, clinical manifestations, diagnostic tools, and current and future prophylactic and therapeutic options for C. difficile infection.
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Affiliation(s)
- Stefano Di Bella
- Clinical Department of
Medical, Surgical and Health Sciences, Trieste
University, Trieste,
Italy
| | - Gianfranco Sanson
- Clinical Department of
Medical, Surgical and Health Sciences, Trieste
University, Trieste,
Italy
| | - Jacopo Monticelli
- Infectious Diseases
Unit, Trieste University Hospital
(ASUGI), Trieste,
Italy
| | - Verena Zerbato
- Infectious Diseases
Unit, Trieste University Hospital
(ASUGI), Trieste,
Italy
| | - Luigi Principe
- Microbiology and
Virology Unit, Great Metropolitan Hospital
“Bianchi-Melacrino-Morelli”,
Reggio Calabria, Italy
| | - Mauro Giuffrè
- Clinical Department of
Medical, Surgical and Health Sciences, Trieste
University, Trieste,
Italy
- Department of Internal
Medicine (Digestive Diseases), Yale School of Medicine, Yale
University, New Haven,
Connecticut, USA
| | - Giuseppe Pipitone
- Infectious Diseases
Unit, ARNAS Civico-Di Cristina
Hospital, Palermo,
Italy
| | - Roberto Luzzati
- Clinical Department of
Medical, Surgical and Health Sciences, Trieste
University, Trieste,
Italy
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Zheng YM, Wu HY, Ye MM, Cai JY, Yuan Y, Xie WR, Xu JT, Liu T, He XX, Wu LH. Comparison of the use of a spiral nasojejunal tube and transendoscopic enteral tubing in washed microbiota transplantation via the mid-gut route. Heliyon 2024; 10:e30310. [PMID: 38742080 PMCID: PMC11089310 DOI: 10.1016/j.heliyon.2024.e30310] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2024] [Revised: 04/20/2024] [Accepted: 04/23/2024] [Indexed: 05/16/2024] Open
Abstract
Background Methods for washed microbiota transplantation (WMT) through the mid-gut include transendoscopic enteral tubing (TET) and manual spiral nasojejunal tube (SNT) placement have not been studied. Methods This prospective interventional study was performed at a single centre. Patients were divided into the SNT and mid-gut TET groups based on their conditions and wishes. In the SNT group, an SNT was passively inserted into the stomach, and abdominal X-rays were taken within 24 h to confirm tube placement in the small intestine. In the mid-gut TET group, mid-gut TET was placed in the small intestine for gastroscopy. Data on the clinical efficacy of WMT, intubation time, cost, overall comfort score, adverse reactions, etc., were collected from the two groups. Results Sixty-three patients were included in the study (SNT group (n = 40) and mid-gut TET group (n = 23)). The clinical efficacy of WMT in the SNT and mid-gut TET groups was 90 % and 95.7 %, respectively (P = 0.644). Compared with the mid-gut TET group, the SNT group showed a shorter operation time (120 s vs. 258 s, P = 0.001) and a lower average cost (641.7 yuan vs. 1702.1 yuan, P = 0.001). There was no significant difference in the overall comfort score or the incidence of common discomfort symptoms between the two groups. Conclusion The different implantation methods have different advantages; compared with mid-gut TET placement, manual SNT placement provides some benefits.
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Affiliation(s)
- Ya-Mei Zheng
- Department of Gastroenterology, The First Affiliated Hospital of Guangdong Pharmaceutical University, Research Center for Engineering Techniques of Microbiota-Targeted Therapies of Guangdong Province, Guangzhou, 510080, Guangdong Province, China
| | - Hui-Yi Wu
- Department of Gastroenterology, The First Affiliated Hospital of Guangdong Pharmaceutical University, Research Center for Engineering Techniques of Microbiota-Targeted Therapies of Guangdong Province, Guangzhou, 510080, Guangdong Province, China
| | - Meng-Meng Ye
- Department of Gastroenterology, The First Affiliated Hospital of Guangdong Pharmaceutical University, Research Center for Engineering Techniques of Microbiota-Targeted Therapies of Guangdong Province, Guangzhou, 510080, Guangdong Province, China
| | - Jie-Yi Cai
- Department of Gastroenterology, The First Affiliated Hospital of Guangdong Pharmaceutical University, Research Center for Engineering Techniques of Microbiota-Targeted Therapies of Guangdong Province, Guangzhou, 510080, Guangdong Province, China
| | - Yu Yuan
- Department of Gastroenterology, The First Affiliated Hospital of Guangdong Pharmaceutical University, Research Center for Engineering Techniques of Microbiota-Targeted Therapies of Guangdong Province, Guangzhou, 510080, Guangdong Province, China
| | - Wen-Rui Xie
- Department of Gastroenterology, The First Affiliated Hospital of Guangdong Pharmaceutical University, Research Center for Engineering Techniques of Microbiota-Targeted Therapies of Guangdong Province, Guangzhou, 510080, Guangdong Province, China
| | - Jia-Ting Xu
- Department of Gastroenterology, The First Affiliated Hospital of Guangdong Pharmaceutical University, Research Center for Engineering Techniques of Microbiota-Targeted Therapies of Guangdong Province, Guangzhou, 510080, Guangdong Province, China
| | - Tao Liu
- Department of Gastroenterology, The First Affiliated Hospital of Guangdong Pharmaceutical University, Research Center for Engineering Techniques of Microbiota-Targeted Therapies of Guangdong Province, Guangzhou, 510080, Guangdong Province, China
| | - Xing-Xiang He
- Department of Gastroenterology, The First Affiliated Hospital of Guangdong Pharmaceutical University, Research Center for Engineering Techniques of Microbiota-Targeted Therapies of Guangdong Province, Guangzhou, 510080, Guangdong Province, China
| | - Li-Hao Wu
- Department of Gastroenterology, The First Affiliated Hospital of Guangdong Pharmaceutical University, Research Center for Engineering Techniques of Microbiota-Targeted Therapies of Guangdong Province, Guangzhou, 510080, Guangdong Province, China
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Sadowsky MJ, Matson M, Mathai PP, Pho M, Staley C, Evert C, Weldy M, Khoruts A. Successful Treatment of Recurrent Clostridioides difficile Infection Using a Novel, Drinkable, Oral Formulation of Fecal Microbiota. Dig Dis Sci 2024; 69:1778-1784. [PMID: 38457115 DOI: 10.1007/s10620-024-08351-7] [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: 09/30/2023] [Accepted: 02/09/2024] [Indexed: 03/09/2024]
Abstract
BACKGROUND Fecal microbiota transplants can be administered orally in encapsulated form or require invasive procedures to administer liquid formulations. There is a need for an oral liquid formulation of fecal microbiota for patients who are unable to swallow capsules, especially if they require multiple, repeated administrations. AIMS These studies were conducted to develop a protocol to manufacture an organoleptically acceptable powdered fecal microbiota formulation that can be suspended in a liquid carrier and used for fecal microbiota transplantation. METHODS Several processing steps were investigated, including extra washes of microbiota prior to lyophilization and an addition of a flavoring agent. The viability of bacteria in the transplant formulation was tested using live/dead microscopy staining and engraftment into antibiotic-treated mice. After development of a clinical protocol for suspension of the powdered microbiota, the new formulation was tested in three elderly patients with recurrent Clostridioides difficile infections and who have difficulties in swallowing capsules. Changes in the microbial community structure in one of the patients were characterized using 16S rRNA gene profiling and engraftment analysis. RESULTS The processing steps used to produce an organoleptically acceptable suspension of powdered fecal microbiota did not result in loss of its viability. The powder could be easily suspended in a liquid carrier. The use of the new formulation was associated with abrogation of the cycle of C. difficile infection recurrences in the three patients. CONCLUSION We developed a novel organoleptically acceptable liquid formulation of fecal microbiota that is suitable for use in clinical trials for patients with difficulties in swallowing capsules.
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Affiliation(s)
- Michael J Sadowsky
- BioTechnology Institute, University of Minnesota, St. Paul, MN, USA
- Department of Soil, Water, and Climate, Department of Plant and Microbial Biology, University of Minnesota, St. Paul, MN, USA
- Department of Medicine, Division of Gastroenterology, Hepatology, and Nutrition, University of Minnesota, 3-184 Wallin Medical BioSciences Building, 2101 6th St. S.E., Minneapolis, MN, 55416, USA
| | - Michael Matson
- Department of Medicine, Division of Gastroenterology, Hepatology, and Nutrition, University of Minnesota, 3-184 Wallin Medical BioSciences Building, 2101 6th St. S.E., Minneapolis, MN, 55416, USA
| | - Prince P Mathai
- BioTechnology Institute, University of Minnesota, St. Paul, MN, USA
| | - Maradi Pho
- Department of Medicine, Division of Gastroenterology, Hepatology, and Nutrition, University of Minnesota, 3-184 Wallin Medical BioSciences Building, 2101 6th St. S.E., Minneapolis, MN, 55416, USA
| | - Christopher Staley
- BioTechnology Institute, University of Minnesota, St. Paul, MN, USA
- Department of Surgery, Division of Basic and Translational Research, University of Minnesota, Minneapolis, MN, USA
| | - Clayton Evert
- Department of Medicine, Division of Gastroenterology, Hepatology, and Nutrition, University of Minnesota, 3-184 Wallin Medical BioSciences Building, 2101 6th St. S.E., Minneapolis, MN, 55416, USA
| | - Melissa Weldy
- Department of Medicine, Division of Gastroenterology, Hepatology, and Nutrition, University of Minnesota, 3-184 Wallin Medical BioSciences Building, 2101 6th St. S.E., Minneapolis, MN, 55416, USA
| | - Alexander Khoruts
- BioTechnology Institute, University of Minnesota, St. Paul, MN, USA.
- Department of Medicine, Division of Gastroenterology, Hepatology, and Nutrition, University of Minnesota, 3-184 Wallin Medical BioSciences Building, 2101 6th St. S.E., Minneapolis, MN, 55416, USA.
- Center for Immunology, University of Minnesota, Minneapolis, MN, USA.
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Monday L, Tillotson G, Chopra T. Microbiota-Based Live Biotherapeutic Products for Clostridioides Difficile Infection- The Devil is in the Details. Infect Drug Resist 2024; 17:623-639. [PMID: 38375101 PMCID: PMC10876012 DOI: 10.2147/idr.s419243] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2023] [Accepted: 02/12/2024] [Indexed: 02/21/2024] Open
Abstract
Clostridioides difficile infection (CDI) remains a significant contributor to healthcare costs and morbidity due to high rates of recurrence. Currently, available antibiotic treatment strategies further disrupt the fecal microbiome and do not address the alterations in commensal flora (dysbiosis) that set the stage for CDI. Advances in microbiome-based research have resulted in the development of new agents, classified as live biotherapeutic products (LBPs), for preventing recurrent CDI (rCDI) by restoring eubiosis. Prior to the LBPs, fecal microbiota transplantation (FMT) was available for this purpose; however, lack of large-scale availability and safety concerns have remained barriers to its widespread use. The LBPs are an exciting development, but questions remain. Some are derived directly from human stool while other developmental products contain a defined microbial consortium manufactured ex vivo, and they may be composed of either living bacteria or their spores, making it difficult to compare members of this heterogenous drug class to one another. None have been studied head-to head or against FMT in preventing rCDI. As a class, they have considerable variability in their biologic composition, biopharmaceutic science, route of administration, stages of development, and clinical trial data. This review will start by explaining the role of dysbiosis in CDI, then give the details of the biopharmaceutical components for the LBPs which are approved or in development including how they differ from FMT and from one another. We then discuss the clinical trials of the LBPs currently approved for rCDI and end with the future clinical directions of LBPs beyond C. difficile.
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Affiliation(s)
- Lea Monday
- Division of Infectious Diseases, Wayne State University School of Medicine, Detroit, MI, USA
| | | | - Teena Chopra
- Division of Infectious Diseases, Wayne State University School of Medicine, Detroit, MI, USA
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Zhou X, Chen R, Cai Y, Chen Q. Fecal Microbiota Transplantation: A Prospective Treatment for Type 2 Diabetes Mellitus. Diabetes Metab Syndr Obes 2024; 17:647-659. [PMID: 38347911 PMCID: PMC10860394 DOI: 10.2147/dmso.s447784] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/01/2023] [Accepted: 01/23/2024] [Indexed: 02/15/2024] Open
Abstract
Purpose of Review The aim of this review is to summarize the role of gastrointestinal microbiome (GM) in the development of type 2 diabetes mellitus (T2DM). Besides, we discuss the feasibility of applying FMT in the treatment of T2DM and propose a series of processes to refine the use of FMT in the treatment of T2DM. Recent Findings T2DM is a metabolic disease which is connected with the GM. According to many researches, GM can produce a variety of metabolites such as bile acid, short chain fatty acids, lipopolysaccharides and trimethylamine oxide which play an important role in metabolism. FMT is a method to regulate GM and has been observed to be effective in the treatment of metabolic diseases such as T2DM in some mouse models and people. However, there is still a lack of direct evidence for the use of FMT in the treatment of T2DM, and the process of FMT is not standardized. Summary Dysregulation of GM is closely related to the development of T2DM. Promoting the conversion of GM in T2DM patients to normal population through FMT can reduce insulin resistance and lower their blood glucose level, which is an optional treatment for T2DM patients in the future. At present, the feasibility and limitations of applying FMT to the treatment of T2DM need to be further studied.
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Affiliation(s)
- Xiaolan Zhou
- Department of Endocrinology, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, People’s Republic of China
| | - Rumeng Chen
- School of Life Sciences, Beijing University of Chinese Medicine, Beijing, People’s Republic of China
| | - Yichen Cai
- Department of Endocrinology, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, People’s Republic of China
| | - Qiu Chen
- Department of Endocrinology, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, People’s Republic of China
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Abstract
Antibiotics have benefitted human health since their introduction nearly a century ago. However, the rise of antibiotic resistance may portend the dawn of the "post-antibiotic age." With the narrow pipeline for novel antimicrobials, we need new approaches to deal with the rise of multidrug resistant organisms. In the last 2 decades, the role of the intestinal microbiota in human health has been acknowledged and studied widely. Of the various activities carried out by the gut microbiota, colonization resistance is a key function that helps maintain homeostasis. Therefore, re-establishing a healthy microbiota is a novel strategy for treating drug resistance organisms. Preliminary studies suggest that this is a viable approach. However, the extent of their success still needs to be examined. Herein, we will review work in this area and suggest where future studies can further investigate this method for dealing with the threat of antibiotic resistance.
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Affiliation(s)
- Nguyen T Q Nhu
- Division of Infectious Diseases, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA
| | - Vincent B Young
- Division of Infectious Diseases, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA
- Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, Michigan, USA
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12
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Schneemann M, Heils L, Moos V, Weiß F, Krug SM, Weiner J, Beule D, Gerhard R, Schulzke JD, Bücker R. A Colonic Organoid Model Challenged with the Large Toxins of Clostridioides difficile TcdA and TcdB Exhibit Deregulated Tight Junction Proteins. Toxins (Basel) 2023; 15:643. [PMID: 37999506 PMCID: PMC10674794 DOI: 10.3390/toxins15110643] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2023] [Revised: 10/25/2023] [Accepted: 11/01/2023] [Indexed: 11/25/2023] Open
Abstract
BACKGROUND Clostridioides difficile toxins TcdA and TcdB are responsible for diarrhea and colitis. Lack of functional studies in organoid models of the gut prompted us to elucidate the toxin's effects on epithelial barrier function and the molecular mechanisms for diarrhea and inflammation. METHODS Human adult colon organoids were cultured on membrane inserts. Tight junction (TJ) proteins and actin cytoskeleton were analyzed for expression via Western blotting and via confocal laser-scanning microscopy for subcellular localization. RESULTS Polarized intestinal organoid monolayers were established from stem cell-containing colon organoids to apply toxins from the apical side and to perform functional measurements in the organoid model. The toxins caused a reduction in transepithelial electrical resistance in human colonic organoid monolayers with sublethal concentrations. Concomitantly, we detected increased paracellular permeability fluorescein and FITC-dextran-4000. Human colonic organoid monolayers exposed to the toxins exhibited redistribution of barrier-forming TJ proteins claudin-1, -4 and tricellulin, whereas channel-forming claudin-2 expression was increased. Perijunctional F-actin cytoskeleton organization was affected. CONCLUSIONS Adult stem cell-derived human colonic organoid monolayers were applicable as a colon infection model for electrophysiological measurements. The TJ changes noted can explain the epithelial barrier dysfunction and diarrhea in patients, as well as increased entry of luminal antigens triggering inflammation.
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Affiliation(s)
- Martina Schneemann
- Clinical Physiology, Nutritional Medicine, Charité—Universitätsmedizin Berlin, Campus Benjamin Franklin, 12203 Berlin, Germany
| | - Lucas Heils
- Clinical Physiology, Nutritional Medicine, Charité—Universitätsmedizin Berlin, Campus Benjamin Franklin, 12203 Berlin, Germany
| | - Verena Moos
- Department of Gastroenterology, Infectious Diseases and Rheumatology, Charité—Universitätsmedizin Berlin, Campus Benjamin Franklin, 12203 Berlin, Germany
| | - Franziska Weiß
- Clinical Physiology, Nutritional Medicine, Charité—Universitätsmedizin Berlin, Campus Benjamin Franklin, 12203 Berlin, Germany
| | - Susanne M. Krug
- Clinical Physiology, Nutritional Medicine, Charité—Universitätsmedizin Berlin, Campus Benjamin Franklin, 12203 Berlin, Germany
| | - January Weiner
- Core Unit Bioinformatics (CUBI), Berlin Institute of Health at Charité—Universitätsmedizin Berlin, 10117 Berlin, Germany
| | - Dieter Beule
- Core Unit Bioinformatics (CUBI), Berlin Institute of Health at Charité—Universitätsmedizin Berlin, 10117 Berlin, Germany
| | - Ralf Gerhard
- Institute of Toxicology, Hannover Medical School, 30625 Hannover, Germany
| | - Jörg-Dieter Schulzke
- Clinical Physiology, Nutritional Medicine, Charité—Universitätsmedizin Berlin, Campus Benjamin Franklin, 12203 Berlin, Germany
| | - Roland Bücker
- Clinical Physiology, Nutritional Medicine, Charité—Universitätsmedizin Berlin, Campus Benjamin Franklin, 12203 Berlin, Germany
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Ferar K, Hall TO, Crawford DC, Rowley R, Satterfield BA, Li R, Gragert L, Karlson EW, de Andrade M, Kullo IJ, McCarty CA, Kho A, Hayes MG, Ritchie MD, Crane PK, Mirel DB, Carlson C, Connolly JJ, Hakonarson H, Crenshaw AT, Carrell D, Luo Y, Dikilitas O, Denny JC, Jarvik GP, Crosslin DR. Genetic variation in the human leukocyte antigen region confers susceptibility to Clostridioides difficile infection. Sci Rep 2023; 13:18532. [PMID: 37898691 PMCID: PMC10613277 DOI: 10.1038/s41598-023-45649-4] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2022] [Accepted: 10/22/2023] [Indexed: 10/30/2023] Open
Abstract
Clostridioides difficile (C. diff.) infection (CDI) is a leading cause of hospital acquired diarrhea in North America and Europe and a major cause of morbidity and mortality. Known risk factors do not fully explain CDI susceptibility, and genetic susceptibility is suggested by the fact that some patients with colons that are colonized with C. diff. do not develop any infection while others develop severe or recurrent infections. To identify common genetic variants associated with CDI, we performed a genome-wide association analysis in 19,861 participants (1349 cases; 18,512 controls) from the Electronic Medical Records and Genomics (eMERGE) Network. Using logistic regression, we found strong evidence for genetic variation in the DRB locus of the MHC (HLA) II region that predisposes individuals to CDI (P > 1.0 × 10-14; OR 1.56). Altered transcriptional regulation in the HLA region may play a role in conferring susceptibility to this opportunistic enteric pathogen.
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Affiliation(s)
- Kathleen Ferar
- Department of Biomedical Informatics and Medical Education, University of Washington, Seattle, WA, USA.
| | - Taryn O Hall
- Optum Genomics, UnitedHealth Group, Minnetonka, MN, USA
| | - Dana C Crawford
- Department of Population and Quantitative Health Sciences, Cleveland Institute for Computational Biology, Case Western Reserve University, Cleveland, OH, USA
- Department of Genetics and Genome Sciences, Cleveland Institute for Computational Biology, Case Western Reserve University, Cleveland, OH, USA
| | - Robb Rowley
- National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA
| | | | - Rongling Li
- National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA
| | - Loren Gragert
- Division of Biomedical Informatics and Genomics, John W. Deming Department of Medicine, Tulane University School of Medicine, New Orleans, LA, USA
| | | | - Mariza de Andrade
- Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, MN, USA
| | - Iftikhar J Kullo
- Department of Cardiovascular Diseases, Mayo Clinic, Rochester, MN, USA
| | - Catherine A McCarty
- University of Minnesota Medical School, Duluth, MN, USA
- Center for Human Genetics, Marshfield Clinic Research Foundation, Marshfield, WI, USA
| | - Abel Kho
- Divisions of General Internal Medicine and Preventive Medicine, Northwestern University, Chicago, IL, USA
| | - M Geoffrey Hayes
- Division of Endocrinology, Metabolism, and Molecular Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA
| | - Marylyn D Ritchie
- Department of Biochemistry and Molecular Biology, Center for Systems Genomics, Pennsylvania State University, University Park, PA, USA
| | - Paul K Crane
- Division of General Internal Medicine, University of Washington, Seattle, WA, USA
| | | | - Christopher Carlson
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
| | - John J Connolly
- Center for Applied Genomics, The Children's Hospital of Philadelphia, Philadelphia, PA, USA
| | - Hakon Hakonarson
- Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, PA, USA
| | | | - David Carrell
- Kaiser Permanente Washington Health Research Institute, Seattle, WA, USA
| | - Yuan Luo
- Northwestern University Feinberg School of Medicine, Chicago, IL, USA
| | - Ozan Dikilitas
- Department of Cardiovascular Diseases, Mayo Clinic, Rochester, MN, USA
| | - Joshua C Denny
- Department of Biomedical Informatics, Vanderbilt University, Nashville, TN, USA
| | - Gail P Jarvik
- Department of Medicine (Medical Genetics), University of Washington Medical Center, Seattle, WA, USA
| | - David R Crosslin
- Division of Biomedical Informatics and Genomics, John W. Deming Department of Medicine, Tulane University School of Medicine, New Orleans, LA, USA.
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Feuerstadt P, Oneto C, Tillotson G, Van Hise NW. Patient Perception of Route of Rectal Administration of Live Biotherapeutic Product for Recurrent Clostridioides difficile Infection. Patient Prefer Adherence 2023; 17:2153-2159. [PMID: 37667688 PMCID: PMC10475298 DOI: 10.2147/ppa.s415681] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/04/2023] [Accepted: 08/19/2023] [Indexed: 09/06/2023] Open
Abstract
Introduction CDI is a recurrent disease that is treated with antibiotics, but patients commonly experience repeat infections with significant impacts on hospital budgets and patient health quality. Standard of care management includes the antibiotics, vancomycin and fidaxomicin, which frequently provide clinical response, but do not avoid recurrence of Clostridioides difficile infection (rCDI). These recurrent infections occur due to dysbiosis of the colonic microbiota. One adjunctive therapeutic approach is to restore the deficient gastrointestinal flora using fecal microbiota transplantation (FMT) or live biotherapeutic products (LBP) when given after standard of care antimicrobials, which have been successful in reducing repeat infections with success rates up to 88%. FMT or LBP can be given by various routes. Methods Two groups of subjects aged ≥18 years with at least one previous CDI episode within the previous 36 months completed self-administered online surveys to assess the acceptability of an LBP administered rectally. Group 1 consisted of LBP-recipients who had received RBL (REBYOTA) rectally as part of the Phase III PUNCH CD3 clinical trial. Group 2 consisted of LBP-naïve subjects who volunteered to participate and had experienced CDI within the prior 36 months but had no history of receiving FMT or LBP therapy. Results LBP-recipients considered rectal administration easy (96%) and quick (94%), while 98% of respondents considered the lack of need for bowel preparation appealing. Most LBP-recipients (96%) wished they had earlier access to RBL. Most LBP-naïve subjects (87%) were likely or somewhat likely to consider a rectally administered treatment and 80% preferred a treatment option that does not require bowel preparation. Many of these subjects (76%) expressed interest in finding out about new treatment options for rCDI. Discussion LBP-recipients and LBP-naïve subjects alike felt that rectal delivery of microbiome therapy is not only acceptable but highly interesting as a treatment avenue.
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Affiliation(s)
- Paul Feuerstadt
- Division of Digestive Disease, Yale School of Medicine, New Haven, CT, USA
- PACT Gastroenterology Center, Hamden, CT, USA
| | - Caterina Oneto
- Department of Medicine, New York University Langone, New York, NY, USA
- Vanguard Gastroenterology, New York, NY, USA
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MacNair CR, Tsai CN, Rutherford ST, Tan MW. Returning to Nature for the Next Generation of Antimicrobial Therapeutics. Antibiotics (Basel) 2023; 12:1267. [PMID: 37627687 PMCID: PMC10451936 DOI: 10.3390/antibiotics12081267] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2023] [Revised: 07/29/2023] [Accepted: 07/30/2023] [Indexed: 08/27/2023] Open
Abstract
Antibiotics found in and inspired by nature are life-saving cures for bacterial infections and have enabled modern medicine. However, the rise in resistance necessitates the discovery and development of novel antibiotics and alternative treatment strategies to prevent the return to a pre-antibiotic era. Once again, nature can serve as a source for new therapies in the form of natural product antibiotics and microbiota-based therapies. Screening of soil bacteria, particularly actinomycetes, identified most of the antibiotics used in the clinic today, but the rediscovery of existing molecules prompted a shift away from natural product discovery. Next-generation sequencing technologies and bioinformatics advances have revealed the untapped metabolic potential harbored within the genomes of environmental microbes. In this review, we first highlight current strategies for mining this untapped chemical space, including approaches to activate silent biosynthetic gene clusters and in situ culturing methods. Next, we describe how using live microbes in microbiota-based therapies can simultaneously leverage many of the diverse antimicrobial mechanisms found in nature to treat disease and the impressive efficacy of fecal microbiome transplantation and bacterial consortia on infection. Nature-provided antibiotics are some of the most important drugs in human history, and new technologies and approaches show that nature will continue to offer valuable inspiration for the next generation of antibacterial therapeutics.
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Affiliation(s)
- Craig R. MacNair
- Department of Infectious Diseases, Genentech Inc., South San Francisco, CA 94080, USA;
| | - Caressa N. Tsai
- School of Law, University of California, Berkeley, Berkeley, CA 94704, USA;
| | - Steven T. Rutherford
- Department of Infectious Diseases, Genentech Inc., South San Francisco, CA 94080, USA;
| | - Man-Wah Tan
- Department of Infectious Diseases, Genentech Inc., South San Francisco, CA 94080, USA;
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16
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Fecal Microbiota Transplantation Research over the Past Decade: Current Status and Trends. THE CANADIAN JOURNAL OF INFECTIOUS DISEASES & MEDICAL MICROBIOLOGY = JOURNAL CANADIEN DES MALADIES INFECTIEUSES ET DE LA MICROBIOLOGIE MEDICALE 2023; 2023:6981721. [PMID: 36654766 PMCID: PMC9842422 DOI: 10.1155/2023/6981721] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 10/25/2022] [Revised: 11/28/2022] [Accepted: 12/29/2022] [Indexed: 01/11/2023]
Abstract
Background Fecal microbiota transplantation (FMT) is a current research hotspot, with a surge in the output of publications over the past decade. This study dedicates to the exploration of the research status and highlights significant themes and future trends in FMT research with the aid of bibliometric analysis. Methods FMT publications from 2012 to 2021 were retrieved on August 12, 2022, using the SCI-Expanded of Web of Science (WoS). The Bibliometrix in R program, Microsoft Office Excel, VOSviewer, and CiteSpace were utilized for bibliometrics and visual analysis, revealing the main publications, journals, countries, agencies, authors, and keywords distribution in FMT research. Results There were 2,931 papers included. FMT research presented a growing trend from 2012 to 2021. The countries with the most publications and contributions in FMT area were China and the United States. The high-yield institutions were Harvard University, Udice French Research Universities, and the University of California System. The primary authors were Nieuwdorp Max, Allegretti Jessica R, and Kassam Zain. Frontiers in Microbiology and Science were the top-ranked journals in publications and total citations, respectively. The important topics primarily included FMT-related mechanisms and the usage of FMT in Clostridium difficile infection (CDI), inflammatory bowel disease (IBD), irritable bowel syndrome (IBS), metabolic disease, neurological disorders, and psychiatric disorders. Future research would primarily concentrate on neurological disorders, chemotherapy and immunotherapy for malignant tumors, and FMT-related consensus and guidelines. Conclusion With the help of bibliometric analysis, we were able to obtain the understanding of the status and trends of global FMT-related research. The field of FMT is undergoing tremendous progress, and our findings can guide clinical researchers' and practitioners' future work in the rapidly evolving field of FMT.
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Siddiqui R, Mungroo MR, Alharbi AM, Alfahemi H, Khan NA. The Use of Gut Microbial Modulation Strategies as Interventional Strategies for Ageing. Microorganisms 2022; 10:microorganisms10091869. [PMID: 36144471 PMCID: PMC9506335 DOI: 10.3390/microorganisms10091869] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2022] [Revised: 09/07/2022] [Accepted: 09/14/2022] [Indexed: 11/16/2022] Open
Abstract
Gut microbial composition codevelops with the host from birth and is influenced by several factors, including drug use, radiation, psychological stress, dietary changes and physical stress. Importantly, gut microbial dysbiosis has been clearly associated with several diseases, including cancer, rheumatoid arthritis and Clostridium difficile-associated diarrhoea, and is known to affect human health and performance. Herein, we discuss that a shift in the gut microbiota with age and reversal of age-related modulation of the gut microbiota could be a major contributor to the incidence of numerous age-related diseases or overall human performance. In addition, it is suggested that the gut microbiome of long-lived animals such as reptiles should be investigated for their unique properties and contribution to the potent defense system of these species could be extrapolated for the benefit of human health. A range of techniques can be used to modulate the gut microbiota to have higher abundance of “beneficial” microbes that have been linked with health and longevity.
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Affiliation(s)
- Ruqaiyyah Siddiqui
- College of Arts and Sciences, American University of Sharjah, Sharjah P.O. Box 26666, United Arab Emirates
| | - Mohammad Ridwane Mungroo
- Department of Clinical Sciences, College of Medicine, University of Sharjah, Sharjah P.O. Box 27272, United Arab Emirates
| | - Ahmad M. Alharbi
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Taif University, Taif 21944, Saudi Arabia
| | - Hasan Alfahemi
- Department of Medical Microbiology, Faculty of Medicine, Al-Baha University, Al-Baha 65799, Saudi Arabia
| | - Naveed Ahmed Khan
- Department of Clinical Sciences, College of Medicine, University of Sharjah, Sharjah P.O. Box 27272, United Arab Emirates
- Correspondence:
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Pavanello A, Martins IP, Tófolo LP, Previate C, Matiusso CCI, Francisco FA, Prates KV, Alves VS, de Almeida DL, Ribeiro TA, Malta A, Mathias PCDF. Fecal Microbiota Transplantation During Lactation Programs the Metabolism of Adult Wistar Rats in a Sex-specific Way. Arch Med Res 2022; 53:492-500. [PMID: 35840468 DOI: 10.1016/j.arcmed.2022.06.007] [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: 01/31/2022] [Revised: 05/27/2022] [Accepted: 06/30/2022] [Indexed: 11/02/2022]
Abstract
BACKGROUND The intestinal microbiota is involved in many physiological processes. However, the effects of microbiota in metabolic programming still unknow. We evaluated whether the transplantation of fecal microbiota during early life can program health or disease during adulthood in a model of lean and obese male and female Wistar rats. METHODS Parental obesity were induced using a small litter (SL, 3 pups/dam) model. At 90 d old, normal litter (NL, 9 pups/dam) and SL males and females (parents) from different litters were mated: NL male vs. NL female; SL male vs. SL female. After birth, male and female offspring rats were also standardized in normal litters or small litters . From the 10th until 25th d of life, the NL and SL male and female offspring received via gavage of a solution containing the diluted feces of the opposite dam (fecal microbiota, M) or saline solution (S). At 90 d of age, biometric and biochemical parameters were assessed. RESULTS NLM male rats transplanted with obese microbiota showed increased body weight, and fat pad deposition, hyperinsulinemia, glucose intolerance and dyslipidemia. SLM male rats transplanted with lean microbiota had decreased retroperitoneal and mesenteric fat, triglycerides and VLDL levels and improvement of glucose tolerance. Despite SLM female rats showed higher visceral fat, microbiota transplantation in female rats caused no changes in these parameters compared with control groups. CONCLUSION Fecal microbiota transplantation during lactation induces long-term effects on the metabolism of male Wistar rats. However, female rats were resistant to metabolic alterations caused by the treatment.
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Affiliation(s)
- Audrei Pavanello
- Department of Biotechnology, Genetics, and Cellular Biology, State University of Maringá, Maringá, PR, Brazil
| | - Isabela Peixoto Martins
- Department of Biotechnology, Genetics, and Cellular Biology, State University of Maringá, Maringá, PR, Brazil; Departament of Morphological Sciences, State University of Maringá, Maringá, PR, Brazil
| | - Laize Peron Tófolo
- Department of Biotechnology, Genetics, and Cellular Biology, State University of Maringá, Maringá, PR, Brazil
| | - Carina Previate
- Department of Biotechnology, Genetics, and Cellular Biology, State University of Maringá, Maringá, PR, Brazil
| | | | - Flávio Andrade Francisco
- Department of Biotechnology, Genetics, and Cellular Biology, State University of Maringá, Maringá, PR, Brazil
| | - Kelly Valério Prates
- Department of Biotechnology, Genetics, and Cellular Biology, State University of Maringá, Maringá, PR, Brazil
| | - Vander Silva Alves
- Department of Biotechnology, Genetics, and Cellular Biology, State University of Maringá, Maringá, PR, Brazil
| | - Douglas Lopes de Almeida
- Department of Biotechnology, Genetics, and Cellular Biology, State University of Maringá, Maringá, PR, Brazil
| | - Tatiane Aparecida Ribeiro
- Department of Biotechnology, Genetics, and Cellular Biology, State University of Maringá, Maringá, PR, Brazil; Department of Biochemistry and Biomedical Science, McMaster University-Hamilton ON Canada
| | - Ananda Malta
- Department of Biotechnology, Genetics, and Cellular Biology, State University of Maringá, Maringá, PR, Brazil.
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Cruz N, Abernathy GA, Dichosa AEK, Kumar A. The Age of Next-Generation Therapeutic-Microbe Discovery: Exploiting Microbe-Microbe and Host-Microbe Interactions for Disease Prevention. Infect Immun 2022; 90:e0058921. [PMID: 35384688 PMCID: PMC9119102 DOI: 10.1128/iai.00589-21] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Humans are considered "superorganisms," harboring a diverse microbial collective that outnumbers human cells 10 to 1. Complex and gravely understudied host- and microbe-microbe interactions-the product of millions of years of host-microbe coevolution-govern the superorganism in almost every aspect of life functions and overall well-being. Abruptly disrupting these interactions via extrinsic factors has undesirable consequences for the host. On the other hand, supplementing commensal or beneficial microbes may mitigate perturbed interactions or enhance the interactive relationships that ultimately benefit all parties. Hence, immense efforts have focused on dissecting the innumerable host- and microbe-microbe relationships to characterize if a "positive" or "negative" interaction is at play and to exploit such behavior for broader implications. For example, microbiome research has worked to identify and isolate naturally antipathogenic microbes that may offer therapeutic potential either in a direct, one-on-one application or by leveraging its unique metabolic properties. However, the discovery and isolation of such desired therapeutic microbes from complex microbiota have proven challenging. Currently, there is no conventional technique to universally and functionally screen for these microbes. With this said, we first describe in this review the historical (probiotics) and current (fecal microbiota or defined consortia) perspectives on therapeutic microbes, present the discoveries of therapeutic microbes through exploiting microbe-microbe and host-microbe interactions, and detail our team's efforts in discovering therapeutic microbes via our novel microbiome screening platform. We conclude this minireview by briefly discussing challenges and possible solutions with therapeutic microbes' applications and paths ahead for discovery.
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Affiliation(s)
- Nathan Cruz
- B-10: Biosecurity and Public Health Group, Bioscience Division, Los Alamos National Laboratory, Los Alamos, New Mexico, USA
| | - George A. Abernathy
- B-10: Biosecurity and Public Health Group, Bioscience Division, Los Alamos National Laboratory, Los Alamos, New Mexico, USA
| | - Armand E. K. Dichosa
- B-10: Biosecurity and Public Health Group, Bioscience Division, Los Alamos National Laboratory, Los Alamos, New Mexico, USA
| | - Anand Kumar
- B-10: Biosecurity and Public Health Group, Bioscience Division, Los Alamos National Laboratory, Los Alamos, New Mexico, USA
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Gupta K, Tappiti M, Nazir AM, Koganti B, Memon MS, Aslam Zahid MB, Shantha Kumar V, Mostafa JA. Fecal Microbiota Transplant in Recurrent Clostridium Difficile Infections: A Systematic Review. Cureus 2022; 14:e24754. [PMID: 35693372 PMCID: PMC9174020 DOI: 10.7759/cureus.24754] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2021] [Accepted: 05/05/2022] [Indexed: 11/10/2022] Open
Abstract
Fecal Microbiota Transplantation (FMT) is the process of transferring the fecal microbiome from a healthy donor to an individual with repeated multiple episodes of Clostridium difficile infection. It is also known as stool transplant. Fecal microbiota transplant is effective and safe in various studies, the approval from the Food and Drug Administration (FDA) remains pending. The main objective of this systemic review is to evaluate the efficacy and safety of stool transplant in studies with only treatment groups (FMT) and studies with treatment (FMT) and antibiotic (AB) groups and previous studies. Online databases PubMed, PubMed Central, Science Direct, Google Scholar, and Embase were searched for relevant articles in the last five years (2016 to 2021) using automation tools. Following the removal of duplicates, screening of eligibility criteria, titles/abstracts, and quality appraisal were done by two authors independently. In total, seven observational studies are in this review article. Out of the seven observational studies, five are retrospective and two prospective. Two of the five retrospective and one of two prospective studies have a control group. In both the prospective studies and one retrospective study, FMT efficacy of (68% to 93%) was demonstrated in the elderly population despite high index comorbidities. In the younger individuals with inflammatory bowel disease, and efficacy of 90% or above was found. The most common side effects were minor such as fever, abdominal pain, bloating, and flatulence. In one study, two cases of aspiration events occurred attributed to the gastroscopy route of donor feces delivery. There was no statistical significance in the incidence of diseases such as (allergies, autoimmune diseases, cancer, inflammatory bowel diseases, and neurological diseases like dementia and migraine). Fecal microbiota transplantation has shown to be effective and safe in recurrent Clostridium difficile infections. Since very few pragmatic studies have demonstrated its efficacy and safety, their application is not well established. Robust studies, both observation and experiment, are required in the future to well-establish its effectiveness, safety in the treatment of recurrent Clostridium difficile infection.
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Gweon TG, Lee YJ, Kim KO, Yim SK, Soh JS, Kim SY, Park JJ, Shin SY, Lee TH, Choi CH, Cho YS, Yong D, Chung JW, Lee KJ, Lee OY, Choi MG, Choi M, Gut Microbiota Therapy Research Group Under the Korean Society of Neurogastroenterology Motility. Clinical Practice Guidelines for Fecal Microbiota Transplantation in Korea. J Neurogastroenterol Motil 2022; 28:28-42. [PMID: 34980687 PMCID: PMC8748844 DOI: 10.5056/jnm21221] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/16/2021] [Accepted: 12/08/2021] [Indexed: 12/05/2022] Open
Abstract
Fecal microbiota transplantation (FMT) is a highly efficacious and safe modality for the treatment of recurrent or refractory Clostridioides difficile infection (CDI), with overall success rates of 90%. Thus, FMT has been widely used for 10 years. The incidence and clinical characteristics of CDI, the main indication for FMT, differ between countries. To date, several guidelines have been published. However, most of them were published in Western countries and therefore cannot represent the Korean national healthcare systems. One of the barriers to performing FMT is a lack of national guidelines. Accordingly, multidisciplinary experts in this field have developed practical guidelines for FMT. The purpose of these guidelines is to aid physicians performing FMT, which can be adapted to treat CDI and other conditions.
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Affiliation(s)
- Tae-Geun Gweon
- Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Yoo Jin Lee
- Department of Internal Medicine, Keimyung University School of Medicine, Daegu, Korea
| | - Kyeong Ok Kim
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Yeungnam University College of Medicine, Daegu, Korea
| | - Sung Kyun Yim
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Jeonbuk National University Medical School and Hospital, Jeonju, Jeollabuk-do, Korea
| | - Jae Seung Soh
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of Hallym College of Medicine, Hallym University, Anyang, Gyeonggi-do, Korea
| | - Seung Young Kim
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Jeonbuk National University Medical School, Jeonju, Jeollabuk-do, Korea
| | - Jae Jun Park
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
| | - Seung Yong Shin
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Chung-Ang University College of Medicine, Seoul, Korea
| | - Tae Hee Lee
- Institute for Digestive Research, Digestive Disease Center, Soonchunhyang University College of Medicine, Seoul, Korea
| | - Chang Hwan Choi
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Chung-Ang University College of Medicine, Seoul, Korea
| | - Young-Seok Cho
- Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Dongeun Yong
- Department of Laboratory Medicine and Research Institute of Bacterial Resistance, Yonsei University College of Medicine, Seoul, Korea
| | - Jin-Won Chung
- Division of Infectious Diseases, Department of Internal Medicine, Chung-Ang University College of Medicine, Seoul, Korea
| | - Kwang Jae Lee
- Department of Internal Medicine, Ajou University School of Medicine, Suwon, Gyeonggi-do, Korea
| | - Oh Young Lee
- Department of Internal Medicine, Hanyang University School of Medicine, Seoul, Korea
| | - Myung-Gyu Choi
- Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Miyoung Choi
- Division of Healthcare Technology Assessment Research, National Evidence-Based Healthcare Collaboration Agency, Seoul, Korea
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22
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Requena T, Pérez Martínez G. Probiotics, Prebiotics, Synbiotics, Postbiotics and Other Biotics. What's Next? COMPREHENSIVE GUT MICROBIOTA 2022:197-210. [DOI: 10.1016/b978-0-12-819265-8.00094-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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23
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Popa D, Neamtu B, Mihalache M, Boicean A, Banciu A, Banciu DD, Moga DFC, Birlutiu V. Fecal Microbiota Transplant in Severe and Non-Severe Clostridioides difficile Infection. Is There a Role of FMT in Primary Severe CDI? J Clin Med 2021; 10:jcm10245822. [PMID: 34945118 PMCID: PMC8707415 DOI: 10.3390/jcm10245822] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2021] [Revised: 11/20/2021] [Accepted: 12/07/2021] [Indexed: 11/23/2022] Open
Abstract
Background: Faecal microbiota transplant (FMT) is a highly effective therapy for recurrent Clostridioides difficile infection (rCDI) with cure rates ranging between 85 and 92%. The FMT role for primary Clostridioides difficile infection (CDI) has yet to be settled because of limited data and small-sample studies presented in the current literature. Our study goals were to report the risk factors and the risk of recurrence after FMT for each CDI episode (first, second, and third) and to explore if there is a role of FMT in primary severe CDI. Methods: We conducted a retrospective study to analyze the clinical characteristics and the outcomes of 96 FMT patients with a prior 10 day course of antibiotic treatment in the medical records, of which 71 patients with recurrent CDI and 25 patients with a primary CDI. Results: The overall primary cure rate in our study was 88.5% and the primary cure rate for the severe forms was 85.7%. The data analysis revealed 5.25%, 15.15%, and 27.3% FMT recurrence rates for primary, secondary, and tertiary severe CDI. The risk of recurrence was significantly associated with FMT after the second and the third CDI severe episodes (p < 0.05), but not with FMT after the first severe CDI episode. Conclusions: This study brings new data in supporting the FMT role in CDI treatment, including the primary severe CDI, however, further prospective and controlled studies on larger cohorts should be performed in this respect.
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Affiliation(s)
- Daniel Popa
- Faculty of Medicine, Lucian Blaga University of Sibiu, 550169 Sibiu, Romania; (D.P.); (M.M.); (A.B.); (D.F.C.M.); (V.B.)
- Dr. Alexandru Augustin Military Hospital of Sibiu, 550024 Sibiu, Romania
- Polisano Clinic Sibiu, 550253 Sibiu, Romania
| | - Bogdan Neamtu
- Faculty of Medicine, Lucian Blaga University of Sibiu, 550169 Sibiu, Romania; (D.P.); (M.M.); (A.B.); (D.F.C.M.); (V.B.)
- Pediatric Research Department, Pediatric Clinical Hospital Sibiu, 550166 Sibiu, Romania
- Correspondence: ; Tel.: +40-773994375
| | - Manuela Mihalache
- Faculty of Medicine, Lucian Blaga University of Sibiu, 550169 Sibiu, Romania; (D.P.); (M.M.); (A.B.); (D.F.C.M.); (V.B.)
- County Clinical Emergency Hospital of Sibiu, 550245 Sibiu, Romania
| | - Adrian Boicean
- Faculty of Medicine, Lucian Blaga University of Sibiu, 550169 Sibiu, Romania; (D.P.); (M.M.); (A.B.); (D.F.C.M.); (V.B.)
- County Clinical Emergency Hospital of Sibiu, 550245 Sibiu, Romania
| | - Adela Banciu
- Department of Bioengineering and Biotechnology, Faculty of Medical Engineering, Polytechnic University of Bucharest, 011061 Bucharest, Romania; (A.B.); (D.D.B.)
| | - Daniel Dumitru Banciu
- Department of Bioengineering and Biotechnology, Faculty of Medical Engineering, Polytechnic University of Bucharest, 011061 Bucharest, Romania; (A.B.); (D.D.B.)
| | - Doru Florian Cornel Moga
- Faculty of Medicine, Lucian Blaga University of Sibiu, 550169 Sibiu, Romania; (D.P.); (M.M.); (A.B.); (D.F.C.M.); (V.B.)
- Dr. Alexandru Augustin Military Hospital of Sibiu, 550024 Sibiu, Romania
| | - Victoria Birlutiu
- Faculty of Medicine, Lucian Blaga University of Sibiu, 550169 Sibiu, Romania; (D.P.); (M.M.); (A.B.); (D.F.C.M.); (V.B.)
- County Clinical Emergency Hospital of Sibiu, 550245 Sibiu, Romania
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24
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Infection risk and prophylaxis in patients with lymphoid cancer. Blood 2021; 139:1517-1528. [PMID: 34748625 DOI: 10.1182/blood.2019003687] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2020] [Accepted: 05/05/2021] [Indexed: 11/20/2022] Open
Abstract
Infections are a common cause of morbidity and mortality in patients with lymphoid cancer. With evolving cancer therapeutics, including new targeted and immunotherapies, clinicians need to be aware of additional risk factors and infections that may arise in patients treated with these agents. This "How I Treat" article will highlight fundamental issues including risk factors for infection, infectious diseases screenings and antimicrobial prophylaxis recommendations in patients with lymphoid cancers. We present 4 scenarios of patients with lymphoid cancers with varied infections and describe a treatment approach based on a combination of evidence-based data and experience, as there are limitations in objective infection data especially with newer agents. The goal of this discussion is to provide a framework for institutions and health care providers to develop their own approach in preventing and treating infections in patients with lymphoid cancer.
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25
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The Role of Fecal Microbiota Transplantation in the Treatment of Inflammatory Bowel Disease. J Clin Med 2021; 10:jcm10184055. [PMID: 34575166 PMCID: PMC8465860 DOI: 10.3390/jcm10184055] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2021] [Revised: 09/02/2021] [Accepted: 09/03/2021] [Indexed: 12/12/2022] Open
Abstract
The exact pathogenesis of inflammatory bowel disease (IBD) is still not completely understood. It is hypothesized that a genetic predisposition leads to an exaggerated immune response to an environmental trigger, leading to uncontrolled inflammation. As there is no known causative treatment, current management strategies for inflammatory bowel disease focus on correcting the excessive immune response to environmental (including microbial) triggers. In recent years, there has been growing interest in new avenues of treatment, including targeting the microbial environment itself. Fecal microbiota transplantation (FMT) is a novel treatment modality showing promising results in early studies. The article discusses the rationale for the use of FMT in inflammatory bowel disease and the yet-unresolved questions surrounding its optimal use in practice.
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Gholam-Mostafaei FS, Yadegar A, Asadzadeh Aghdaei H, Shahrokh S, Ebrahimi Daryani N, Zali MR. Fecal microbiota transplantation for recurrent Clostridioides difficile infection in patients with concurrent ulcerative colitis. Acta Microbiol Immunol Hung 2021. [PMID: 34383708 DOI: 10.1556/030.2021.01498] [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: 05/12/2021] [Accepted: 07/28/2021] [Indexed: 11/19/2022]
Abstract
Treatment of recurrent Clostridioides difficile infection (rCDI) has emerged as an important management dilemma particularly in patients with underlying inflammatory bowel disease (IBD). Fecal microbiota transplantation (FMT) has been used as a safe and highly effective treatment option for rCDI refractory to standard antibiotic therapies. The aim of this study was to report the efficacy of FMT in Iranian rCDI patients with concurrent IBD. A total of seven consecutive patients with ulcerative colitis (UC) who had experienced 3 episodes of rCDI were enrolled in this study. All patients received at least a single FMT administered during colonoscopy by direct infusion of minimally processed donor stool. Patients were followed for a minimum of 6 months for assessment of treatment efficacy and adverse events (AEs) attributable to FMT. All 7 UC patients (100%) experienced a durable clinical response to a single FMT following 2 months after the procedure. One patient received a second FMT in which a successful resolution of rCDI was ultimately achieved. No serious AEs from FMT were noted. FMT through colonoscopy was a safe, simple and effective alternative treatment approach for rCDI in patients with underlying IBD. However, its use and efficacy should be pursued in long-term prospective controlled trials.
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Affiliation(s)
- Fahimeh Sadat Gholam-Mostafaei
- 1Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Abbas Yadegar
- 2Foodborne and Waterborne Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Hamid Asadzadeh Aghdaei
- 1Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Shabnam Shahrokh
- 3Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Nasser Ebrahimi Daryani
- 4Department of Gastroenterology and Hepatology, Tehran University of Medical Sciences, Tehran, Iran
| | - Mohammad Reza Zali
- 3Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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27
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Opportunities for Nanomedicine in Clostridioides difficile Infection. Antibiotics (Basel) 2021; 10:antibiotics10080948. [PMID: 34438998 PMCID: PMC8388953 DOI: 10.3390/antibiotics10080948] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2021] [Revised: 07/30/2021] [Accepted: 08/03/2021] [Indexed: 12/19/2022] Open
Abstract
Clostridioides difficile, a spore-forming bacterium, is a nosocomial infectious pathogen which can be found in animals as well. Although various antibiotics and disinfectants were developed, C. difficile infection (CDI) remains a serious health problem. C. difficile spores have complex structures and dormant characteristics that contribute to their resistance to harsh environments, successful transmission and recurrence. C. difficile spores can germinate quickly after being exposed to bile acid and co-germinant in a suitable environment. The vegetative cells produce endospores, and the mature spores are released from the hosts for dissemination of the pathogen. Therefore, concurrent elimination of C. difficile vegetative cells and inhibition of spore germination is essential for effective control of CDI. This review focused on the molecular pathogenesis of CDI and new trends in targeting both spores and vegetative cells of this pathogen, as well as the potential contribution of nanotechnologies for the effective management of CDI.
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28
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Manipulating the Microbiome: An Alternative Treatment for Bile Acid Diarrhoea. MICROBIOLOGY RESEARCH 2021. [DOI: 10.3390/microbiolres12020023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
Bile acid diarrhoea (BAD) is a widespread gastrointestinal disease that is often misdiagnosed as irritable bowel syndrome and is estimated to affect 1% of the United Kingdom (UK) population alone. BAD is associated with excessive bile acid synthesis secondary to a gastrointestinal or idiopathic disorder (also known as primary BAD). Current licensed treatment in the UK has undesirable effects and has been the same since BAD was first discovered in the 1960s. Bacteria are essential in transforming primary bile acids into secondary bile acids. The profile of an individual’s bile acid pool is central in bile acid homeostasis as bile acids regulate their own synthesis. Therefore, microbiome dysbiosis incurred through changes in diet, stress levels and the introduction of antibiotics may contribute to or be the cause of primary BAD. This literature review focuses on primary BAD, providing an overview of bile acid metabolism, the role of the human gut microbiome in BAD and the potential options for therapeutic intervention in primary BAD through manipulation of the microbiome.
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29
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Тикунов АЮ, Морозов ВВ, Швалов АН, Бардашева АВ, Шрайнер ЕВ, Максимова ОА, Волошина ИО, Морозова ВВ, Власов ВВ, Тикунова НВ. [Fecal microbiome change in patients with ulcerative colitis after fecal microbiota transplantation]. Vavilovskii Zhurnal Genet Selektsii 2021; 24:168-175. [PMID: 33659796 PMCID: PMC7716530 DOI: 10.18699/vj20.610] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022] Open
Abstract
Intestinal human microbiota is a dynamic system that is under the pressures of its host organism and external factors. Microbiota disruption caused by these factors can lead to severe diseases including inflammatory and oncological diseases of the gastrointestinal tract. One of the possible approaches in managing the intestinal microbiota is fecal microbiota transplantation (FT) - transfer of the microbiota from the stool of a healthy donor to the intestinal tract of a recipient patient. Currently, this procedure is recognized as an efficacious method to normalize the intestinal microbiota mainly in inflammatory diseases of the gastrointestinal tract. In Russia, pilot studies of the effectiveness of FT in patients with ulcerative colitis have been conducted for several years, and these studies were started in Novosibirsk. The aim of this study was to assess the change of intestinal microbiome in 20 patients with ulcerative colitis after a single FT procedure. The main method is a comparative analysis of 16S ribosomal RNA sequence libraries constructed using fecal samples obtained from patients with ulcerative colitis before and after FT and sequenced on the Illumina MiSeq platform. The obtained results showed that FT led to an increase in average biodiversity in samples after FT compared to samples before FT; however, the difference was not significant. In the samples studied, the proportion of Firmicutes sequences, the major gastrointestinal microbiota of healthy people, was decreased (~32 % vs. >70 %), while the proportion of Proteobacteria sequences was increased (>9 % vs. <5 %). In some samples collected before FT, sequences of pathogenic Firmicutes and Proteobacteria were detected, including Acinetobacter spp., Enterococcus spp., Klebsiella pneumoniae, Proteus mirabilis, Staphylococcus aureus, Stenotrophomonas maltophylia, Streptococcus spp. In most cases, the proportion of such sequences after FT substantially decreased in appropriate samples. The exception was the Clostridium difficile sequences, which accounted for <0.5 % of the sequences in samples from almost half of the patients and after FT, the share of such C. difficile sequences was significantly reduced only in samples from three patients. It should be noted that the proportion of Lactobacillus spp. increased ten-fold and their species composition significantly expanded. According to the obtained results, a preliminary conclusion can be made that even a single FT procedure can lead to an increase in the biodiversity of the gastrointestinal microbiota in patients and to the optimization of the taxonomic composition of the microbiota.
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Affiliation(s)
- А Ю Тикунов
- Институт химической биологии и фундаментальной медицины Сибирского отделения Российской академии наук, Новосибирск, Россия
| | - В В Морозов
- Институт химической биологии и фундаментальной медицины Сибирского отделения Российской академии наук, Новосибирск, Россия
| | - А Н Швалов
- Государственный научный центр вирусологии и биотехнологии «Вектор» Роспотребнадзора Российской Федерации, р. п. Кольцово, Новосибирская область, Россия 3 ООО «Центр персонализированной
| | - А В Бардашева
- Институт химической биологии и фундаментальной медицины Сибирского отделения Российской академии наук, Новосибирск, Россия
| | - Е В Шрайнер
- Институт химической биологии и фундаментальной медицины Сибирского отделения Российской академии наук, Новосибирск, Россия
| | - О А Максимова
- ООО «Центр персонализированной медицины», Новосибирск, Россия
| | - И О Волошина
- ООО «Центр персонализированной медицины», Новосибирск, Россия
| | - В В Морозова
- Институт химической биологии и фундаментальной медицины Сибирского отделения Российской академии наук, Новосибирск, Россия
| | - В В Власов
- Институт химической биологии и фундаментальной медицины Сибирского отделения Российской академии наук, Новосибирск, Россия
| | - Н В Тикунова
- Институт химической биологии и фундаментальной медицины Сибирского отделения Российской академии наук, Новосибирск, Россия
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Emerging role of Gut-microbiota-brain axis in depression and therapeutic implication. Prog Neuropsychopharmacol Biol Psychiatry 2021; 106:110138. [PMID: 33075447 DOI: 10.1016/j.pnpbp.2020.110138] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/29/2020] [Revised: 08/19/2020] [Accepted: 10/09/2020] [Indexed: 12/11/2022]
Abstract
The human body can be considered a superorganism in which it's eukaryotic cells and prokaryotic microorganisms coexist. Almost every organ system of the body lives a symbiotic life with these commensal bacteria. Intestinal microbiota has an important role in shaping, organizing and maintaining mental functions from as early as the intrauterine period. Microbiota-based approaches are becoming more prominent in understanding and treating the etiopathogenesis of neuropsychiatric disorders, especially depression. Antidepressant drugs, which are the first-line option in the treatment of depression today, also contain antimicrobial and immunomodulatory mechanisms of action. Treatment options for directly modifying the microbiota composition include prebiotics, probiotics (psychobiotics) and fecal microbiota transplantation. There are few preclinical and clinical studies on the efficacy and reliability of these treatment options in depression. This article will review pertinent studies on the role of intestinal microbiota in depression and discuss the treatment potential of altering ones gut microbiome.
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Keller JJ, Ooijevaar RE, Hvas CL, Terveer EM, Lieberknecht SC, Högenauer C, Arkkila P, Sokol H, Gridnyev O, Mégraud F, Kump PK, Nakov R, Goldenberg SD, Satokari R, Tkatch S, Sanguinetti M, Cammarota G, Dorofeev A, Gubska O, Laniro G, Mattila E, Arasaradnam RP, Sarin SK, Sood A, Putignani L, Alric L, Baunwall SMD, Kupcinskas J, Link A, Goorhuis AG, Verspaget HW, Ponsioen C, Hold GL, Tilg H, Kassam Z, Kuijper EJ, Gasbarrini A, Mulder CJJ, Williams HRT, Vehreschild MJGT. A standardised model for stool banking for faecal microbiota transplantation: a consensus report from a multidisciplinary UEG working group. United European Gastroenterol J 2021; 9:229-247. [PMID: 33151137 PMCID: PMC8259288 DOI: 10.1177/2050640620967898] [Citation(s) in RCA: 92] [Impact Index Per Article: 23.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/02/2020] [Accepted: 09/27/2020] [Indexed: 12/21/2022] Open
Abstract
BACKGROUND Faecal microbiota transplantation is an emerging therapeutic option, particularly for the treatment of recurrent Clostridioides difficile infection. Stool banks that organise recruitment and screening of faeces donors are being embedded within the regulatory frameworks described in the European Union Tissue and Cells Directive and the technical guide to the quality and safety of tissue and cells for human application, published by the European Council. OBJECTIVE Several European and international consensus statements concerning faecal microbiota transplantation have been issued. While these documents provide overall guidance, we aim to provide a detailed description of all processes that relate to the collection, handling and clinical application of human donor stool in this document. METHODS Collaborative subgroups of experts on stool banking drafted concepts for all domains pertaining to stool banking. During a working group meeting in the United European Gastroenterology Week 2019 in Barcelona, these concepts were discussed and finalised to be included in our overall guidance document about faecal microbiota transplantation. RESULTS A guidance document for all domains pertaining to stool banking was created. This document includes standard operating manuals for several processes involved with stool banking, such as handling of donor material, storage and donor screening. CONCLUSION The implementation of faecal microbiota transplantation by stool banks in concordance with our guidance document will enable quality assurance and guarantee the availability of donor faeces preparations for patients.
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Understanding Human Microbiota Offers Novel and Promising Therapeutic Options against Candida Infections. Pathogens 2021; 10:pathogens10020183. [PMID: 33572162 PMCID: PMC7915436 DOI: 10.3390/pathogens10020183] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2020] [Revised: 01/20/2021] [Accepted: 02/02/2021] [Indexed: 12/12/2022] Open
Abstract
Human fungal pathogens particularly of Candida species are one of the major causes of hospital acquired infections in immunocompromised patients. The limited arsenal of antifungal drugs to treat Candida infections with concomitant evolution of multidrug resistant strains further complicates the management of these infections. Therefore, deployment of novel strategies to surmount the Candida infections requires immediate attention. The human body is a dynamic ecosystem having microbiota usually involving symbionts that benefit from the host, but in turn may act as commensal organisms or affect positively (mutualism) or negatively (pathogenic) the physiology and nourishment of the host. The composition of human microbiota has garnered a lot of recent attention, and despite the common occurrence of Candida spp. within the microbiota, there is still an incomplete picture of relationships between Candida spp. and other microorganism, as well as how such associations are governed. These relationships could be important to have a more holistic understanding of the human microbiota and its connection to Candida infections. Understanding the mechanisms behind commensalism and pathogenesis is vital for the development of efficient therapeutic strategies for these Candida infections. The concept of host-microbiota crosstalk plays critical roles in human health and microbiota dysbiosis and is responsible for various pathologies. Through this review, we attempted to analyze the types of human microbiota and provide an update on the current understanding in the context of health and Candida infections. The information in this article will help as a resource for development of targeted microbial therapies such as pre-/pro-biotics and microbiota transplant that has gained advantage in recent times over antibiotics and established as novel therapeutic strategy.
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Ramai D, Zakhia K, Fields PJ, Ofosu A, Patel G, Shahnazarian V, Lai JK, Dhaliwal A, Reddy M, Chang S. Fecal Microbiota Transplantation (FMT) with Colonoscopy Is Superior to Enema and Nasogastric Tube While Comparable to Capsule for the Treatment of Recurrent Clostridioides difficile Infection: A Systematic Review and Meta-Analysis. Dig Dis Sci 2021; 66:369-380. [PMID: 32166622 DOI: 10.1007/s10620-020-06185-7] [Citation(s) in RCA: 62] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/25/2019] [Accepted: 02/28/2020] [Indexed: 12/31/2022]
Abstract
BACKGROUND Several routes of fecal microbiota transplantation (FMT) administration are available for treating recurrent Clostridioides difficile infections (CDI), the most recent of which are capsules. AIM To assess the efficacy of colonoscopy, capsule, enema, and nasogastric tube (NGT) FMT for the treatment of recurrent CDI. METHODS We reported clinical outcomes of colonoscopy, capsule, enema, and NGT FMT for the treatment of recurrent CDI according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. During January 2000 to January 2018, three databases were searched: PubMed, EMBASE, and CINAHL. Primary outcome was overall cure rate which was assessed using a random effects model; secondary outcomes included adverse effects as well as subgroup analyses comparing donor relationship, sample preparation, and study design. RESULTS Twenty-six studies (1309 patients) were included in the study. FMT was administered using colonoscopy in 16 studies (483 patients), NGT in five studies (149 patients), enema in four studies (360 patients), and capsules in four studies (301 patients). The random effects of pooled FMT cure rates were colonoscopy 94.8% (CI 92.4-96.8%; I2 15.6%), capsule 92.1% (CI 88.6-95.0%; I2 7.1%), enema 87.2% (CI 83.4-90.5%; I2 0%), and NGT/NDT 78.1% (CI 71.6-84.1%; I2 0%). On subgroup analysis of colonoscopy FMT, sample preparation methods had comparable cure rates: fresh 94.9% compared to 94.5%. Similarly, cure rates were unaffected by donor relationship: mixed 94.5% compared to unrelated donor 95.7%. CONCLUSION CDI cure rates with FMT performed with colonoscopy are superior to enema and NGT FMT, while those with FMT with colonoscopy and capsule are comparable.
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Affiliation(s)
- Daryl Ramai
- Department of Medicine, The Brooklyn Hospital Center, Clinical Affiliate of The Mount Sinai Hospital, 121 DeKalb Ave, Brooklyn, NY, 11201, USA.
| | - Karl Zakhia
- Department of Medicine, The Brooklyn Hospital Center, Clinical Affiliate of The Mount Sinai Hospital, 121 DeKalb Ave, Brooklyn, NY, 11201, USA
| | - Paul J Fields
- School of Medicine, Windward Islands Research and Education Foundation, St. George's University, True Blue, Grenada
| | - Andrew Ofosu
- Division of Gastroenterology and Hepatology, The Brooklyn Hospital Center, Clinical Affiliate of The Mount Sinai Hospital, 121 DeKalb Ave, Brooklyn, NY, 11201, USA
| | - Goonja Patel
- School of Medicine, Windward Islands Research and Education Foundation, St. George's University, True Blue, Grenada
| | - Vahe Shahnazarian
- Division of Gastroenterology and Hepatology, The Brooklyn Hospital Center, Clinical Affiliate of The Mount Sinai Hospital, 121 DeKalb Ave, Brooklyn, NY, 11201, USA
| | - Jonathan K Lai
- Department of Pathology, McGill University, 1001 Decarie Boulevard, Montreal, QC, H4A 3J1, Grenada
| | - Amaninder Dhaliwal
- Division of Gastroenterology, University of Nebraska Medical Center, S 42nd and Emile St, Omaha, NE, 68198, USA
| | - Madhavi Reddy
- Division of Gastroenterology and Hepatology, The Brooklyn Hospital Center, Clinical Affiliate of The Mount Sinai Hospital, 121 DeKalb Ave, Brooklyn, NY, 11201, USA
| | - Shannon Chang
- Division of Gastroenterology, NYU Langone Health, 40 East 38th Street, 23rd Floor, New York, NY, 10016, USA
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Marcella C, Cui B, Kelly CR, Ianiro G, Cammarota G, Zhang F. Systematic review: the global incidence of faecal microbiota transplantation-related adverse events from 2000 to 2020. Aliment Pharmacol Ther 2021; 53:33-42. [PMID: 33159374 DOI: 10.1111/apt.16148] [Citation(s) in RCA: 123] [Impact Index Per Article: 30.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/24/2020] [Revised: 08/24/2020] [Accepted: 10/20/2020] [Indexed: 12/21/2022]
Abstract
BACKGROUND Faecal microbiota transplantation (FMT) is an effective treatment in C. difficile infection (CDI) and is currently being investigated in other diseases. There is concern around the safety of FMT and that side effects or complications may be under-reported in the medical literature. AIM To evaluate the safety of FMT by summarising the overall reported Adverse Events (AEs) over a 20-year period METHODS: We searched EMBASE, MEDLINE, and Cochrane Library databases, and CNKI and Wanfang Data from January 2000 to April 2020. All original studies reporting FMT-related AEs were considered for inclusion. FMT-related AEs were further classified as delivery-related or microbiota-related. RESULTS Based on the inclusion criteria, 129 studies, which included 4241 patients (5688 FMT courses), were finally eligible. The most common indication for FMT was CDI. Overall, FMT-related AEs were observed in 19% of FMT procedures. The most frequently reported FMT-related AEs were diarrhoea (10%) and abdominal discomfort/pain/cramping (7%). FMT-related serious adverse events (SAEs), including infections and deaths, have been reported in 1.4% of patients who underwent FMT (0.99% microbiota-related SAEs). Four of five FMT-related deaths were reported in patients receiving FMT via the upper gastrointestinal route. Importantly, all reported FMT-related SAEs were in patients with mucosal barrier injury. CONCLUSION Most FMT-related AEs were mild or moderate and self-limiting. Although FMT appears to be highly safe, its methodology should be improved to reduce both delivery-related AEs and, microbiota-related AEs.
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Affiliation(s)
- Cicilia Marcella
- Medical Center of Digestive Disease, the Second Affiliated Hospital of Nanjing Medical University, Nanjing, China
- Key Lab of Holistic Integrative Enterology, Nanjing Medical University, Nanjing, China
| | - Bota Cui
- Medical Center of Digestive Disease, the Second Affiliated Hospital of Nanjing Medical University, Nanjing, China
- Key Lab of Holistic Integrative Enterology, Nanjing Medical University, Nanjing, China
| | - Colleen R Kelly
- Division of Gastroenterology, Alpert Medical School of Brown University, Providence, Rhode Island, USA
| | - Gianluca Ianiro
- Digestive Diseases Center, Fondazione Policlinico Universitario A. Gemelli IRCCS, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Giovanni Cammarota
- Digestive Diseases Center, Fondazione Policlinico Universitario A. Gemelli IRCCS, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Faming Zhang
- Medical Center of Digestive Disease, the Second Affiliated Hospital of Nanjing Medical University, Nanjing, China
- Key Lab of Holistic Integrative Enterology, Nanjing Medical University, Nanjing, China
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Gut mycobiomes are altered in people with type 2 Diabetes Mellitus and Diabetic Retinopathy. PLoS One 2020; 15:e0243077. [PMID: 33259537 PMCID: PMC7707496 DOI: 10.1371/journal.pone.0243077] [Citation(s) in RCA: 64] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2020] [Accepted: 11/14/2020] [Indexed: 01/14/2023] Open
Abstract
Studies have documented dysbiosis in the gut mycobiome in people with Type 2 diabetes mellitus (T2DM). However, it is not known whether dysbiosis in the gut mycobiome of T2DM patients would be reflected in people with diabetic retinopathy (DR) and if so, is the observed mycobiome dysbiosis similar in people with T2DM and DR. Gut mycobiomes were generated from healthy controls (HC), people with T2DM and people with DR through Illumina sequencing of ITS2 region. Data were analysed using QIIME and R software. Dysbiotic changes were observed in people with T2DM and DR compared to HC at the phyla and genera level. Mycobiomes of HC, T2DM and DR could be discriminated by heat map analysis, Beta diversity analysis and LEfSE analysis. Spearman correlation of fungal genera indicated more negative correlation in HC compared to T2DM and DR mycobiomes. This study demonstrates dysbiosis in the gut mycobiomes in people with T2DM and DR compared to HC. These differences were significant both at the phyla and genera level between people with T2DM and DR as well. Such studies on mycobiomes may provide new insights and directions to identification of specific fungi associated with T2DM and DR and help developing novel therapies for Diabetes Mellitus and DR.
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Is a healthy microbiome responsible for lower mortality in COVID-19? Biologia (Bratisl) 2020; 76:819-829. [PMID: 33078028 PMCID: PMC7557238 DOI: 10.2478/s11756-020-00614-8] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2020] [Accepted: 09/30/2020] [Indexed: 12/17/2022]
Abstract
The novel severe acute respiratory syndrome Coronavirus 2 (SARS-CoV-2) is the cause of an ongoing pandemic with significant case fatality ratio (CFR) worldwide. Although SARS-CoV-2 primarily causes respiratory infection by binding to ACE2 receptors present on alveolar epithelial cells, studies have been published linking the disease to the small intestine enterocytes and its microbiome. Dysbiosis of microbiome, mainly intestinal and lung, can affect the course of the disease. Environmental factors, such as reduced intake of commensal bacteria from the environment or their products in the diet, play an important role in microbiome formation, which can significantly affect the immune response. In elderly, obese or chronically ill people, the microbiota is often damaged. Therefore, we speculate that a good microbiome may be one of the factors responsible for lower CFR from the coronavirus disease 2019 (COVID-19). An approach using tailored nutrition and supplements known to improve the intestinal microbiota and its immune function might help minimize the impact of the disease at least on people at higher risk from coronavirus.
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Azimirad M, Yadegar A, Gholami F, Shahrokh S, Asadzadeh Aghdaei H, Ianiro G, Suzuki H, Cammarota G, Zali MR. Treatment of Recurrent Clostridioides difficile Infection Using Fecal Microbiota Transplantation in Iranian Patients with Underlying Inflammatory Bowel Disease. J Inflamm Res 2020; 13:563-570. [PMID: 32982371 PMCID: PMC7509309 DOI: 10.2147/jir.s265520] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2020] [Accepted: 09/07/2020] [Indexed: 12/15/2022] Open
Abstract
PURPOSE Fecal microbiota transplantation (FMT) is an effective treatment option for patients with recurrent Clostridioides difficile infection (rCDI). However, there is a paucity of evidence regarding its efficacy and safety in patients with rCDI and concurrent inflammatory bowel disease (IBD). Here, we present a single-center experience of FMT for treatment of rCDI in Iranian patients with IBD. PATIENTS AND METHODS Eight patients with established IBD (7 with ulcerative colitis and 1 with Crohn's disease) who underwent at least one FMT via colonoscopy for treatment of rCDI were enrolled in this study. Demographics, pre-FMT and post-FMT IBD activity, efficacy for rCDI and adverse events (AEs) were assessed during a 6-month follow-up period. All patients had experienced 3 episodes of rCDI and were refractory to conventional therapies with metronidazole and vancomycin. Primary cure and secondary cure rates were assessed after FMT treatments. RESULTS A total of 10 FMTs were performed via colonoscopy in 8 patients (6/8; 75% men) with a median age of 35 years (range: 22-60). Two patients received a second FMT. Overall, the primary and secondary cure rates were 75% and 100%, respectively. Two patients developed CPE-producing C. perfringens diagnoses after second FMTs. There were no other AEs, and no patient experienced IBD flare. CONCLUSION We demonstrated that FMT appears to be an effective, safe and rational therapeutic alternative for resolution of rCDI in patients with underlying IBD. Furthermore, we suggest implementing the CPE-producing C. perfringens testing in the screening of FMT donors.
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Affiliation(s)
- Masoumeh Azimirad
- Foodborne and Waterborne Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Abbas Yadegar
- Foodborne and Waterborne Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Fatemeh Gholami
- Foodborne and Waterborne Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Shabnam Shahrokh
- Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Hamid Asadzadeh Aghdaei
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Gianluca Ianiro
- Digestive Disease Center, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Catholic University of Sacred Heart, Rome, Italy
| | - Hidekazu Suzuki
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Tokai University School of Medicine, Isehara, Kanagawa259-1193, Japan
| | - Giovanni Cammarota
- Digestive Disease Center, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Catholic University of Sacred Heart, Rome, Italy
| | - Mohammad Reza Zali
- Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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Appaneal HJ, Caffrey AR, LaPlante KL. What Is the Role for Metronidazole in the Treatment of Clostridium difficile Infection? Results From a National Cohort Study of Veterans With Initial Mild Disease. Clin Infect Dis 2020; 69:1288-1295. [PMID: 30561531 DOI: 10.1093/cid/ciy1077] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2018] [Accepted: 12/12/2018] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND Metronidazole may still be an appropriate therapeutic option for mild Clostridium difficile infection (CDI) in select patients, but data are limited to guide clinicians in identifying these patients. METHODS Our 2-stage study included a national cohort of Veterans with a first episode of mild CDI (2010-2014). First, among those treated with metronidazole, we identified predictors of success, defined as absence of all-cause mortality or recurrence 30 days posttreatment, using multivariable unconditional logistic regression. Second, among a subgroup of patients with characteristics predictive of success identified in the first stage, we compared clinical outcomes among those treated with metronidazole compared with vancomycin, using Cox proportional hazards models for time to 30-day all-cause mortality, CDI recurrence, and failure. RESULTS Among 3656 patients treated with metronidazole, we identified 3282 patients with success and 374 patients without success (failure). Younger age was the only independent predictor of success. Age ≤65 years was associated with an odds of success 1.63 times higher (95% confidence interval [CI], 1.29-2.06) than age >65 years. Among 115 propensity score-matched pairs ≤65 years of age, no significant differences were observed between metronidazole and vancomycin (reference) for all-cause mortality (hazard ratio [HR], 0.29 [95% CI, .06-1.38]), CDI recurrence (HR, 0.62 [95% CI, .26-1.49]), or failure (HR, 0.50 [95% CI, .23-1.07]). CONCLUSIONS Among patients ≤65 years of age with initial mild CDI, clinical outcomes were similar with metronidazole and vancomycin. These data suggest that metronidazole may be considered for the treatment of initial mild CDI among patients 65 years of age or younger.
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Affiliation(s)
- Haley J Appaneal
- Infectious Diseases Research Program, Providence Veterans Affairs Medical Center, Kingston.,College of Pharmacy, University of Rhode Island, Kingston.,Center of Innovation in Long-Term Support Services, Providence Veterans Affairs Medical Center, Providence, Rhode Island
| | - Aisling R Caffrey
- Infectious Diseases Research Program, Providence Veterans Affairs Medical Center, Kingston.,College of Pharmacy, University of Rhode Island, Kingston.,Center of Innovation in Long-Term Support Services, Providence Veterans Affairs Medical Center, Providence, Rhode Island.,Brown University School of Public Health, Providence, Rhode Island
| | - Kerry L LaPlante
- Infectious Diseases Research Program, Providence Veterans Affairs Medical Center, Kingston.,College of Pharmacy, University of Rhode Island, Kingston.,Center of Innovation in Long-Term Support Services, Providence Veterans Affairs Medical Center, Providence, Rhode Island.,Division of Infectious Diseases, Warren Alpert Medical School, Brown University, Providence, Rhode Island
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Nieman DC, Pence BD. Exercise immunology: Future directions. JOURNAL OF SPORT AND HEALTH SCIENCE 2020; 9:432-445. [PMID: 32928447 PMCID: PMC7498623 DOI: 10.1016/j.jshs.2019.12.003] [Citation(s) in RCA: 78] [Impact Index Per Article: 15.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/24/2019] [Revised: 11/21/2019] [Accepted: 11/25/2019] [Indexed: 05/07/2023]
Abstract
Several decades of research in the area of exercise immunology have shown that the immune system is highly responsive to acute and chronic exercise training. Moderate exercise bouts enhance immunosurveillance and when repeated over time mediate multiple health benefits. Most of the studies prior to 2010 relied on a few targeted outcomes related to immune function. During the past decade, technologic advances have created opportunities for a multi-omics and systems biology approach to exercise immunology. This article provides an overview of metabolomics, lipidomics, and proteomics as they pertain to exercise immunology, with a focus on immunometabolism. This review also summarizes how the composition and diversity of the gut microbiota can be influenced by exercise, with applications to human health and immunity. Exercise-induced improvements in immune function may play a critical role in countering immunosenescence and the development of chronic diseases, and emerging omics technologies will more clearly define the underlying mechanisms. This review summarizes what is currently known regarding a multi-omics approach to exercise immunology and provides future directions for investigators.
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Affiliation(s)
- David C Nieman
- Human Performance Laboratory, Appalachian State University, North Carolina Research Campus, Kannapolis, NC 28081, USA.
| | - Brandt D Pence
- School of Health Studies, University of Memphis, Memphis, TN 38152, USA
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40
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Gulati M, Singh SK, Corrie L, Kaur IP, Chandwani L. Delivery routes for faecal microbiota transplants: Available, anticipated and aspired. Pharmacol Res 2020; 159:104954. [DOI: 10.1016/j.phrs.2020.104954] [Citation(s) in RCA: 58] [Impact Index Per Article: 11.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/19/2020] [Revised: 05/11/2020] [Accepted: 05/20/2020] [Indexed: 02/06/2023]
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An ecological framework to understand the efficacy of fecal microbiota transplantation. Nat Commun 2020; 11:3329. [PMID: 32620839 PMCID: PMC7334230 DOI: 10.1038/s41467-020-17180-x] [Citation(s) in RCA: 50] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2019] [Accepted: 06/11/2020] [Indexed: 02/08/2023] Open
Abstract
Human gut microbiota plays critical roles in physiology and disease. Our understanding of ecological principles that govern the dynamics and resilience of this highly complex ecosystem remains rudimentary. This knowledge gap becomes more problematic as new approaches to modifying this ecosystem, such as fecal microbiota transplantation (FMT), are being developed as therapeutic interventions. Here we present an ecological framework to understand the efficacy of FMT in treating conditions associated with a disrupted gut microbiota, using the recurrent Clostridioides difficile infection as a prototype disease. This framework predicts several key factors that determine the efficacy of FMT. Moreover, it offers an efficient algorithm for the rational design of personalized probiotic cocktails to decolonize pathogens. We analyze data from both preclinical mouse experiments and a clinical trial of FMT to validate our theoretical framework. The presented results significantly improve our understanding of the ecological principles of FMT and have a positive translational impact on the rational design of general microbiota-based therapeutics. Here, the authors present a theoretical framework based on community ecology and network science to investigate the efficacy of fecal microbiota transplantation in conditions associated with a disrupted gut microbiota, using the recurrent Clostridioides difficile infection as a prototype disease.
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42
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Hong AS, Yu WY, Hong JM, Cross CL, Azab M, Ohning G, Jayaraj M. Proton pump inhibitor in upper gastrointestinal fecal microbiota transplant: A systematic review and analysis. J Gastroenterol Hepatol 2020; 35:932-940. [PMID: 31830335 DOI: 10.1111/jgh.14958] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/22/2019] [Revised: 11/17/2019] [Accepted: 12/02/2019] [Indexed: 12/20/2022]
Abstract
BACKGROUND AND AIMS Fecal microbiota transplantation (FMT) is used in recurrent Clostridioides difficile infections. However, protocols are facility dependent, and one variable is whether pre-procedural proton pump inhibitors (PPIs) are given. In theory, PPIs reduce acidity and protect the transplanted microbiome for the most potent dose. We conducted a systematic review to study the effect of PPIs on FMT delivered by upper gastrointestinal (GI) routes. METHODS We searched Pubmed/Medline, Cochrane Library, Embase, Scopus, and Web of Science through December 16, 2018 using variations of keywords "fecal microbiota transplant" and "Clostridium difficile infection." Two authors independently reviewed 4210 results and found 11 qualifying studies with data on upper GI FMT, use of PPIs, and the rate of treatment failure at follow-up. RESULTS Of 233 included patients, treatment failure occurred in 20.6% of those with use of PPIs versus 22.6% in the group without (relative risk 0.91; confidence interval 0.56-1.50). Limitations include the lack of studies directly comparing outcomes based on use of PPIs and inability to control for possible confounders such as chronic PPI use, amount of stool transplanted, and pre-FMT antibiotics. CONCLUSIONS We did not find evidence supporting a clinically significant benefit from routine use of PPIs in FMT protocol. It is possible that the theoretical benefit from improved survival of transplanted microbiota is offset by negative effects on the microbiome. We suggest that routine use of PPIs in upper GI FMT be reconsidered. Further investigation is needed to optimize protocols for safety and efficacy.
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Affiliation(s)
- Annie S Hong
- University of Nevada Las Vegas School of Medicine, Las Vegas, Nevada, USA.,Department of Internal Medicine, University of Nevada Las Vegas School of Medicine, Las Vegas, Nevada, USA
| | - Wen Yuan Yu
- University of Nevada Las Vegas School of Medicine, Las Vegas, Nevada, USA.,Department of Internal Medicine, University of Nevada Las Vegas School of Medicine, Las Vegas, Nevada, USA
| | - Jenny M Hong
- University of Nevada Las Vegas School of Medicine, Las Vegas, Nevada, USA
| | - Chad L Cross
- University of Nevada Las Vegas School of Medicine, Las Vegas, Nevada, USA
| | - Mohamed Azab
- Department of Gastroenterology, Loma Linda University School of Medicine, Loma Linda, California, USA
| | - Gordon Ohning
- University of Nevada Las Vegas School of Medicine, Las Vegas, Nevada, USA.,Department of Gastroenterology, University of Nevada Las Vegas School of Medicine, Las Vegas, Nevada, USA
| | - Mahendran Jayaraj
- University of Nevada Las Vegas School of Medicine, Las Vegas, Nevada, USA.,Department of Gastroenterology, University of Nevada Las Vegas School of Medicine, Las Vegas, Nevada, USA
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Tang LL, Feng WZ, Cheng JJ, Gong YN. Clinical remission of ulcerative colitis after different modes of faecal microbiota transplantation: a meta-analysis. Int J Colorectal Dis 2020; 35:1025-1034. [PMID: 32388604 DOI: 10.1007/s00384-020-03599-7] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 04/13/2020] [Indexed: 02/04/2023]
Abstract
BACKGROUND Ulcerative colitis (UC) is a chronic, recurrent and destructive disease of the gastrointestinal tract. Faecal microbiota transplantation (FMT) is a therapeutic measure in which faecal microbiota from healthy people is transplanted into patients. AIM To systematically evaluate the safety and effectiveness of treating UC with different modes of FMT. METHODS Seven databases were searched by two independent researchers and studies related to randomized controlled trials were included in the analysis. RESULTS Seven studies on UC involving 431 patients were included in the analysis. The results showed that FMT had better efficacy than placebo (OR = 2.29, 95% CI 1.48-3.53, P = 0.0002). Subgroup analyses of influencing factors showed that frozen faeces from multiple donors delivered via the lower gastrointestinal tract had a better curative effect than placebo (OR = 2.76, 95% CI 1.59-4.79, P = 0.0003; OR = 2.93, 95% CI 1.67-5.71, P = 0.0002; and OR = 2.70, 95% CI 1.67-4.37, P < 0.0001); the difference in efficacy between mixed faeces from a single donor transplanted through the upper gastrointestinal tract and placebo was not significant(P = 0.05, P = 0.09 and P = 0.98). The analysis of side effects showed no significant difference between FMT and placebo (P = 0.43). CONCLUSIONS It may be safe and effective to transplant frozen faeces from multiple donors through the lower gastrointestinal tract to treat UC.
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Affiliation(s)
- Li-Li Tang
- Shaanxi University of Chinese Medicine, Xianyang, Shaanxi, China
| | - Wen-Zhe Feng
- Affiliated Hospital of Shaanxi University of Chinese Medicine, Xianyang, Shaanxi, China.
| | - Jia-Jun Cheng
- Shaanxi University of Chinese Medicine, Xianyang, Shaanxi, China
| | - Yan-Ni Gong
- Shaanxi University of Chinese Medicine, Xianyang, Shaanxi, China
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McCune V, Quraishi M, Manzoor S, Moran C, Banavathi K, Steed H, Massey D, Trafford G, Iqbal T, Hawkey P. Results from the first English stool bank using faecal microbiota transplant as a medicinal product for the treatment of Clostridioides difficile infection. EClinicalMedicine 2020; 20:100301. [PMID: 32300746 PMCID: PMC7152830 DOI: 10.1016/j.eclinm.2020.100301] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/05/2019] [Revised: 02/05/2020] [Accepted: 02/19/2020] [Indexed: 01/01/2023] Open
Abstract
BACKGROUND Faecal Microbiota Transplant (FMT) has improved outcomes for the treatment of Clostridioides difficile infection (CDI) compared to antibiotic therapy. FMT is classified as a medicinal product in the United Kingdom, similar to the USA and Canada, limiting supply via stool banks without appropriate licencing. In the largest UK cohort to date, we describe the clinical outcomes for 124 patients receiving FMT for recurrent or refractory CDI and present a framework to produce FMT as a licenced medicinal product. METHODS Anonymous unrelated healthy donors, screened via health assessment and microbiological testing donated stool. In aerobic conditions FMT aliquots were prepared for immediate use or frozen storage, following a production framework developed to comply with Good Manufacturing Practice. Outcome measures were clinical response to FMT defined as resolution of diarrhoea within seven days and clinical cure defined as response without diarrhoea recurrence at 90 days. FINDINGS Clinical response was 83·9% (95% CI 76·0%-90·0%) after one treatment. Clinical cure was 78·2% (95% CI 67·4%-89·0%) across the cohort. Refractory cases appeared to have a lower initial clinical response rate compared to recurrent cases, however at day 90 there were no differences observed between these groups. INTERPRETATION The methodology developed here enabled successful licencing of FMT by The Medicines and Healthcare products Regulatory Agency as a medicinal product. This has widened the availability of FMT in the National Health Service via a stool bank and can be applied in other centres across the world to improve access to safe and quality assured treatments.
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Affiliation(s)
- V.L. McCune
- Public Health England, Public Health Laboratory Birmingham, University Hospitals Birmingham NHS Foundation Trust, Heartlands Hospital, Bordesley Green East, Birmingham B5 9SS, England
- Institute of Microbiology and Infection, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham B15 2TH, England
- Microbiome Treatment Centre, IBR West Link Level 2, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, West Midlands B15 2TT, England
- Corresponding author.
| | - M.N. Quraishi
- Microbiome Treatment Centre, IBR West Link Level 2, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, West Midlands B15 2TT, England
- Department of Gastroenterology, University Hospitals Birmingham NHS Foundation Trust, Birmingham B15 2TH, England
| | - S. Manzoor
- Microbiome Treatment Centre, IBR West Link Level 2, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, West Midlands B15 2TT, England
| | - C.E. Moran
- Directorate of Infectious Diseases, University Hospitals Birmingham NHS Foundation Trust, Heartlands Hospital, Bordesley Green East, Birmingham B5 9SS, England
| | - K. Banavathi
- Department of Microbiology, University Hospitals of North Midlands, Stoke-on-Trent ST4 6QG, England
| | - H. Steed
- Department of Gastroenterology, The Royal Wolverhampton NHS Trust, New cross Hospital, Wolverhampton WV10 0QP, England
| | - D.C.O Massey
- Department of Gastroenterology, Cambridge University Hospitals NHS Foundation Trust, Hills Road, Cambridge CB2 0QQ, England
| | - G.R Trafford
- Department of Microbiology, University Hospitals Coventry and Warwickshire NHS Trust, Coventry, CV2 2DX CV2 2 DX University Hospital, Clifford Bridge Road, Coventry CV2 2DX, England
| | - T.H. Iqbal
- Microbiome Treatment Centre, IBR West Link Level 2, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, West Midlands B15 2TT, England
- Department of Gastroenterology, University Hospitals Birmingham NHS Foundation Trust, Birmingham B15 2TH, England
| | - P.M. Hawkey
- Institute of Microbiology and Infection, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham B15 2TH, England
- Microbiome Treatment Centre, IBR West Link Level 2, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, West Midlands B15 2TT, England
- Department of Microbiology, University Hospitals Birmingham NHS Foundation Trust, Birmingham, B15 2TH, England
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Insights into the Role of Human Gut Microbiota in Clostridioides difficile Infection. Microorganisms 2020; 8:microorganisms8020200. [PMID: 32023967 PMCID: PMC7074861 DOI: 10.3390/microorganisms8020200] [Citation(s) in RCA: 52] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2020] [Revised: 01/29/2020] [Accepted: 01/31/2020] [Indexed: 12/18/2022] Open
Abstract
Clostridioides difficile infection (CDI) has emerged as a major health problem worldwide. A major risk factor for disease development is prior antibiotic use, which disrupts the normal gut microbiota by altering its composition and the gut’s metabolic functions, leading to the loss of colonization resistance and subsequent CDI. Data from human studies have shown that the presence of C. difficile, either as a colonizer or as a pathogen, is associated with a decreased level of gut microbiota diversity. The investigation of the gut’s microbial communities, in both healthy subjects and patients with CDI, elucidate the role of microbiota and improve the current biotherapeutics for patients with CDI. Fecal microbiota transplantation has a major role in managing CDI, aiming at re-establishing colonization resistance in the host gastrointestinal tract by replenishing the gut microbiota. New techniques, such as post-genomics, proteomics and metabolomics analyses, can possibly determine in the future the way in which C. difficile eradicates colonization resistance, paving the way for the development of new, more successful treatments and prevention. The aim of the present review is to present recent data concerning the human gut microbiota with a focus on its important role in health and disease.
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Appaneal HJ, Caffrey AR, Beganovic M, Avramovic S, LaPlante KL. Predictors of Clostridioides difficile recurrence across a national cohort of veterans in outpatient, acute, and long-term care settings. Am J Health Syst Pharm 2019; 76:581-590. [PMID: 31361830 DOI: 10.1093/ajhp/zxz032] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
PURPOSE The greatest challenge in treating Clostridioides difficile infection (CDI) is disease recurrence, which occurs in about 20% of patients, usually within 30 days of treatment cessation. We sought to identify independent predictors of first recurrence among a national cohort of veterans with CDI. METHODS We conducted a case-control study among acute and long-term care Veterans Affairs (VA) inpatients and outpatients with a first CDI episode (positive stool sample for C. difficile toxin[s] and receipt of at least 2 days of CDI treatment) between 2010 and 2014. Cases experienced first recurrence within 30 days from the end of treatment. Controls were those without first recurrence matched 4:1 to cases on year, facility, and severity. Multivariable conditional logistic regression was used to identify predictors of first recurrence. RESULTS We identified 32 predictors of first recurrence among 974 cases and 3,896 matched controls. Significant predictors included medication use prior to (probiotics, fluoroquinolones, laxatives, third- or fourth-generation cephalosporins), during (first- or second-generation cephalosporins, penicillin/amoxicillin/ampicillin, third- and fourth-generation cephalosporins), and after CDI treatment (probiotics, any antibiotic, proton pump inhibitors [PPIs], and immunosuppressants). Other predictors included current biliary tract disease, malaise/fatigue, cellulitis/abscess, solid organ cancer, medical history of HIV, multiple myeloma, abdominal pain, and ulcerative colitis. CONCLUSION In a large national cohort of outpatient and acute and long-term care inpatients, treatment with certain antibiotics, PPIs, immunosuppressants, and underlying disease were among the most important risk factors for first CDI recurrence.
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Affiliation(s)
- Haley J Appaneal
- Infectious Diseases Research Program, Providence Veterans Affairs Medical Center, Providence, RI, and College of Pharmacy, University of Rhode Island, Kingston, RI
| | - Aisling R Caffrey
- Diseases Research Program, Providence Veterans Affairs Medical Center, Providence, RI, and College of Pharmacy, University of Rhode Island, Kingston, RI
| | - Maya Beganovic
- Diseases Research Program, Providence Veterans Affairs Medical Center, Providence, RI, and College of Pharmacy, University of Rhode Island, Kingston, RI
| | - Sanja Avramovic
- Health Administration and Policy, George Mason University, Fairfax, VA
| | - Kerry L LaPlante
- Infectious Diseases Research Program, Providence Veterans Affairs Medical Center, Providence, RI, and College of Pharmacy, University of Rhode Island, Kingston, RI
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Khoruts A, Hoffmann DE, Palumbo FB. The Impact of Regulatory Policies on the Future of Fecal Microbiota Transplantation. THE JOURNAL OF LAW, MEDICINE & ETHICS : A JOURNAL OF THE AMERICAN SOCIETY OF LAW, MEDICINE & ETHICS 2019; 47:482-504. [PMID: 31957587 DOI: 10.1177/1073110519897726] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/10/2023]
Abstract
In this article, the authors explore the impact of a potential future regulatory decision by FDA whether or not to continue its enforcement discretion policy allowing physicians to perform, and stool banks to sell, stool product for fecal microbiota transplantation as a treatment for recurrent Clostridium Difficile infection without an Investigative New Drug (IND) application. The paper looks at the Agency's regulatory options in light of the current gut microbiota based products that are in the FDA pipeline for drug approval and the potential impact and repercussions of their approval on FDA action. In laying out FDA's options we consider the implications of market exclusivity and off-label use of newly approved drugs. Ultimately, we explore the potential impact of FDA's decision on patients, research, and innovation.
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Affiliation(s)
- Alexander Khoruts
- Alexander Khoruts, M.D., is Professor of Medicine, Division of Gastroenterology, Hepatology, and Nutrition, Director, Luminal GI Section, and Medical Director of the Microbiota Therapeutics Program, Center for Immunology; BioTechnology Institute; Cancer Center; MICaB Graduate Program, University of Minnesota. Diane E. Hoffmann, J.D., Sc.M., is Jacob A. France Professor of Health Law and Director, Law & Health Care Program University of Maryland Francis King Carey School of Law. Francis B. Palumbo, Ph.D., J.D., is Professor and Executive Director, Center on Drugs and Public Policy, University of Maryland School of Pharmacy
| | - Diane E Hoffmann
- Alexander Khoruts, M.D., is Professor of Medicine, Division of Gastroenterology, Hepatology, and Nutrition, Director, Luminal GI Section, and Medical Director of the Microbiota Therapeutics Program, Center for Immunology; BioTechnology Institute; Cancer Center; MICaB Graduate Program, University of Minnesota. Diane E. Hoffmann, J.D., Sc.M., is Jacob A. France Professor of Health Law and Director, Law & Health Care Program University of Maryland Francis King Carey School of Law. Francis B. Palumbo, Ph.D., J.D., is Professor and Executive Director, Center on Drugs and Public Policy, University of Maryland School of Pharmacy
| | - Francis B Palumbo
- Alexander Khoruts, M.D., is Professor of Medicine, Division of Gastroenterology, Hepatology, and Nutrition, Director, Luminal GI Section, and Medical Director of the Microbiota Therapeutics Program, Center for Immunology; BioTechnology Institute; Cancer Center; MICaB Graduate Program, University of Minnesota. Diane E. Hoffmann, J.D., Sc.M., is Jacob A. France Professor of Health Law and Director, Law & Health Care Program University of Maryland Francis King Carey School of Law. Francis B. Palumbo, Ph.D., J.D., is Professor and Executive Director, Center on Drugs and Public Policy, University of Maryland School of Pharmacy
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49
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Mullish BH, Quraishi MN, Segal JP, McCune VL, Baxter M, Marsden GL, Moore D, Colville A, Bhala N, Iqbal TH, Settle C, Kontkowski G, Hart AL, Hawkey PM, Williams HR, Goldenberg SD. The use of faecal microbiota transplant as treatment for recurrent or refractory Clostridium difficile infection and other potential indications: joint British Society of Gastroenterology (BSG) and Healthcare Infection Society (HIS) guidelines. J Hosp Infect 2019; 100 Suppl 1:S1-S31. [PMID: 30173851 DOI: 10.1016/j.jhin.2018.07.037] [Citation(s) in RCA: 40] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2018] [Accepted: 07/23/2018] [Indexed: 02/08/2023]
Affiliation(s)
- Benjamin H Mullish
- Division of Integrative Systems Medicine and Digestive Disease, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, London, UK; Departments of Gastroenterology and Hepatology, St Mary's Hospital, Imperial College Healthcare NHS Trust, Paddington, London, UK
| | - Mohammed Nabil Quraishi
- Department of Gastroenterology, Queen Elizabeth Hospital Birmingham, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK
| | - Jonathan P Segal
- Division of Integrative Systems Medicine and Digestive Disease, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, London, UK; Inflammatory Bowel Disease Unit, St Mark's Hospital, Harrow, London, UK
| | - Victoria L McCune
- Public Health England, Public Health Laboratory Birmingham, Birmingham, UK; Institute of Microbiology and Infection, University of Birmingham, Birmingham, UK
| | - Melissa Baxter
- Department of Microbiology, Royal Devon and Exeter NHS Foundation Trust, Exeter, UK
| | | | - David Moore
- Institute of Applied Health Research, University of Birmingham, Birmingham, UK
| | - Alaric Colville
- Department of Microbiology, Royal Devon and Exeter NHS Foundation Trust, Exeter, UK
| | - Neeraj Bhala
- Department of Gastroenterology, Queen Elizabeth Hospital Birmingham, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK; Institute of Applied Health Research, University of Birmingham, Birmingham, UK; Institute of Translational Medicine, University of Birmingham, Edgbaston, Birmingham, UK
| | - Tariq H Iqbal
- Department of Gastroenterology, Queen Elizabeth Hospital Birmingham, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK; Institute of Translational Medicine, University of Birmingham, Edgbaston, Birmingham, UK
| | - Christopher Settle
- Department of Microbiology, City Hospitals Sunderland NHS Foundation Trust, Sunderland, UK
| | | | - Ailsa L Hart
- Division of Integrative Systems Medicine and Digestive Disease, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, London, UK; Inflammatory Bowel Disease Unit, St Mark's Hospital, Harrow, London, UK
| | - Peter M Hawkey
- Institute of Microbiology and Infection, University of Birmingham, Birmingham, UK
| | - Horace Rt Williams
- Division of Integrative Systems Medicine and Digestive Disease, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, London, UK; Departments of Gastroenterology and Hepatology, St Mary's Hospital, Imperial College Healthcare NHS Trust, Paddington, London, UK
| | - Simon D Goldenberg
- Centre for Clinical Infection and Diagnostics Research, King's College London, London, UK; Department of Microbiology, Guy's and St Thomas' NHS Foundation Trust, London UK.
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50
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Schepici G, Silvestro S, Bramanti P, Mazzon E. The Gut Microbiota in Multiple Sclerosis: An Overview of Clinical Trials. Cell Transplant 2019; 28:1507-1527. [PMID: 31512505 PMCID: PMC6923550 DOI: 10.1177/0963689719873890] [Citation(s) in RCA: 117] [Impact Index Per Article: 19.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Multiple sclerosis (MS) is a chronic, inflammatory, demyelinating, and
degenerative disease that affects the central nervous system. A recent study
showed that interaction between the immune system and the gut microbiota plays a
crucial role in the development of MS. This review reports the clinical studies
carried out in recent years that aimed to evaluate the composition of the
microbiota in patients with relapsing–remitting MS (RR-MS). We also report what
is available in the literature regarding the effectiveness of fecal microbiota
transplantation and the role of the diet in restoring the intestinal bacterial
population. Studies report that patients with RR-MS have a microbiota that,
compared with healthy controls, has higher amounts of
Pedobacteria, Flavobacterium,
Pseudomonas, Mycoplana,
Acinetobacter, Eggerthella,
Dorea, Blautia,
Streptococcus and Akkermansia. In
contrast, MS patients have a microbiota with impoverished microbial populations
of Prevotella, Bacteroides,
Parabacteroides, Haemophilus,
Sutterella, Adlercreutzia,
Coprobacillus, Lactobacillus,
Clostridium, Anaerostipes and
Faecalibacterium. In conclusion, the restoration of the
microbial population in patients with RR-MS appears to reduce inflammatory
events and the reactivation of the immune system.
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Affiliation(s)
- Giovanni Schepici
- IRCCS Centro Neurolesi "Bonino Pulejo", Messina, Italy.,Both the authors contributed equally to this article
| | - Serena Silvestro
- IRCCS Centro Neurolesi "Bonino Pulejo", Messina, Italy.,Both the authors contributed equally to this article
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