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Fasano A, Matera M. Probiotics to Prevent Celiac Disease and Inflammatory Bowel Diseases. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2024; 1449:95-111. [PMID: 39060733 DOI: 10.1007/978-3-031-58572-2_6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 07/28/2024]
Abstract
The incidence of chronic inflammatory diseases (CIDs) is dramatically increasing in the developed world, resulting in an increased burden of disease in childhood. Currently, there are limited effective strategies for treating or preventing these conditions. To date, myriads of cross-sectional studies have described alterations in the composition of the gut microbiota in a variety of disease states, after the disease has already occurred. We suggest that to mechanically link these microbiome changes with disease pathogenesis, a prospective cohort design is needed to capture changes that precede or coincide with disease onset and symptoms. In addition, these prospective studies must integrate microbiological, metagenomic, meta transcriptomic and metabolomic data with minimal and standardized clinical and environmental metadata that allow to correctly compare and interpret the results of the analysis of the human microbiota in order to build a system-level model of the interactions between the host and the development of the disease. The creation of new biological computational models thus constructed will allow us to finally move from the detection of simple elements of "association" to the identification of elements of real "causality" allowing to provide a mechanistic approach to the exploration of the development of CIDs.This can only be done when these diseases are studied as complex biological networks. In this chapter we discuss the current knowledge regarding the contribution of the microbiome to CID in childhood, focusing on celiac disease and inflammatory bowel disease, with the overall aim of identifying pathways to shift research from descriptive to mechanistic approaches. We then examine how some components of the microbiota, through epigenetic reprogramming, can start the march from genetic predisposition to clinical expression of CIDs, thus opening up new possibilities for intervention, through microbiota therapy targeting the manipulation of the composition and function of the microbiota, for future applications of precision medicine and primary prevention.
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Affiliation(s)
- Alessio Fasano
- Research Centre for Immunology and Mucosal Biology and Division of Pediatric Gastroenterology and Nutrition, Massachusetts General Hospital for Children - Harvard Medical School, Boston, USA, MA.
- Mucosal Immunology and Biology Research Center and Division of Pediatric Gastroenterology and Nutrition, Mass General for Children - Harvard Medical School, Boston, MA, USA.
| | - Mariarosaria Matera
- Neonatologist, Neurodevelopmental Clinics and Pediatric Clinical Microbiomic - Misericordia Hospital, Grosseto, Italy
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Paris T, Kiss A, Signor L, Lutfalla G, Blaise M, Boeri Erba E, Chaloin L, Yatime L. The IbeA protein from adherent invasive Escherichia coli is a flavoprotein sharing structural homology with FAD-dependent oxidoreductases. FEBS J 2024; 291:177-203. [PMID: 37786987 DOI: 10.1111/febs.16969] [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: 06/30/2023] [Revised: 09/22/2023] [Accepted: 09/29/2023] [Indexed: 10/04/2023]
Abstract
Invasion of brain endothelium protein A (IbeA) is a virulence factor specific to pathogenic Escherichia coli. Originally identified in the K1 strain causing neonatal meningitis, it was more recently found in avian pathogenic Escherichia coli (APEC) and adherent invasive Escherichia coli (AIEC). In these bacteria, IbeA facilitates host cell invasion and intracellular survival, in particular, under harsh conditions like oxidative stress. Furthermore, IbeA from AIEC contributes to intramacrophage survival and replication, thus enhancing the inflammatory response within the intestine. Therefore, this factor is a promising drug target for anti-AIEC strategies in the context of Crohn's disease. Despite such an important role, the biological function of IbeA remains largely unknown. In particular, its exact nature and cellular localization, i.e., membrane-bound invasin versus cytosolic factor, are still of debate. Here, we developed an efficient protocol for recombinant expression of IbeA under native conditions and demonstrated that IbeA from AIEC is a soluble, homodimeric flavoprotein. Using mass spectrometry and tryptophan fluorescence measurements, we further showed that IbeA preferentially binds flavin adenine dinucleotide (FAD), with an affinity in the one-hundred nanomolar range and optimal binding under reducing conditions. 3D-modeling with AlphaFold revealed that IbeA shares strong structural homology with FAD-dependent oxidoreductases. Finally, we used ligand docking, mutational analyses, and molecular dynamics simulations to identify the FAD binding pocket within IbeA and characterize possible conformational changes occurring upon ligand binding. Overall, we suggest that the role of IbeA in the survival of AIEC within host cells, notably macrophages, is linked to modulation of redox processes.
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Affiliation(s)
- Théo Paris
- LPHI, Univ. Montpellier, CNRS, INSERM, France
| | - Agneta Kiss
- Univ. Grenoble Alpes, CEA, CNRS, IBS, Grenoble, France
| | - Luca Signor
- Univ. Grenoble Alpes, CEA, CNRS, IBS, Grenoble, France
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Flores E, Dutta S, Bosserman R, van Hoof A, Krachler AM. Colonization of larval zebrafish ( Danio rerio) with adherent-invasive Escherichia coli prevents recovery of the intestinal mucosa from drug-induced enterocolitis. mSphere 2023; 8:e0051223. [PMID: 37971273 PMCID: PMC10732064 DOI: 10.1128/msphere.00512-23] [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: 09/05/2023] [Accepted: 10/07/2023] [Indexed: 11/19/2023] Open
Abstract
IMPORTANCE Although inflammatory bowel diseases are on the rise, what factors influence IBD risk and severity, and the underlying mechanisms remain to be fully understood. Although host genetics, microbiome, and environmental factors have all been shown to correlate with the development of IBD, cause and effect are difficult to disentangle in this context. For example, AIEC is a known pathobiont found in IBD patients, but it remains unclear if gut inflammation during IBD facilitates colonization with AIEC, or if AIEC colonization makes the host more susceptible to pro-inflammatory stimuli. It is critical to understand the mechanisms that contribute to AIEC infections in a susceptible host in order to develop successful therapeutics. Here, we show that the larval zebrafish model recapitulates key features of AIEC infections in other animal models and can be utilized to address these gaps in knowledge.
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Affiliation(s)
- Erika Flores
- Microbiology and Infectious Diseases Program, MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, University of Texas, Houston, Texas, USA
- Department of Microbiology and Molecular Genetics, The University of Texas Health Science Center at Houston, Houston, Texas, USA
| | - Soumita Dutta
- Department of Microbiology and Molecular Genetics, The University of Texas Health Science Center at Houston, Houston, Texas, USA
| | - Rachel Bosserman
- Department of Microbiology and Molecular Genetics, The University of Texas Health Science Center at Houston, Houston, Texas, USA
| | - Ambro van Hoof
- Microbiology and Infectious Diseases Program, MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, University of Texas, Houston, Texas, USA
- Department of Microbiology and Molecular Genetics, The University of Texas Health Science Center at Houston, Houston, Texas, USA
| | - Anne-Marie Krachler
- Microbiology and Infectious Diseases Program, MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, University of Texas, Houston, Texas, USA
- Department of Microbiology and Molecular Genetics, The University of Texas Health Science Center at Houston, Houston, Texas, USA
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Zangara MT, Darwish L, Coombes BK. Characterizing the Pathogenic Potential of Crohn's Disease-Associated Adherent-Invasive Escherichia coli. EcoSal Plus 2023; 11:eesp00182022. [PMID: 37220071 PMCID: PMC10729932 DOI: 10.1128/ecosalplus.esp-0018-2022] [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: 03/20/2023] [Accepted: 05/04/2023] [Indexed: 01/28/2024]
Abstract
The microbiome of Crohn's disease (CD) patients is composed of a microbial community that is considered dysbiotic and proinflammatory in nature. The overrepresentation of Enterobacteriaceae species is a common feature of the CD microbiome, and much attention has been given to understanding the pathogenic role this feature plays in disease activity. Over 2 decades ago, a new Escherichia coli subtype called adherent-invasive E. coli (AIEC) was isolated and linked to ileal Crohn's disease. Since the isolation of the first AIEC strain, additional AIEC strains have been isolated from both inflammatory bowel disease (IBD) patients and non-IBD individuals using the original in vitro phenotypic characterization methods. Identification of a definitive molecular marker of the AIEC pathotype has been elusive; however, significant advancements have been made in understanding the genetic, metabolic, and virulence determinants of AIEC infection biology. Here, we review the current knowledge of AIEC pathogenesis to provide additional, objective measures that could be considered in defining AIEC and their pathogenic potential.
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Affiliation(s)
- Megan T. Zangara
- Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario, Canada
| | - Lena Darwish
- Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario, Canada
| | - Brian K. Coombes
- Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario, Canada
- Michael G. DeGroote Institute for Infectious Disease Research, Hamilton, Ontario, Canada
- Farncombe Family Digestive Health Research Institute, Hamilton, Ontario, Canada
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Hamed SA, Mohan A, Navaneetha Krishnan S, Wang A, Drikic M, Prince NL, Lewis IA, Shearer J, Keita ÅV, Söderholm JD, Shutt TE, McKay DM. Butyrate reduces adherent-invasive E. coli-evoked disruption of epithelial mitochondrial morphology and barrier function: involvement of free fatty acid receptor 3. Gut Microbes 2023; 15:2281011. [PMID: 38078655 PMCID: PMC10730202 DOI: 10.1080/19490976.2023.2281011] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/24/2023] [Accepted: 11/05/2023] [Indexed: 12/18/2023] Open
Abstract
Gut bacteria provide benefits to the host and have been implicated in inflammatory bowel disease (IBD), where adherent-invasive E. coli (AIEC) pathobionts (e.g., strain LF82) are associated with Crohn's disease. E. coli-LF82 causes fragmentation of the epithelial mitochondrial network, leading to increased epithelial permeability. We hypothesized that butyrate would limit the epithelial mitochondrial disruption caused by E. coli-LF82. Human colonic organoids and the T84 epithelial cell line infected with E. coli-LF82 (MOI = 100, 4 h) showed a significant increase in mitochondrial network fission that was reduced by butyrate (10 mM) co-treatment. Butyrate reduced the loss of mitochondrial membrane potential caused by E. coli-LF82 and increased expression of PGC-1α mRNA, the master regulator of mitochondrial biogenesis. Metabolomics revealed that butyrate significantly altered E. coli-LF82 central carbon metabolism leading to diminished glucose uptake and increased succinate secretion. Correlating with preservation of mitochondrial network form/function, butyrate reduced E. coli-LF82 transcytosis across T84-cell monolayers. The use of the G-protein inhibitor, pertussis toxin, implicated GPCR signaling as critical to the effect of butyrate, and the free fatty acid receptor three (FFAR3, GPR41) agonist, AR420626, reproduced butyrate's effect in terms of ameliorating the loss of barrier function and reducing the mitochondrial fragmentation observed in E. coli-LF82 infected T84-cells and organoids. These data indicate that butyrate helps maintain epithelial mitochondrial form/function when challenged by E. coli-LF82 and that this occurs, at least in part, via FFAR3. Thus, loss of butyrate-producing bacteria in IBD in the context of pathobionts would contribute to loss of epithelial mitochondrial and barrier functions that could evoke disease and/or exaggerate a low-grade inflammation.
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Affiliation(s)
- Samira A. Hamed
- Gastrointestinal Research Group, Inflammation Research Network, Host-Parasite Interactions Program, Department of Physiology & Pharmacology, Calvin, Phoebe and Joan Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, Canada
| | - Armaan Mohan
- Departments of Medical Genetics and Biochemistry & Molecular Biology, Alberta Children’s Hospital Research Institute, Hotchkiss Brain Institute, Snyder Institute, Cumming School of Medicine, University of Calgary, Calgary, Canada
| | - Saranya Navaneetha Krishnan
- Gastrointestinal Research Group, Inflammation Research Network, Host-Parasite Interactions Program, Department of Physiology & Pharmacology, Calvin, Phoebe and Joan Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, Canada
| | - Arthur Wang
- Gastrointestinal Research Group, Inflammation Research Network, Host-Parasite Interactions Program, Department of Physiology & Pharmacology, Calvin, Phoebe and Joan Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, Canada
| | - Marija Drikic
- Calgary Metabolomics Research Facility, Department of Biological Sciences, Faculty of Science, University of Calgary, Calgary, Canada
| | - Nicole L. Prince
- Gastrointestinal Research Group, Inflammation Research Network, Host-Parasite Interactions Program, Department of Physiology & Pharmacology, Calvin, Phoebe and Joan Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, Canada
| | - Ian A. Lewis
- Calgary Metabolomics Research Facility, Department of Biological Sciences, Faculty of Science, University of Calgary, Calgary, Canada
| | - Jane Shearer
- Department of Biochemistry and Molecular Biology, Faculty of Kinesiology, University of Calgary, Calgary, Canada
| | - Åsa V. Keita
- Department of Biomedical and Clinical Sciences, Division of Surgery, Orthopedics and Oncology, Linköping University, Linköping, Sweden
| | - Johan D. Söderholm
- Department of Biomedical and Clinical Sciences, Division of Surgery, Orthopedics and Oncology, Linköping University, Linköping, Sweden
| | - Timothy E. Shutt
- Departments of Medical Genetics and Biochemistry & Molecular Biology, Alberta Children’s Hospital Research Institute, Hotchkiss Brain Institute, Snyder Institute, Cumming School of Medicine, University of Calgary, Calgary, Canada
| | - Derek M. McKay
- Gastrointestinal Research Group, Inflammation Research Network, Host-Parasite Interactions Program, Department of Physiology & Pharmacology, Calvin, Phoebe and Joan Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, Canada
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Estevinho MM, Cabeda J, Santiago M, Machado E, Silva R, Duro M, Pita I, Morais R, Macedo G, Bull TJ, Magro F, Sarmento A. Viable Mycobacterium avium subsp. paratuberculosis Colonizes Peripheral Blood of Inflammatory Bowel Disease Patients. Microorganisms 2023; 11:1520. [PMID: 37375022 DOI: 10.3390/microorganisms11061520] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2023] [Revised: 05/31/2023] [Accepted: 06/04/2023] [Indexed: 06/29/2023] Open
Abstract
Pathobionts, particularly Mycobacterium avium subsp. paratuberculosis (MAP) and Escherichia coli isolates with adherence/invasive ability (AIEC) have been associated with inflammatory bowel disease (IBD), particularly Crohn's disease (CD). This study aimed to evaluate the frequency of viable MAP and AIEC in a cohort of IBD patients. As such, MAP and E. coli cultures were established from faecal and blood samples (with a total n = 62 for each) of patients with CD (n = 18), ulcerative colitis (UC, n = 15), or liver cirrhosis (n = 7), as well as from healthy controls (HC, n = 22). Presumptive positive cultures were tested by polymerase chain reaction (PCR), for a positive confirmation of MAP or E. coli identity. E. coli-confirmed isolates were then tested for AIEC identity using adherence and invasion assays in the epithelial cell line of Caco-2 and survival and replication assays in the macrophage cell line of J774. MAP sub-culture and genome sequencing were also performed. MAP was more frequently cultured from the blood and faecal samples of patients with CD and cirrhosis. E. coli presumptive colonies were isolated from the faecal samples of most individuals, in contrast to what was registered for the blood samples. Additionally, from the confirmed E. coli isolates, only three had an AIEC-like phenotype (i.e., one CD patient and two UC patients). This study confirmed the association between MAP and CD; however, it did not find a strong association between the presence of AIEC and CD. It may be hypothesized that the presence of viable MAP in the bloodstream of CD patients contributes to disease reactivation.
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Affiliation(s)
- Maria Manuela Estevinho
- Department of Gastroenterology, Vila Nova de Gaia/Espinho Hospital Center, 4434-502 Vila Nova de Gaia, Portugal
- Department of Biomedicine, Unit of Pharmacology and Therapeutics, Faculty of Medicine, University of Porto, 4050-313 Porto, Portugal
| | - José Cabeda
- FP-I3ID, Universidade Fernando Pessoa, 4200-150 Porto, Portugal
- Escola Superior de Saúde Fernando Pessoa, 4200-253 Porto, Portugal
- Centro Interdisciplinar de Investigação Marinha e Ambiental (CIIMAR, CIMAR), 4450-208 Matosinhos, Portugal
| | - Mafalda Santiago
- Department of Biomedicine, Unit of Pharmacology and Therapeutics, Faculty of Medicine, University of Porto, 4050-313 Porto, Portugal
| | - Elisabete Machado
- FP-I3ID, Universidade Fernando Pessoa, 4200-150 Porto, Portugal
- UCIBIO-Applied Molecular Biosciences Unit, Laboratory of Microbiology, Department of Biological Sciences, REQUIMTE, Faculty of Pharmacy, University of Porto, 4050-313 Porto, Portugal
- Faculdade de Ciências da Saúde, Universidade Fernando Pessoa, 4200-150 Porto, Portugal
| | - Ricardo Silva
- FP-I3ID, Universidade Fernando Pessoa, 4200-150 Porto, Portugal
- Escola Superior de Saúde Fernando Pessoa, 4200-253 Porto, Portugal
| | - Mary Duro
- FP-I3ID, Universidade Fernando Pessoa, 4200-150 Porto, Portugal
- Escola Superior de Saúde Fernando Pessoa, 4200-253 Porto, Portugal
- LAQV@REQUIMTE, Faculty of Pharmacy, University of Porto, 4050-313 Porto, Portugal
| | - Inês Pita
- Department of Gastroenterology, Entre Douro e Vouga Hospital Center, 4520-211 Santa Maria da Feira, Portugal
| | - Rui Morais
- Department of Gastroenterology, São João University Hospital Center, 4200-319 Porto, Portugal
| | - Guilherme Macedo
- Department of Gastroenterology, São João University Hospital Center, 4200-319 Porto, Portugal
| | - Tim J Bull
- Institute of Infection and Immunity, St George's University of London, London SW17 ORE, UK
| | - Fernando Magro
- Department of Biomedicine, Unit of Pharmacology and Therapeutics, Faculty of Medicine, University of Porto, 4050-313 Porto, Portugal
- Department of Gastroenterology, São João University Hospital Center, 4200-319 Porto, Portugal
| | - Amélia Sarmento
- FP-I3ID, Universidade Fernando Pessoa, 4200-150 Porto, Portugal
- Faculdade de Ciências da Saúde, Universidade Fernando Pessoa, 4200-150 Porto, Portugal
- I3S, Instituto de Investigação e Inovação em Saúde, Universidade do Porto, 4200-150 Porto, Portugal
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Chen X, Mendes BG, Alves BS, Duan Y. Phage therapy in gut microbiome. PROGRESS IN MOLECULAR BIOLOGY AND TRANSLATIONAL SCIENCE 2023; 201:93-118. [PMID: 37770177 DOI: 10.1016/bs.pmbts.2023.04.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/03/2023]
Abstract
Phage therapy, the use of bacteriophage viruses for bacterial infection treatment, has been around for almost a century, but with the increase in antibiotic use, its importance has declined rapidly. There has been renewed interest in revisiting this practice due to the general decline in the effectiveness of antibiotics, combined with improved understanding of human microbiota and advances in sequencing technologies. Phage therapy has been proposed as a clinical alternative to restore the gut microbiota in the absence of an effective treatment. That is due to its immunomodulatory and bactericidal effects against its target bacteria. In the gastrointestinal diseases field, phage therapy has been studied mainly as a promising tool in infectious diseases treatment, such as cholera and diarrhea. However, many studies have been conducted in non-communicable diseases, such as the targeting of adherent invasive Escherichia coli in Crohn's disease, the treatment of Clostridioides difficile in ulcerative colitis, the eradication of Fusobacterium nucleatum in colorectal cancer, the targeting of alcohol-producing Klebsiella pneumoniae in non-alcoholic fatty liver disease, or Enterococcus faecalis in alcohol-associated hepatitis. This review will summarize the changes in the gut microbiota and the phageome in association with some gastrointestinal and liver diseases and highlight the recent scientific advances in phage therapy as a therapeutic tool for their treatment.
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Affiliation(s)
- Xingyao Chen
- Department of Infectious Diseases, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China; The CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China
| | - Beatriz G Mendes
- Department of Clinical Analysis, Health Sciences Center, Federal University of Santa Catarina, Campus Universitário Trindade, Florianópolis, Santa Catarina, Brazil
| | - Bruno Secchi Alves
- Department of Clinical Analysis, Health Sciences Center, Federal University of Santa Catarina, Campus Universitário Trindade, Florianópolis, Santa Catarina, Brazil
| | - Yi Duan
- Department of Infectious Diseases, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China; The CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China.
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Evidence for a Causal Role for Escherichia coli Strains Identified as Adherent-Invasive (AIEC) in Intestinal Inflammation. mSphere 2023; 8:e0047822. [PMID: 36883813 PMCID: PMC10117065 DOI: 10.1128/msphere.00478-22] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/09/2023] Open
Abstract
Enrichment of adherent-invasive Escherichia coli (AIEC) has been consistently detected in subsets of inflammatory bowel disease (IBD) patients. Although some AIEC strains cause colitis in animal models, these studies did not systematically compare AIEC with non-AIEC strains, and causal links between AIEC and disease are still disputed. Specifically, it remains unclear whether AIEC shows enhanced pathogenicity compared to that of commensal E. coli found in the same ecological microhabitat and if the in vitro phenotypes used to classify strains as AIEC are pathologically relevant. Here, we utilized in vitro phenotyping and a murine model of intestinal inflammation to systematically compare strains identified as AIEC with those identified as non-AIEC and relate AIEC phenotypes to pathogenicity. Strains identified as AIEC caused, on average, more severe intestinal inflammation. Intracellular survival/replication phenotypes routinely used to classify AIEC positively correlated with disease, while adherence to epithelial cells and tumor necrosis factor alpha production by macrophages did not. This knowledge was then applied to design and test a strategy to prevent inflammation by selecting E. coli strains that adhered to epithelial cells but poorly survived/replicated intracellularly. Two E. coli strains that ameliorated AIEC-mediated disease were subsequently identified. In summary, our results show a relationship between intracellular survival/replication in E. coli and pathology in murine colitis, suggesting that strains possessing these phenotypes might not only become enriched in human IBD but also contribute to disease. We provide new evidence that specific AIEC phenotypes are pathologically relevant and proof of principle that such mechanistic information can be therapeutically exploited to alleviate intestinal inflammation. IMPORTANCE Inflammatory bowel disease (IBD) is associated with an altered gut microbiota composition, including expansion of Proteobacteria. Many species in this phylum are thought to contribute to disease under certain conditions, including adherent-invasive Escherichia coli (AIEC) strains, which are enriched in some patients. However, whether this bloom contributes to disease or is just a response to IBD-associated physiological changes is unknown. Although assigning causality is challenging, appropriate animal models can test the hypothesis that AIEC strains have an enhanced ability to cause colitis in comparison to other gut commensal E. coli strains and to identify bacterial traits contributing to virulence. We observed that AIEC strains are generally more pathogenic than commensal E. coli and that bacterial intracellular survival/replication phenotypes contributed to disease. We also found that E. coli strains lacking primary virulence traits can prevent inflammation. Our findings provide critical information on E. coli pathogenicity that may inform development of IBD diagnostic tools and therapies.
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Bile Acids and the Microbiome: Making Sense of This Dynamic Relationship in Their Role and Management in Crohn's Disease. Can J Gastroenterol Hepatol 2022; 2022:8416578. [PMID: 35360442 PMCID: PMC8964223 DOI: 10.1155/2022/8416578] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/19/2021] [Accepted: 03/05/2022] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND Bile acids help maintain the physiological balance of the gut microbiome and the integrity of the intestinal epithelial barrier. Similarly, intestinal bacteria play a major role in bile acid metabolism as they are involved in crucial biotransformation steps in the enterohepatic circulation pathway. Understanding the relationship between bile acid signalling and the gut microbiome in Crohn's disease can help target new and innovative treatment strategies. AIMS This review summarises the relationship between bile acids and the microbiome in Crohn's disease and discusses potential novel therapeutic options. METHODS We performed a literature review on bile acid signalling, its effect on the gut microbiome, and therapeutic applications in Crohn's disease. RESULTS Current research suggests that there is a strong interplay between the dysregulated microbiota, bile acid metabolism, and the mucosal immune system that can result in a changed immunological function, triggering the inflammatory response in Crohn's disease. Recent studies have demonstrated an association with altering the enterohepatic circulation and activating the farnesoid X receptor signalling pathway with the use of probiotics and faecal microbial transplantation, respectively. Bile acid sequestrants have been shown to have anti-inflammatory, cytoprotective, and anti-apoptotic properties with the potential to alter the intestinal microbial composition, suggesting a possible role in inducing and maintaining Crohn's disease. CONCLUSIONS Active Crohn's disease has been correlated with changes in bacterial concentrations, which may be associated with changes in bile acid modification. Further research should focus on targeting these areas for future therapeutic options.
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López-Siles M, Camprubí-Font C, Gómez del Pulgar EM, Sabat Mir M, Busquets D, Sanz Y, Martinez-Medina M. Prevalence, Abundance, and Virulence of Adherent-Invasive Escherichia coli in Ulcerative Colitis, Colorectal Cancer, and Coeliac Disease. Front Immunol 2022; 13:748839. [PMID: 35359974 PMCID: PMC8960851 DOI: 10.3389/fimmu.2022.748839] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2021] [Accepted: 01/31/2022] [Indexed: 01/08/2023] Open
Abstract
BACKGROUND & AIMS Adherent-invasive E. coli (AIEC) has largely been implicated in the pathogenesis of Crohn's disease (CD). E. coli strains with similar genetic backgrounds and virulence genes profiles have been associated with other intestinal disorders, such as ulcerative colitis (UC), colorectal cancer (CRC), and coeliac disease (CeD), but the role of AIEC in these diseases remains unexplored. We aimed to assess the distribution, abundance, and pathogenic features of AIEC in UC, CRC, and CeD. METHODS The AIEC phenotype was investigated in 4,233 E. coli isolated from the ileum and colon of 14 UC and 15 CRC patients and in 38 fecal E. coli strains obtained from 17 CeD and 10 healthy (H) children. AIEC prevalence and abundance were compared with previous data from CD patients and H controls. Clonality, virulence gene carriage, and phylogenetic origin were determined for the AIEC identified. RESULTS In UC, AIEC prevalence was intermediate between CD and H subjects (UC: 35.7%, CD: 55.0%, H: 21.4%), and similar to CD patients with colonic disease (C-CD: 40.0%). In CRC, the prevalence was lower (6.7%) than these groups. In patients with AIEC, the estimated abundance was similar across all intestinal conditions. All AIEC strains isolated from UC and CRC belonged to the B1 phylogroup, except for a strain of the A phylogroup, and the majority (75% of clonally distinct AIEC) harbored the Afa/Dr operon and the cdt gene. None of the E. coli isolated from the CeD cohort were AIEC. Nonetheless, E. coli strains isolated from active CeD patients showed higher invasion indices than those isolated from H and inactive CeD pediatric patients. CONCLUSION We support the hypothesis that AIEC-like strains can be involved not only in CD but also in UC. Further works are needed to study the virulence particularities of these groups of strains and to determine if there is a causative link between AIEC and UC. In contrast, we rule out the possible association of AIEC with CRC. In addition, to further study the E. coli strains in CeD for their possible pathogenic role would be of interest.
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Affiliation(s)
- Mireia López-Siles
- Microbiology of Intestinal Diseases, Biology Department, Universitat de Girona, Girona, Spain
| | - Carla Camprubí-Font
- Microbiology of Intestinal Diseases, Biology Department, Universitat de Girona, Girona, Spain
| | - Eva M. Gómez del Pulgar
- Instituto de Agroquímica y Tecnología de Alimentos, Spanish National Research Council (CSIC), Paterna, Spain
| | - Miriam Sabat Mir
- Department of Gastroenterology, Hospital Santa Caterina, Salt, Spain
| | - David Busquets
- Department of Gastroenterology, Hospital Universitari Doctor Josep Trueta, Girona, Spain
| | - Yolanda Sanz
- Instituto de Agroquímica y Tecnología de Alimentos, Spanish National Research Council (CSIC), Paterna, Spain
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Dong F, Xiao F, Li X, Li Y, Wang X, Yu G, Zhang T, Wang Y. Pediococcus pentosaceus CECT 8330 protects DSS-induced colitis and regulates the intestinal microbiota and immune responses in mice. J Transl Med 2022; 20:33. [PMID: 35033121 PMCID: PMC8761308 DOI: 10.1186/s12967-022-03235-8] [Citation(s) in RCA: 54] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2021] [Accepted: 01/05/2022] [Indexed: 12/12/2022] Open
Abstract
Background Compelling evidences demonstrated that gut microbiota dysbiosis plays a critical role in the pathogenesis of inflammatory bowel diseases (IBD). Therapies for targeting the microbiota may provide alternative options for the treatment of IBD, such as probiotics. Here, we aimed to investigate the protective effect of a probiotic strain, Pediococcus pentosaceus (P. pentosaceus) CECT 8330, on dextran sulfate sodium (DSS)-induced colitis in mice. Methods C57BL/6 mice were administered phosphate-buffered saline (PBS) or P. pentosaceus CECT 8330 (5 × 108 CFU/day) once daily by gavage for 5 days prior to or 2 days after colitis induction by DSS. Weight, fecal conditions, colon length and histopathological changes were examined. ELISA and flow cytometry were applied to determine the cytokines and regulatory T cells (Treg) ratio. Western blot was used to examine the tight junction proteins (TJP) in colonic tissues. Fecal short-chain fatty acids (SCFAs) levels and microbiota composition were analyzed by targeted metabolomics and 16S rRNA gene sequencing, respectively. The Kyoto Encyclopedia of Genes and Genomes (KEGG) and Cluster of orthologous groups of proteins (COG) pathway analysis were used to predict the microbial functional profiles. Results P. pentosaceus CECT 8330 treatment protected DSS-induced colitis in mice as evidenced by reducing the weight loss, disease activity index (DAI) score, histological damage, and colon length shortening. P. pentosaceus CECT 8330 decreased the serum levels of proinflammatory cytokines (TNF-α, IL-1β, and IL-6), and increased level of IL-10 in DSS treated mice. P. pentosaceus CECT 8330 upregulated the expression of ZO-1, Occludin and the ratio of Treg cells in colon tissue. P. pentosaceus CECT 8330 increased the fecal SCFAs level and relative abundances of several protective bacteria genera, including norank_f_Muribaculaceae, Lactobacillus, Bifidobacterium, and Dubosiella. Furthermore, the increased abundances of bacteria genera were positively correlated with IL-10 and SCFAs levels, and negatively associated with IL-6, IL-1β, and TNF-α, respectively. The KEGG and COG pathway analysis revealed that P. pentosaceus CECT 8330 could partially recover the metabolic pathways altered by DSS. Conclusions P. pentosaceus CECT 8330 administration protects the DSS-induced colitis and modulates the gut microbial composition and function, immunological profiles, and the gut barrier function. Therefore, P. pentosaceus CECT 8330 may serve as a promising probiotic to ameliorate intestinal inflammation. Supplementary Information The online version contains supplementary material available at 10.1186/s12967-022-03235-8.
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Affiliation(s)
- Fang Dong
- Department of Gastroenterology, Hepatology and Nutrition, Shanghai Children's Hospital, Shanghai Jiao Tong University, 355 Luding Road, Shanghai, 200062, China
| | - Fangfei Xiao
- Department of Gastroenterology, Hepatology and Nutrition, Shanghai Children's Hospital, Shanghai Jiao Tong University, 355 Luding Road, Shanghai, 200062, China
| | - Xiaolu Li
- Department of Gastroenterology, Hepatology and Nutrition, Shanghai Children's Hospital, Shanghai Jiao Tong University, 355 Luding Road, Shanghai, 200062, China
| | - Youran Li
- Department of Gastroenterology, Hepatology and Nutrition, Shanghai Children's Hospital, Shanghai Jiao Tong University, 355 Luding Road, Shanghai, 200062, China
| | - Xufei Wang
- Department of Gastroenterology, Hepatology and Nutrition, Shanghai Children's Hospital, Shanghai Jiao Tong University, 355 Luding Road, Shanghai, 200062, China
| | - Guangjun Yu
- Institue of Pediatric Infection, Immunity and Critical Care Medicine, Shanghai Children's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200062, China
| | - Ting Zhang
- Department of Gastroenterology, Hepatology and Nutrition, Shanghai Children's Hospital, Shanghai Jiao Tong University, 355 Luding Road, Shanghai, 200062, China. .,Institue of Pediatric Infection, Immunity and Critical Care Medicine, Shanghai Children's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200062, China.
| | - Yizhong Wang
- Department of Gastroenterology, Hepatology and Nutrition, Shanghai Children's Hospital, Shanghai Jiao Tong University, 355 Luding Road, Shanghai, 200062, China. .,Institue of Pediatric Infection, Immunity and Critical Care Medicine, Shanghai Children's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200062, China.
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12
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Schupack DA, Mars RAT, Voelker DH, Abeykoon JP, Kashyap PC. The promise of the gut microbiome as part of individualized treatment strategies. Nat Rev Gastroenterol Hepatol 2022; 19:7-25. [PMID: 34453142 PMCID: PMC8712374 DOI: 10.1038/s41575-021-00499-1] [Citation(s) in RCA: 80] [Impact Index Per Article: 26.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 07/14/2021] [Indexed: 02/07/2023]
Abstract
Variability in disease presentation, progression and treatment response has been a central challenge in medicine. Although variability in host factors and genetics are important, it has become evident that the gut microbiome, with its vast genetic and metabolic diversity, must be considered in moving towards individualized treatment. In this Review, we discuss six broad disease groups: infectious disease, cancer, metabolic disease, cardiovascular disease, autoimmune or inflammatory disease, and allergic and atopic diseases. We highlight current knowledge on the gut microbiome in disease pathogenesis and prognosis, efficacy, and treatment-related adverse events and its promise for stratifying existing treatments and as a source of novel therapies. The Review is not meant to be comprehensive for each disease state but rather highlights the potential implications of the microbiome as a tool to individualize treatment strategies in clinical practice. Although early, the outlook is optimistic but challenges need to be overcome before clinical implementation, including improved understanding of underlying mechanisms, longitudinal studies with multiple data layers reflecting gut microbiome and host response, standardized approaches to testing and reporting, and validation in larger cohorts. Given progress in the microbiome field with concurrent basic and clinical studies, the microbiome will likely become an integral part of clinical care within the next decade.
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Affiliation(s)
- Daniel A Schupack
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA
| | - Ruben A T Mars
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA
| | - Dayne H Voelker
- Division of Internal Medicine, Mayo Clinic, Rochester, MN, USA
| | - Jithma P Abeykoon
- Division of Hematology and Oncology, Mayo Clinic, Rochester, MN, USA
| | - Purna C Kashyap
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA.
- Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, MN, USA.
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13
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Aloi M, Cucchiara S. Crohn’s Disease. TEXTBOOK OF PEDIATRIC GASTROENTEROLOGY, HEPATOLOGY AND NUTRITION 2022:379-391. [DOI: 10.1007/978-3-030-80068-0_28] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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14
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Serrano-Gómez G, Mayorga L, Oyarzun I, Roca J, Borruel N, Casellas F, Varela E, Pozuelo M, Machiels K, Guarner F, Vermeire S, Manichanh C. Dysbiosis and relapse-related microbiome in inflammatory bowel disease: A shotgun metagenomic approach. Comput Struct Biotechnol J 2021; 19:6481-6489. [PMID: 34938418 PMCID: PMC8665270 DOI: 10.1016/j.csbj.2021.11.037] [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: 08/01/2021] [Revised: 10/18/2021] [Accepted: 11/27/2021] [Indexed: 02/07/2023] Open
Abstract
CD more dysbiotic than UC both at the microbial taxonomic and functional level. E. coli enriched in CD and almost undetected in UC. Production of propionate driven by E. coli in CD and by Anaerostipes hadrus in UC and healthy controls. Microbial signatures and random forest enabled discrimination of IBD vs. non-IBD and prediction of flare. Crohn’s disease (CD) and ulcerative colitis (UC), the two main forms of inflammatory bowel disease (IBD), affect several million people worldwide. CD and UC are characterized by periods of clinical remission and relapse. Although IBD patients present chronic alterations of the gut microbiome, called dysbiosis, little attention has been devoted to the relapse-related microbiome. To address this gap, we generated shotgun metagenomic data from the stools of two European cohorts—134 Spanish (followed up for one year) and 49 Belgian (followed up for 6 months) subjects—to characterize the microbial taxonomic and metabolic profiles present. To assess the predictive value of microbiome data, we added the taxonomic profiles generated from a previous study of 130 Americans. Our results revealed that CD was more dysbiotic than UC compared to healthy controls (HC) and that strategies for energy extraction and propionate production were different in CD compared to UC and HC. Remarkably, CD and UC relapses were not associated with alpha- or beta-diversity, or with a dysbiotic score. However, CD relapse was linked to alterations at the species and metabolic pathway levels, including those involved in propionate production. The random forest method using taxonomic profiles allowed the prediction of CD vs. non-CD with an AUC = 0.938, UC vs. HC with an AUC = 0.646, and CD relapse vs. remission with an AUC = 0.769. Our study validates previous taxonomic findings, points to different relapse-related growth and defence mechanisms in CD compared to UC and HC and provides biomarkers to discriminate IBD subtypes and predict disease activity.
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Affiliation(s)
- Gerard Serrano-Gómez
- Gut Microbiome Lab, Vall d'Hebron Institut de Recerca (VHIR), Vall d'Hebron Hospital Universitari, Vall d'Hebron Barcelona Hospital Campus, Passeig Vall d'Hebron 119-129, 08035 Barcelona, Spain
| | - Luis Mayorga
- Gut Microbiome Lab, Vall d'Hebron Institut de Recerca (VHIR), Vall d'Hebron Hospital Universitari, Vall d'Hebron Barcelona Hospital Campus, Passeig Vall d'Hebron 119-129, 08035 Barcelona, Spain
| | - Iñigo Oyarzun
- Gut Microbiome Lab, Vall d'Hebron Institut de Recerca (VHIR), Vall d'Hebron Hospital Universitari, Vall d'Hebron Barcelona Hospital Campus, Passeig Vall d'Hebron 119-129, 08035 Barcelona, Spain
| | - Joaquim Roca
- Molecular Biology Institute of Barcelona (IBMB), Spanish National Research Council (CSIC), Barcelona, Spain
| | - Natalia Borruel
- Crohn-Colitis Care Unit. Digestive Diseases, Hospital Universitari Vall d'Hebron, Spain
| | - Francesc Casellas
- Crohn-Colitis Care Unit. Digestive Diseases, Hospital Universitari Vall d'Hebron, Spain
| | - Encarna Varela
- Gut Microbiome Lab, Vall d'Hebron Institut de Recerca (VHIR), Vall d'Hebron Hospital Universitari, Vall d'Hebron Barcelona Hospital Campus, Passeig Vall d'Hebron 119-129, 08035 Barcelona, Spain
| | - Marta Pozuelo
- Gut Microbiome Lab, Vall d'Hebron Institut de Recerca (VHIR), Vall d'Hebron Hospital Universitari, Vall d'Hebron Barcelona Hospital Campus, Passeig Vall d'Hebron 119-129, 08035 Barcelona, Spain
| | - Kathleen Machiels
- Translational Research Center for Gastrointestinal Disorders (TARGID), Department of Chronic Diseases Metabolism and Ageing, KU Leuven, Leuven, Belgium
| | - Francisco Guarner
- Gut Microbiome Lab, Vall d'Hebron Institut de Recerca (VHIR), Vall d'Hebron Hospital Universitari, Vall d'Hebron Barcelona Hospital Campus, Passeig Vall d'Hebron 119-129, 08035 Barcelona, Spain
| | - Severine Vermeire
- Translational Research Center for Gastrointestinal Disorders (TARGID), Department of Chronic Diseases Metabolism and Ageing, KU Leuven, Leuven, Belgium.,Department of Gastroenterology and Hepatology, University Hospitals Leuven, KU Leuven, Leuven, Belgium
| | - Chaysavanh Manichanh
- Gut Microbiome Lab, Vall d'Hebron Institut de Recerca (VHIR), Vall d'Hebron Hospital Universitari, Vall d'Hebron Barcelona Hospital Campus, Passeig Vall d'Hebron 119-129, 08035 Barcelona, Spain.,Departament de Medicina, Universitat Autònoma de Barcelona, 08193 Cerdanyola del Vallès, Spain.,Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Spain
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15
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Kamali Dolatabadi R, Feizi A, Halaji M, Fazeli H, Adibi P. The Prevalence of Adherent-Invasive Escherichia coli and Its Association With Inflammatory Bowel Diseases: A Systematic Review and Meta-Analysis. Front Med (Lausanne) 2021; 8:730243. [PMID: 34926490 PMCID: PMC8678049 DOI: 10.3389/fmed.2021.730243] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2021] [Accepted: 10/22/2021] [Indexed: 12/12/2022] Open
Abstract
Inflammatory bowel diseases (IBD), including Crohn's disease (CD) and ulcerative colitis (UC), are known as chronic gastrointestinal inflammatory disorders. The present systematic review and meta analysis was conducted to estimate the prevalence of adherent-invasive Escherichia coli (AIEC) isolates and their phylogenetic grouping among IBD patients compared with the controls. A systematic literature search was conducted among published papers by international authors until April 30, 2020 in Web of Science, Scopus, EMBASE, and PubMed databases. The pooled prevalence of AIEC isolates and their phylogenetic grouping among IBD patients as well as in controls was estimated using fixed or random effects models. Furthermore, for estimating the association of colonization by AIEC with IBD, odds ratio along with 95% confidence interval was reported. A total of 205 articles retrieved by the initial search of databases, 13 case–control studies met the eligibility criteria for inclusion in the meta analysis. There were 465 IBD cases (348 CD and 117 UC) and 307 controls. The pooled prevalence of AIEC isolates were 28% (95% CI: 18–39%), 29% (95% CI: 20–40%), 13% (95% CI: 1–30%), and 9% (95% CI: 3–19%), respectively among IBD, CD, UC, and control group, respectively. Our results revealed that the most frequent AIEC phylogroup in the IBD, CD, and control groups was B2. Fixed-effects meta analysis showed that colonization of AIEC is significantly associated with IBD (OR: 2.93; 95% CI: 1.90–4.52; P < 0.001) and CD (OR: 3.07; 95% CI: 1.99–4.74; P < 0.001), but not with UC (OR: 2.29; 95% CI: 0.81–6.51; P = 0.11). In summary, this meta analysis revealed that colonization by AIEC is more frequent in IBD and is associated with IBD (CD and UC). Our results suggested that the affects of IBD in patients colonized with the AIEC pathovar is not random, it is in fact a specific disease-related pathovar.
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Affiliation(s)
- Razie Kamali Dolatabadi
- Department of Microbiology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Awat Feizi
- Department of Biostatistics and Epidemiology, School of Health, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Mehrdad Halaji
- Infectious Diseases and Tropical Medicine Research Center, Babol University of Medical Sciences, Babol, Iran.,Department of Microbiology, School of Medicine, Babol University of Medical Sciences, Babol, Iran
| | - Hossein Fazeli
- Department of Microbiology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Peyman Adibi
- Gastroenterology and Hepatology Research Center, Isfahan University of Medical Sciences, Isfahan, Iran
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16
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Klaile E, Prada Salcedo JP, Klassert TE, Besemer M, Bothe AK, Durotin A, Müller MM, Schmitt V, Luther CH, Dittrich M, Singer BB, Dandekar T, Slevogt H. Antibody ligation of CEACAM1, CEACAM3, and CEACAM6, differentially enhance the cytokine release of human neutrophils in responses to Candida albicans. Cell Immunol 2021; 371:104459. [PMID: 34847408 DOI: 10.1016/j.cellimm.2021.104459] [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: 07/23/2021] [Revised: 10/27/2021] [Accepted: 11/15/2021] [Indexed: 11/30/2022]
Abstract
Invasive candidiasis is a healthcare-associated fungal infection with a high mortality rate. Neutrophils, the first line of defense during fungal infections, express the immunoregulatory Candida albicans receptors CEACAM1, CEACAM3, and CEACAM6. We analyzed the effects of specific antibodies on C. albicans-induced neutrophil responses. CEACAM6 ligation by 1H7-4B and to some extent CEACAM1 ligation by B3-17, but not CEACAM3 ligation by 308/3-3, resulted in the immediate release of stored CXCL8 and altered transcriptional responses of the C. albicans-stimulated neutrophils. Integrated network analyses and dynamic simulations of signaling cascades predicted alterations in apoptosis and cytokine secretion. We verified that CEACAM6 ligation enhanced Candida-induced neutrophil apoptosis and increased long-term IL-1β/IL-6 release in responses to C. albicans. CEACAM3 ligation, but not CEACAM1 ligation, increased the long-term release of pro-inflammatory IL-1β/IL-6. Taken together, we demonstrated for the first time that ligation of CEACAM receptors differentially affects the regulation of C. albicans-induced immune functions in human neutrophils.
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Affiliation(s)
- Esther Klaile
- ZIK Septomics, University Hospital Jena, Albert-Einstein-Straße 10, 07749 Jena, Germany.
| | - Juan P Prada Salcedo
- Dept. of Bioinformatics, University of Würzburg, Biocenter/Am Hubland, 97074 Würzburg, Germany.
| | - Tilman E Klassert
- ZIK Septomics, University Hospital Jena, Albert-Einstein-Straße 10, 07749 Jena, Germany.
| | - Matthias Besemer
- ZIK Septomics, University Hospital Jena, Albert-Einstein-Straße 10, 07749 Jena, Germany.
| | - Anne-Katrin Bothe
- ZIK Septomics, University Hospital Jena, Albert-Einstein-Straße 10, 07749 Jena, Germany.
| | - Adrian Durotin
- ZIK Septomics, University Hospital Jena, Albert-Einstein-Straße 10, 07749 Jena, Germany.
| | - Mario M Müller
- ZIK Septomics, University Hospital Jena, Albert-Einstein-Straße 10, 07749 Jena, Germany.
| | - Verena Schmitt
- Institute of Anatomy, University Hospital, University Duisburg-Essen, Hufelandstraße 55, 45122 Essen, Germany.
| | - Christian H Luther
- Dept. of Bioinformatics, University of Würzburg, Biocenter/Am Hubland, 97074 Würzburg, Germany.
| | - Marcus Dittrich
- Dept. of Bioinformatics, University of Würzburg, Biocenter/Am Hubland, 97074 Würzburg, Germany; Dept. of Human Genetics, University of Würzburg, Biocenter/Am Hubland, 97074 Würzburg, Germany.
| | - Bernhard B Singer
- Institute of Anatomy, University Hospital, University Duisburg-Essen, Hufelandstraße 55, 45122 Essen, Germany.
| | - Thomas Dandekar
- Dept. of Bioinformatics, University of Würzburg, Biocenter/Am Hubland, 97074 Würzburg, Germany.
| | - Hortense Slevogt
- ZIK Septomics, University Hospital Jena, Albert-Einstein-Straße 10, 07749 Jena, Germany.
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17
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Saiz-Gonzalo G, Hanrahan N, Rossini V, Singh R, Ahern M, Kelleher M, Hill S, O'Sullivan R, Fanning A, Walsh PT, Hussey S, Shanahan F, Nally K, O'Driscoll CM, Melgar S. Regulation of CEACAM Family Members by IBD-Associated Triggers in Intestinal Epithelial Cells, Their Correlation to Inflammation and Relevance to IBD Pathogenesis. Front Immunol 2021; 12:655960. [PMID: 34394073 PMCID: PMC8358819 DOI: 10.3389/fimmu.2021.655960] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2021] [Accepted: 07/09/2021] [Indexed: 12/30/2022] Open
Abstract
Carcinoembryogenic antigen cellular adhesion molecules (CEACAMs) are intercellular adhesion molecules highly expressed in intestinal epithelial cells. CEACAM1, -3, -5, -6, -7 are altered in patients suffering from colon cancer and inflammatory bowel diseases (IBD), but their role in the onset and pathogenesis of IBD is not well known. Herein, we aim to correlate CEACAM1, -3, -5, -6, -7 expression to the degree of inflammation in pediatric and adult IBD colon biopsies and to examine the regulation of CEACAMs on human intestinal epithelial cell lines (C2BBe1/HT29) by different IBD-associated triggers (cytokines, bacteria/metabolites, emulsifiers) and IBD-drugs (6-Mercaptopurine, Prednisolone, Tofacitinib). Biopsies from patients with pediatric Crohn’s disease (CD) and adult ulcerative colitis (UC, active/inactive disease) showed a significant increase in CEACAM3, -5, -6 expression, while CEACAM5 expression was reduced in adult CD patients (active/inactive disease). Intestinal epithelial cells cultured with a pro-inflammatory cytokine cocktail and Adherent-invasive Escherichia coli (AIEC) showed a rapid induction of CEACAM1, -5, -7 followed by a reduced RNA and protein expression overtime and a constant expression of CEACAM3, correlating with IL-8 expression. Cells cultured with the emulsifier polysorbate-80 resulted in a significant induction of CEACAM3, -5, -6, -7 at a late time point, while SCFA treatment reduced CEACAM1, -5, -7 expression. No major alterations in expression of CEACAMs were noted on cells cultured with the commensal Escherichia coli K12 or the pathogen Salmonella typhimurium. IBD drugs, particularly Tofacitinib, significantly reduced cytokine-induced CEACAM1, -3, -5, -6, -7 expression associated with a reduced IL-8 secretion. In conclusion, we provide new evidence on the regulation of CEACAMs by different IBD-associated triggers, identifying a role of CEACAMs in IBD pathogenesis.
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Affiliation(s)
- Gonzalo Saiz-Gonzalo
- APC Microbiome Ireland, University College Cork, National University of Ireland, Cork, Ireland.,Department of Medicine, University College Cork, National University of Ireland, Cork, Ireland.,School of Biochemistry and Cell Biology, University College Cork, National University of Ireland, Cork, Ireland
| | - Naomi Hanrahan
- APC Microbiome Ireland, University College Cork, National University of Ireland, Cork, Ireland.,Department of Medicine, University College Cork, National University of Ireland, Cork, Ireland.,School of Biochemistry and Cell Biology, University College Cork, National University of Ireland, Cork, Ireland
| | - Valerio Rossini
- APC Microbiome Ireland, University College Cork, National University of Ireland, Cork, Ireland
| | - Raminder Singh
- APC Microbiome Ireland, University College Cork, National University of Ireland, Cork, Ireland.,Department of Medicine, University College Cork, National University of Ireland, Cork, Ireland
| | - Mary Ahern
- APC Microbiome Ireland, University College Cork, National University of Ireland, Cork, Ireland
| | - Maebh Kelleher
- APC Microbiome Ireland, University College Cork, National University of Ireland, Cork, Ireland.,School of Pharmacy, University College Cork, National University of Ireland, Cork, Ireland
| | - Shane Hill
- APC Microbiome Ireland, University College Cork, National University of Ireland, Cork, Ireland.,School of Pharmacy, University College Cork, National University of Ireland, Cork, Ireland
| | - Ruairi O'Sullivan
- APC Microbiome Ireland, University College Cork, National University of Ireland, Cork, Ireland.,School of Pharmacy, University College Cork, National University of Ireland, Cork, Ireland
| | - Aine Fanning
- APC Microbiome Ireland, University College Cork, National University of Ireland, Cork, Ireland
| | - Patrick T Walsh
- Department of Clinical Medicine, School of Medicine, Trinity College Dublin, Dublin, Ireland.,National Children's Research Centre, Our Lady's Children's Hospital, Dublin, Ireland
| | - Seamus Hussey
- National Children's Research Centre, Our Lady's Children's Hospital, Dublin, Ireland.,Department of Pediatric Medicine, RCSI University of Medicine and Health Sciences, Dublin, Ireland
| | - Fergus Shanahan
- APC Microbiome Ireland, University College Cork, National University of Ireland, Cork, Ireland
| | - Ken Nally
- APC Microbiome Ireland, University College Cork, National University of Ireland, Cork, Ireland.,School of Biochemistry and Cell Biology, University College Cork, National University of Ireland, Cork, Ireland
| | - Caitriona M O'Driscoll
- APC Microbiome Ireland, University College Cork, National University of Ireland, Cork, Ireland.,School of Pharmacy, University College Cork, National University of Ireland, Cork, Ireland
| | - Silvia Melgar
- APC Microbiome Ireland, University College Cork, National University of Ireland, Cork, Ireland
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18
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Alkaissi LY, Winberg ME, Heil SDS, Haapaniemi S, Myrelid P, Stange EF, Söderholm JD, Keita ÅV. Antagonism of Adherent Invasive E. coli LF82 With Human α-defensin 5 in the Follicle-associated Epithelium of Patients With Ileal Crohn's Disease. Inflamm Bowel Dis 2021; 27:1116-1127. [PMID: 33336693 PMCID: PMC8205628 DOI: 10.1093/ibd/izaa315] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/14/2020] [Indexed: 12/24/2022]
Abstract
BACKGROUND The first visible signs of Crohn's disease (CD) are microscopic erosions over the follicle-associated epithelium (FAE). The aim of the study was to investigate the effects of human α-defensin 5 (HD5) on adherent-invasive Escherichia coli LF82 translocation and HD5 secretion after LF82 exposure in an in vitro model of human FAE and in human FAE ex vivo. METHODS An in vitro FAE-model was set up by the coculture of Raji B cells and Caco-2-cl1 cells. Ileal FAE from patients with CD and controls were mounted in Ussing chambers. The effect of HD5 on LF82 translocation was studied by LF82 exposure to the cells or tissues with or without incubation with HD5. The HD5 secretion was measured in human FAE exposed to LF82 or Salmonella typhimurium. The HD5 levels were evaluated by immunofluorescence, immunoblotting, and ELISA. RESULTS There was an increased LF82 translocation across the FAE-model compared with Caco-2-cl1 (P < 0.05). Incubation of cell/tissues with HD5 before LF82 exposure reduced bacterial passage in both models. Human FAE showed increased LF82 translocation in CD compared with controls and attenuated passage after incubation with sublethal HD5 in both CD and controls (P < 0.05). LF82 exposure resulted in a lower HD5 secretion in CD FAE compared with controls (P < 0.05), whereas Salmonella exposure caused equal secretion on CD and controls. There were significantly lower HD5 levels in CD tissues compared with controls. CONCLUSIONS Sublethal HD5 reduces the ability of LF82 to translocate through FAE. The HD5 is secreted less in CD in response to LF82, despite a normal response to Salmonella. This further implicates the integrated role of antimicrobial factors and barrier function in CD pathogenesis.
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Affiliation(s)
- Lina Y Alkaissi
- Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden
| | - Martin E Winberg
- Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden
| | - Stéphanie D S Heil
- Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden
| | - Staffan Haapaniemi
- Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden
- Department of Surgery, Vrinnevi Hospital, Norrköping, Sweden
| | - Pär Myrelid
- Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden
- Department of Surgery, Linköping University, Linköping, Sweden
| | - Eduard F Stange
- Department of Gastroenterology, Dept. Internal Medicine I, University of Tübingen, 72076 Tübingen, Germany
| | - Johan D Söderholm
- Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden
- Department of Surgery, Linköping University, Linköping, Sweden
| | - Åsa V Keita
- Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden
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19
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Akutko K, Stawarski A. Probiotics, Prebiotics and Synbiotics in Inflammatory Bowel Diseases. J Clin Med 2021; 10:2466. [PMID: 34199428 PMCID: PMC8199601 DOI: 10.3390/jcm10112466] [Citation(s) in RCA: 60] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2021] [Revised: 05/17/2021] [Accepted: 05/31/2021] [Indexed: 12/14/2022] Open
Abstract
Inflammatory bowel diseases (IBD), which include Crohn's disease (CD) and ulcerative colitis (UC), are chronic inflammatory diseases of the digestive tract with periods of remission and relapses. The etiopathogenesis of IBD is multifactorial and has not been fully understood. Hence, only symptomatic treatment of these diseases is possible. The current pharmacological treatment has variable efficacy and is associated with the risk of significant side effects. Therefore, there is a constant need to search for new types of therapies with a high safety profile. Considering that the qualitative and quantitative profile of the gastrointestinal microbiome is often different in patients with IBD than in healthy individuals, there is a need for looking for therapies aimed at restoring intestinal microbiome homeostasis. Thus, the use of strictly defined probiotics, prebiotics and synbiotics may become an alternative form of IBD therapy. There is evidence that treatment with certain probiotic strains, e.g., VSL#3 and Escherischia coli Nissle 1917, is an effective form of therapy to induce remission in patients with mild to moderate UC. So far, the effectiveness of the use of probiotics, prebiotics and synbiotics in inducing or maintaining remission in patients with CD has not been confirmed. There are also reports of possible beneficial effects of fecal microbiota transplantation (FMT) on the course of IBD, especially UC. Further, well-planned studies on a large group of patients are needed to determine the role of specific probiotic strains, prebiotics, synbiotics and FMT in the treatment of IBD in adults and in children.
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Affiliation(s)
- Katarzyna Akutko
- 2nd Department and Clinic of Paediatrics, Gastroenterology and Nutrition, Medical University of Wroclaw, M. Curie-Skłodowskiej St. 50/52, 50-369 Wrocław, Poland;
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Wang Z, Guo K, Gao P, Pu Q, Lin P, Qin S, Xie N, Hur J, Li C, Huang C, Wu M. Microbial and genetic-based framework identifies drug targets in inflammatory bowel disease. Theranostics 2021; 11:7491-7506. [PMID: 34158863 PMCID: PMC8210594 DOI: 10.7150/thno.59196] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2021] [Accepted: 05/14/2021] [Indexed: 02/05/2023] Open
Abstract
Rationale: With increasing incidence and prevalence of inflammatory bowel disease (IBD), it has become one of the major public health threats, and there is an urgent need to develop new therapeutic agents. Although the pathogenesis of IBD is still unclear, previous research has provided evidence for complex interplays between genetic, immune, microbial, and environmental factors. Here, we constructed a gene-microbiota interaction-based framework to discover IBD biomarkers and therapeutics. Methods: We identified candidate biomarkers for IBD by analyzing the publicly available transcriptomic and microbiome data from IBD cohorts. Animal models of IBD and diarrhea were established. The inflammation-correlated microbial and genetic variants in gene knockout mice were identified by 16S rRNA sequences and PCR array. We performed bioinformatic analysis of microbiome functional prediction and drug repurposing. Our validation experiments with cells and animals confirmed anti-inflammatory properties of a drug candidate. Results: We identified the DNA-sensing enzyme cyclic GMP-AMP synthase (cGAS) as a potential biomarker for IBD in both patients and murine models. cGAS knockout mice were less susceptible to DSS-induced colitis. cGAS-associated gut microbiota and host genetic factors relating to IBD pathogenesis were also identified. Using a computational drug repurposing approach, we predicted 43 candidate drugs with high potency to reverse colitis-associated gene expression and validated that brefeldin-a mitigates inflammatory response in colitis mouse model and colon cancer cell lines. Conclusions: By integrating computational screening, microbiota interference, gene knockout techniques, and in vitro and in vivo validation, we built a framework for predicting biomarkers and host-microbe interaction targets and identifying repurposing drugs for IBD, which may be tested further for clinical application. This approach may also be a tool for repurposing drugs for treating other diseases.
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Affiliation(s)
- Zhihan Wang
- West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, Chengdu, Sichuan 610041, China
- Department of Biomedical Sciences, School of Medicine and Health Sciences, University of North Dakota, Grand Forks, ND 58202, USA
| | - Kai Guo
- Department of Neurology, University of Michigan, Ann Arbor, MI 48109, USA
| | - Pan Gao
- Department of Biomedical Sciences, School of Medicine and Health Sciences, University of North Dakota, Grand Forks, ND 58202, USA
- Medical Research Institute, Wuhan University, Wuhan 430071, China
| | - Qinqin Pu
- Department of Biomedical Sciences, School of Medicine and Health Sciences, University of North Dakota, Grand Forks, ND 58202, USA
| | - Ping Lin
- Department of Biomedical Sciences, School of Medicine and Health Sciences, University of North Dakota, Grand Forks, ND 58202, USA
- State Key Laboratory of Trauma, Burns and Combined Injury, Institute of Surgery Research, Daping Hospital, Army Medical University, Chongqing 400038, China
| | - Shugang Qin
- Department of Biomedical Sciences, School of Medicine and Health Sciences, University of North Dakota, Grand Forks, ND 58202, USA
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, Sichuan 610041, China
| | - Na Xie
- West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, Chengdu, Sichuan 610041, China
| | - Junguk Hur
- Department of Biomedical Sciences, School of Medicine and Health Sciences, University of North Dakota, Grand Forks, ND 58202, USA
| | - Changlong Li
- West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, Chengdu, Sichuan 610041, China
| | - Canhua Huang
- West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, Chengdu, Sichuan 610041, China
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, Sichuan 610041, China
| | - Min Wu
- Department of Biomedical Sciences, School of Medicine and Health Sciences, University of North Dakota, Grand Forks, ND 58202, USA
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21
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Porrini C, Ramarao N, Tran SL. Dr. NO and Mr. Toxic - the versatile role of nitric oxide. Biol Chem 2021; 401:547-572. [PMID: 31811798 DOI: 10.1515/hsz-2019-0368] [Citation(s) in RCA: 42] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2019] [Accepted: 12/04/2019] [Indexed: 12/25/2022]
Abstract
Nitric oxide (NO) is present in various organisms from humans, to plants, fungus and bacteria. NO is a fundamental signaling molecule implicated in major cellular functions. The role of NO ranges from an essential molecule to a potent mediator of cellular damages. The ability of NO to react with a broad range of biomolecules allows on one hand its regulation and a gradient concentration and on the other hand to exert physiological as well as pathological functions. In humans, NO is implicated in cardiovascular homeostasis, neurotransmission and immunity. However, NO can also contribute to cardiovascular diseases (CVDs) or septic shock. For certain denitrifying bacteria, NO is part of their metabolism as a required intermediate of the nitrogen cycle. However, for other bacteria, NO is toxic and harmful. To survive, those bacteria have developed processes to resist this toxic effect and persist inside their host. NO also contributes to maintain the host/microbiota homeostasis. But little is known about the impact of NO produced during prolonged inflammation on microbiota integrity, and some pathogenic bacteria take advantage of the NO response to colonize the gut over the microbiota. Taken together, depending on the environmental context (prolonged production, gradient concentration, presence of partners for interaction, presence of oxygen, etc.), NO will exert its beneficial or detrimental function. In this review, we highlight the dual role of NO for humans, pathogenic bacteria and microbiota, and the mechanisms used by each organism to produce, use or resist NO.
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Affiliation(s)
- Constance Porrini
- Université Paris-Saclay, INRAE, AgroParisTech, Micalis Institute, 78350, Jouy-en-Josas, France
| | - Nalini Ramarao
- Université Paris-Saclay, INRAE, AgroParisTech, Micalis Institute, 78350, Jouy-en-Josas, France
| | - Seav-Ly Tran
- Université Paris-Saclay, INRAE, AgroParisTech, Micalis Institute, 78350, Jouy-en-Josas, France
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Nadalian B, Yadegar A, Houri H, Olfatifar M, Shahrokh S, Asadzadeh Aghdaei H, Suzuki H, Zali MR. Prevalence of the pathobiont adherent-invasive Escherichia coli and inflammatory bowel disease: a systematic review and meta-analysis. J Gastroenterol Hepatol 2021; 36:852-863. [PMID: 32929762 DOI: 10.1111/jgh.15260] [Citation(s) in RCA: 44] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/21/2020] [Revised: 07/08/2020] [Accepted: 09/07/2020] [Indexed: 12/21/2022]
Abstract
BACKGROUND AND AIM Escherichia coli pathobionts and particularly the adherent-invasive E. coli (AIEC) may play a putative role in initiating and maintaining the inflammatory process in the intestinal tissues of inflammatory bowel disease (IBD) patients, by providing stimulatory factors that trigger gut immune system activation. The aim of this study is to conduct a systematic review and meta-analysis to determine the prevalence of AIEC among patients with Crohn's disease (CD) and ulcerative colitis (UC). METHODS Electronic databases were searched up to February 2020 for relevant publications reporting the prevalence of AIEC in IBD patients. The prevalence rate of AIEC among CD and UC patients, the odds ratio (OR) and 95% confidence interval (CI) were calculated compared to non-IBD controls. RESULTS The final dataset included 12 studies, all investigating AIEC isolates from ileal/colonic specimens. The OR for prevalence of AIEC in CD patients was 3.27 (95% CI 1.79-5.9) compared with non-IBD controls. The overall pooled prevalence of AIEC among CD patients was 29% (95% CI 0.17-0.45), whereas this prevalence was calculated to be 9% (95% CI 0.03-0.19) in controls. Moreover, the prevalence of AIEC in UC subjects was calculated 12% (95% CI 0.01-0.34), while AIEC showed a prevalence of 5% (95% CI 0.0-0.17) among the controls. The OR for prevalence of AIEC in UC patients was 2.82 (95% CI 1.11-7.14) compared with controls. CONCLUSIONS There is a substantial increase in the prevalence of AIEC in IBD patients compared with controls. This review supports the growing evidence that AIEC could be involved in both CD and UC pathogenesis.
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Affiliation(s)
- Banafsheh Nadalian
- 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
| | - Hamidreza Houri
- Foodborne and Waterborne Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Meysam Olfatifar
- Gastroenterology and Liver 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
| | - Hidekazu Suzuki
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, School of Medicine, Tokai University, Isehara, Japan
| | - 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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Mayorgas A, Dotti I, Martínez-Picola M, Esteller M, Bonet-Rossinyol Q, Ricart E, Salas A, Martínez-Medina M. A Novel Strategy to Study the Invasive Capability of Adherent-Invasive Escherichia coli by Using Human Primary Organoid-Derived Epithelial Monolayers. Front Immunol 2021; 12:646906. [PMID: 33854511 PMCID: PMC8039293 DOI: 10.3389/fimmu.2021.646906] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2021] [Accepted: 03/08/2021] [Indexed: 12/16/2022] Open
Abstract
Over the last decades, Adherent-Invasive Escherichia coli (AIEC) has been linked to the pathogenesis of Crohn’s Disease. AIEC’s characteristics, as well as its interaction with the gut immune system and its role in intestinal epithelial barrier dysfunction, have been extensively studied. Nevertheless, the currently available techniques to investigate the cross-talk between this pathogen and intestinal epithelial cells (IECs) are based on the infection of immortalized cell lines. Despite their many advantages, cell lines cannot reproduce the conditions in tissues, nor do they reflect interindividual variability or gut location-specific traits. In that sense, the use of human primary cultures, either healthy or diseased, offers a system that can overcome all of these limitations. Here, we developed a new infection model by using freshly isolated human IECs. For the first time, we generated and infected monolayer cultures derived from human colonic organoids to study the mechanisms and effects of AIEC adherence and invasion on primary human epithelial cells. To establish the optimal conditions for AIEC invasion studies in human primary organoid-derived epithelial monolayers, we designed an infection-kinetics study to assess the infection dynamics at different time points, as well as with two multiplicities of infection (MOI). Overall, this method provides a model for the study of host response to AIEC infections, as well as for the understanding of the molecular mechanisms involved in adhesion, invasion and intracellular replication. Therefore, it represents a promising tool for elucidating the cross-talk between AIEC and the intestinal epithelium in healthy and diseased tissues.
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Affiliation(s)
- Aida Mayorgas
- Department of Gastroenterology, IDIBAPS, Hospital Clínic, CIBER-EHD, Barcelona, Spain
| | - Isabella Dotti
- Department of Gastroenterology, IDIBAPS, Hospital Clínic, CIBER-EHD, Barcelona, Spain
| | - Marta Martínez-Picola
- Department of Gastroenterology, IDIBAPS, Hospital Clínic, CIBER-EHD, Barcelona, Spain
| | - Miriam Esteller
- Department of Gastroenterology, IDIBAPS, Hospital Clínic, CIBER-EHD, Barcelona, Spain
| | - Queralt Bonet-Rossinyol
- Laboratory of Molecular Microbiology, Department of Biology, Universitat de Girona, Girona, Spain
| | - Elena Ricart
- Department of Gastroenterology, IDIBAPS, Hospital Clínic, CIBER-EHD, Barcelona, Spain
| | - Azucena Salas
- Department of Gastroenterology, IDIBAPS, Hospital Clínic, CIBER-EHD, Barcelona, Spain
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Cococcioni L, Panelli S, Varotto-Boccazzi I, Carlo DD, Pistone D, Leccese G, Zuccotti GV, Comandatore F. IBDs and the pediatric age: Their peculiarities and the involvement of the microbiota. Dig Liver Dis 2021; 53:17-25. [PMID: 33189590 DOI: 10.1016/j.dld.2020.10.033] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/24/2020] [Revised: 10/26/2020] [Accepted: 10/26/2020] [Indexed: 12/11/2022]
Abstract
Inflammatory Bowel Diseases (IBDs) are gastrointestinal disorders characterized by chronic, relapsing inflammation, with growing incidence worldwide over the last decades and distinctive features in the pediatric age. An increasing body of evidence indicates that gut microbiota plays a major role in inflammatory disorders, including IBDs. In this review we will discuss the most recent evidences on dysbiotic changes associated with gut inflammation, as well as environmental and genetic factors contributing to IBD pathogenesis, with a focus on the peculiarities of the pediatric age.
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Affiliation(s)
- Lucia Cococcioni
- Department of Pediatrics, Vittore Buzzi Children's Hospital, Università di Milano, Italy
| | - Simona Panelli
- "L. Sacco" Department of Biomedical and Clinical Sciences and Pediatric Clinical Research Center "Romeo ed Enrica Invernizzi", Università di Milano, Italy.
| | | | - Domenico Di Carlo
- Department of Biosciences and Pediatric Clinical Research Center "Romeo ed Enrica Invernizzi", Università di Milano, Italy
| | - Dario Pistone
- Department of Biomedical Sciences for Health, University di Milano, Italy
| | | | - Gian Vincenzo Zuccotti
- Department of Pediatrics, Vittore Buzzi Children's Hospital, Università di Milano, Italy; "L. Sacco" Department of Biomedical and Clinical Sciences and Pediatric Clinical Research Center "Romeo ed Enrica Invernizzi", Università di Milano, Italy
| | - Francesco Comandatore
- "L. Sacco" Department of Biomedical and Clinical Sciences and Pediatric Clinical Research Center "Romeo ed Enrica Invernizzi", Università di Milano, Italy
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Han Y, Zhao Q, Tang C, Li Y, Zhang K, Li F, Zhang J. Butyrate Mitigates Weanling Piglets From Lipopolysaccharide-Induced Colitis by Regulating Microbiota and Energy Metabolism of the Gut-Liver Axis. Front Microbiol 2020; 11:588666. [PMID: 33363521 PMCID: PMC7752768 DOI: 10.3389/fmicb.2020.588666] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2020] [Accepted: 10/27/2020] [Indexed: 12/14/2022] Open
Abstract
Inflammatory bowel disorder is accompanied by the destruction of immunity homeostasis, gut microbiota perturbation, and chronic inflammatory liver diseases. Butyrate is known as a primary energy source for colonocytes and functional substances for mitigating pathological features of colitis. However, it is still unclear whether butyrate alleviates colitis progression by regulation of microbiota and metabolism in the gut-liver axis. In the present study, we aimed to determine the role of microbiota and metabolism of the gut-liver axis in ameliorating lipopolysaccharide (LPS)-induced colitis in piglets using protected butyrate administration. Eighteen crossbred male piglets were weaned at 30 days old and were randomly allocated to three treatments, with CON (basal diet), LPS (basal diet + LPS), and BT-LPS (basal diet + 3.0 g/kg protected butyrate + LPS). On days 19 and 21, piglets in the LPS and BT-LPS groups were intraperitoneally challenged with LPS at 100 μg/kg body weight. Butyrate administration significantly decreased LPS-induced rise in the clinical score of piglets and colonic histological scores and reduced the susceptibility to LPS-induced severe inflammatory response by decreasing proinflammatory (IL-1β, IL-6, IL-8, and TNF-α) cytokines. Butyrate supplementation accelerated the prevalence of Faecalibacterium and Lactobacillus by enhancing the tricarboxylic acid (TCA) cycle of colonocytes. Dietary supplementation with protected butyrate significantly targeted increased concentrations of butyric acid in the colon and portal venous circulation, and enhanced the TCA cycle in the gut-liver axis by mobilizing amino acid and vitamin B group as a coenzyme. Meanwhile, during this progress, LPS increased fatty acid synthesis that was reversed by butyrate treatment, which was reflected by decreased acylcarnitines. Butyrate-reshaped colonic microbial community and metabolism in the gut-liver axis contributed to morphology integrity and immunity homeostasis by promoting anti-inflammatory (IL-10 and TGF-β) cytokines and suppressing inflammatory mediator hypoxia-inducible factor 1α and its downstream response elements cyclooxygenase 2 and inducible nitric oxide synthase. These results identified the pivotal role of colonic microbiota and metabolism in the gut-liver axis for alleviating inflammatory progression and possible therapeutic targets.
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Affiliation(s)
- Yunsheng Han
- State Key Laboratory of Grassland Agro-Ecosystems, Key Laboratory of Grassland Livestock Industry Innovation, Ministry of Agriculture and Rural Affairs, College of Pastoral Agriculture Science and Technology, Lanzhou University, Lanzhou, China
- State Key Laboratory of Animal Nutrition, Institute of Animal Sciences of Chinese Academy of Agricultural Sciences, Beijing, China
- Scientific Observing and Experiment Station of Animal Genetic Resources and Nutrition in North China of Ministry of Agriculture and Rural Affairs, Institute of Animal Science of Chinese Academy of Agricultural Sciences, Beijing, China
| | - Qingyu Zhao
- State Key Laboratory of Animal Nutrition, Institute of Animal Sciences of Chinese Academy of Agricultural Sciences, Beijing, China
- Scientific Observing and Experiment Station of Animal Genetic Resources and Nutrition in North China of Ministry of Agriculture and Rural Affairs, Institute of Animal Science of Chinese Academy of Agricultural Sciences, Beijing, China
| | - Chaohua Tang
- State Key Laboratory of Animal Nutrition, Institute of Animal Sciences of Chinese Academy of Agricultural Sciences, Beijing, China
- Scientific Observing and Experiment Station of Animal Genetic Resources and Nutrition in North China of Ministry of Agriculture and Rural Affairs, Institute of Animal Science of Chinese Academy of Agricultural Sciences, Beijing, China
| | - Ying Li
- State Key Laboratory of Animal Nutrition, Institute of Animal Sciences of Chinese Academy of Agricultural Sciences, Beijing, China
- Scientific Observing and Experiment Station of Animal Genetic Resources and Nutrition in North China of Ministry of Agriculture and Rural Affairs, Institute of Animal Science of Chinese Academy of Agricultural Sciences, Beijing, China
| | - Kai Zhang
- State Key Laboratory of Animal Nutrition, Institute of Animal Sciences of Chinese Academy of Agricultural Sciences, Beijing, China
- Scientific Observing and Experiment Station of Animal Genetic Resources and Nutrition in North China of Ministry of Agriculture and Rural Affairs, Institute of Animal Science of Chinese Academy of Agricultural Sciences, Beijing, China
| | - Fadi Li
- State Key Laboratory of Grassland Agro-Ecosystems, Key Laboratory of Grassland Livestock Industry Innovation, Ministry of Agriculture and Rural Affairs, College of Pastoral Agriculture Science and Technology, Lanzhou University, Lanzhou, China
| | - Junmin Zhang
- State Key Laboratory of Grassland Agro-Ecosystems, Key Laboratory of Grassland Livestock Industry Innovation, Ministry of Agriculture and Rural Affairs, College of Pastoral Agriculture Science and Technology, Lanzhou University, Lanzhou, China
- State Key Laboratory of Animal Nutrition, Institute of Animal Sciences of Chinese Academy of Agricultural Sciences, Beijing, China
- Scientific Observing and Experiment Station of Animal Genetic Resources and Nutrition in North China of Ministry of Agriculture and Rural Affairs, Institute of Animal Science of Chinese Academy of Agricultural Sciences, Beijing, China
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Study of a classification algorithm for AIEC identification in geographically distinct E. coli strains. Sci Rep 2020; 10:8094. [PMID: 32415168 PMCID: PMC7229014 DOI: 10.1038/s41598-020-64894-5] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2020] [Accepted: 04/21/2020] [Indexed: 01/02/2023] Open
Abstract
Adherent-invasive Escherichia coli (AIEC) have been extensively implicated in Crohn’s disease pathogenesis. Currently, AIEC is identified phenotypically, since no molecular marker specific for AIEC exists. An algorithm based on single nucleotide polymorphisms was previously presented as a potential molecular tool to classify AIEC/non-AIEC, with 84% accuracy on a collection of 50 strains isolated in Girona (Spain). Herein, our aim was to determine the accuracy of the tool using AIEC/non-AIEC isolates from different geographical origins and extraintestinal pathogenic E. coli (ExPEC) strains. The accuracy of the tool was significantly reduced (61%) when external AIEC/non-AIEC strains from France, Chile, Mallorca (Spain) and Australia (82 AIEC, 57 non-AIEC and 45 ExPEC strains in total) were included. However, the inclusion of only the ExPEC strains showed that the tool was fairly accurate at differentiating these two close pathotypes (84.6% sensitivity; 79% accuracy). Moreover, the accuracy was still high (81%) for those AIEC/non-AIEC strains isolated from Girona and Mallorca (N = 63); two collections obtained from independent studies but geographically close. Our findings indicate that the presented tool is not universal since it would be only applicable for strains from similar geographic origin and demonstrates the need to include strains from different origins to validate such tools.
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Martinez-Medina M, Strozzi F, Ruiz Del Castillo B, Serrano-Morillas N, Ferrer Bustins N, Martínez-Martínez L. Antimicrobial Resistance Profiles of Adherent Invasive Escherichia coli Show Increased Resistance to β-Lactams. Antibiotics (Basel) 2020; 9:antibiotics9050251. [PMID: 32414140 PMCID: PMC7277491 DOI: 10.3390/antibiotics9050251] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2020] [Revised: 05/10/2020] [Accepted: 05/11/2020] [Indexed: 02/07/2023] Open
Abstract
The adherent invasive Escherichia coli (AIEC) pathotype has been associated with the aetiology of Crohn’s disease (CD). Scarce reports have shown the antimicrobial resistance (AMR) profiles of AIEC. Despite antibiotics not being recommended to treat CD, antimicrobial therapy could be useful in stratified patients, such as AIEC carriers. We examined the antimicrobial resistance profiles of AIEC strains to identify which therapies could be effective or confer a risk for such patients. Phenotypic resistance to 30 antimicrobials was tested according to CLSI standards. AIEC (n = 22) and non-pathogenic E. coli (non-AIEC) strains (n = 37) isolated from the gut mucosa of 31 CD patients and 18 controls were studied. De novo genome sequencing was carried out for 39 of the 59 strains, and AMR genes were searched using the DeepARG database in these genomes and 33 additional AIEC publicly available genomes. The strains isolated from CD and controls showed similar phenotypic AMR profiles. The genomic analysis did not reveal an increased prevalence of AMR genes. However, AIEC strains were more frequently resistant to β-lactams than non-AIEC strains (11 AIEC (50%) and 5 non-AIEC (22%) strains were resistant to at least one β-lactam; p < 0.042). Two AIEC strains were resistant to expanded-spectrum cephalosporins. One strain carried a plasmid-mediated AmpC β-lactamase (CMY-69), and the other presented mutations in the promotor of the intrinsic chromosomal AmpC related to the hyperproduction of this enzyme. The rest of the strains were resistant to β-lactams not including expanded-spectrum cephalosporins. The majority carried TEM-related β-lactamases. Genomic analysis including external AIEC revealed that the gene sul1 encoding for sulphonamide resistance was more frequent in AIEC strains than non-AIEC strains (34.6% vs. 9.5%, p = 0.030). AMR in AIEC is a matter of concern regarding the putative implication of the pathotype in CD. The high proportion of AIEC resistant to β-lactams warrants caution about the risk there may be in the use of these antimicrobials in AIEC-colonized CD patients.
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Affiliation(s)
- Margarita Martinez-Medina
- Microbiology of Intestinal Disease Group, Biology Department, University of Girona, 17003 Girona, Spain; (N.S.-M.); (N.F.B.)
- Correspondence: ; Tel.: +34-972-418261
| | - Francesco Strozzi
- Data Science Departement, Enterome Biosciences S.A., 75011 Paris, France;
| | - Belén Ruiz Del Castillo
- Service of Microbiology, Hospital Universitario Marqués de Valdecilla, Instituto de Investigación Marqués de Valdecilla (IDIVAL), 39008 Santander, Spain;
| | - Natalia Serrano-Morillas
- Microbiology of Intestinal Disease Group, Biology Department, University of Girona, 17003 Girona, Spain; (N.S.-M.); (N.F.B.)
| | - Nuria Ferrer Bustins
- Microbiology of Intestinal Disease Group, Biology Department, University of Girona, 17003 Girona, Spain; (N.S.-M.); (N.F.B.)
| | - Luis Martínez-Martínez
- Unit of Microbiology, University Hospital Reina Sofia, 14004 Córdoba, Spain;
- Maimonides Biomedical Research Institute, 14004 Córdoba, Spain
- Department of Agricultural Chemistry and Microbiology, University of Córdoba, 14004 Córdoba, Spain
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Camprubí-Font C, Martinez-Medina M. Why the discovery of adherent-invasive Escherichia coli molecular markers is so challenging? World J Biol Chem 2020; 11:1-13. [PMID: 32405343 PMCID: PMC7205867 DOI: 10.4331/wjbc.v11.i1.1] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/23/2019] [Revised: 03/18/2020] [Accepted: 03/31/2020] [Indexed: 02/05/2023] Open
Abstract
Adherent-invasive Escherichia coli (AIEC) strains have been extensively related to Crohn’s disease (CD) etiopathogenesis. Higher AIEC prevalence in CD patients versus controls has been reported, and its mechanisms of pathogenicity have been linked to CD physiopathology. In CD, the therapeutic armamentarium remains limited and non-curative; hence, the necessity to better understand AIEC as a putative instigator or propagator of the disease is certain. Nonetheless, AIEC identification is currently challenging because it relies on phenotypic assays based on infected cell cultures which are highly time-consuming, laborious and non-standardizable. To address this issue, AIEC molecular mechanisms and virulence genes have been studied; however, a specific and widely distributed genetic AIEC marker is still missing. The finding of molecular tools to easily identify AIEC could be useful in the identification of AIEC carriers who could profit from personalized treatment. Also, it would significantly promote AIEC epidemiological studies. Here, we reviewed the existing data regarding AIEC genetics and presented those molecular markers that could assist with AIEC identification. Finally, we highlighted the problems behind the discovery of exclusive AIEC biomarkers and proposed strategies to facilitate the search of AIEC signature sequences.
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Affiliation(s)
- Carla Camprubí-Font
- Laboratory of Molecular Microbiology, Department of Biology, University of Girona, Girona 17003, Spain
| | - Margarita Martinez-Medina
- Laboratory of Molecular Microbiology, Department of Biology, University of Girona, Girona 17003, Spain
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Integrating omics for a better understanding of Inflammatory Bowel Disease: a step towards personalized medicine. J Transl Med 2019; 17:419. [PMID: 31836022 PMCID: PMC6909475 DOI: 10.1186/s12967-019-02174-1] [Citation(s) in RCA: 45] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2019] [Accepted: 12/08/2019] [Indexed: 02/06/2023] Open
Abstract
Background Inflammatory Bowel Disease (IBD) is a multifactorial chronic disease. Understanding only one aspect of IBD pathogenesis does not reflect the complex nature of IBD nor will it improve its clinical management. Therefore, it is vital to dissect the interactions between the different players in IBD pathogenesis in order to understand the biology of the disease and enhance its clinical outcomes. Aims To provide an overview of the available omics data used to assess the potential mechanisms through which various players are contributing to IBD pathogenesis and propose a precision medicine model to fill the current knowledge gap in IBD. Results Several studies have reported microbial dysbiosis, immune and metabolic dysregulation in IBD patients, however, this data is not sufficient to create signatures that can differentiate between the disease subtypes or between disease relapse and remission. Conclusions We summarized the current knowledge in the application of omics in IBD patients, and we showed that the current knowledge gap in IBD hinders the improvements of clinical decision for treatment as well as the prediction of disease relapse. We propose one way to fill this gap by implementing integrative analysis of various omics datasets generated from one patient at a single time point.
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Yang M, Jia W, Wang D, Han F, Niu W, Zhang H, Shih DQ, Zhang X. Effects and Mechanism of Constitutive TL1A Expression on Intestinal Mucosal Barrier in DSS-Induced Colitis. Dig Dis Sci 2019; 64:1844-1856. [PMID: 30949903 DOI: 10.1007/s10620-019-05580-z] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/21/2018] [Accepted: 03/05/2019] [Indexed: 02/08/2023]
Abstract
OBJECTIVE The role of TL1A in the intestinal mucosa barrier in inflammatory bowel disease (IBD) is still unclear. This study was aimed to investigate the expression levels of tight junction protein (TJ), myosin light chain kinase (MLCK), MyD88 and tumor necrosis factor (TNF) receptor-associated factor-6 (TRAF6) and how TL1A influences the intestinal barrier in IBD. METHODS The mouse models of IBD were built using FMS-TL1A-GFP-transgenic mice and wild-type mice. The morphological and histopathological changes, bacterial translocation, permeability of colonic mucosa, and LPS level were assessed. Caco-2 cells were used to further investigate the association between TL1A and TNF-α and LPS. The protein level and mRNA changes of TJ proteins including ZO-1, occluding, JAMA, claudin-1, claudin-2, and claudin-3 were investigated using Western blot and real-time PCR. Protein changes of MLCK, MyD88 and TNF receptor-associated factor-6 (TRAF6), and TNF-α mRNA in the mouse colon were further assessed. RESULTS The IBD models were successfully built. Cooper HS score and histopathological score of the colon were higher in DSS/WT group than in control/WT group (P < 0.05), higher in DSS/Tg group than in control/Tg group (P < 0.05), and higher in DSS/Tg group than in DSS/WT group. PAS, colonic permeability of the colon, and FITC-D examination showed the similar results and trends. Compared with control/WT group, the levels of TL1A and claudin-2 were higher and the levels of ZO-1, occludin, JAMA, claudin-1, and claudin-3 were lower in DSS/WT group (P < 0.05). Compared with control/Tg group, the levels of TL1A and claudin-2 were higher and the levels of ZO-1, occludin, JAMA, claudin-1, and claudin-3 were lower in DSS/Tg group. Compared with Caco-2 + TNF-α group, the expression level of occludin and claudin-1 in Caco-2 + LV-TNFSF15 + TNF-α group was significantly lower (P < 0.05); p-MLC level was significantly higher. Compared with Caco-2 + LPS group, the expression level of occludin and claudin-1 significantly decreased in Caco-2 + LV-TNFSF15 + LPS group; MyD88 and TRAF6 expression level significantly increased. CONCLUSION The results suggested that TL1A could impair intestinal epithelial barrier in the mouse model of IBD and might regulate TJ expression via MLCK/p-MLC pathway and LPS-mediated MyD88/TRAF6 pathway.
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Affiliation(s)
- Mingyue Yang
- Department of Gastroenterology, The Second Hospital of Hebei Medical University, No. 80 Huanghe Road, Yuhua District, Shijiazhuang, 050000, Hebei, China
| | - Wenxiu Jia
- Department of Gastroenterology, The Second Hospital of Hebei Medical University, No. 80 Huanghe Road, Yuhua District, Shijiazhuang, 050000, Hebei, China
| | - Dong Wang
- Department of Gastroenterology, The Second Hospital of Hebei Medical University, No. 80 Huanghe Road, Yuhua District, Shijiazhuang, 050000, Hebei, China
| | - Fei Han
- Department of Gastroenterology, The Second Hospital of Hebei Medical University, No. 80 Huanghe Road, Yuhua District, Shijiazhuang, 050000, Hebei, China
| | - Weiwei Niu
- Department of Gastroenterology, The Second Hospital of Hebei Medical University, No. 80 Huanghe Road, Yuhua District, Shijiazhuang, 050000, Hebei, China
| | - Hong Zhang
- Department of Gastroenterology, The Second Hospital of Hebei Medical University, No. 80 Huanghe Road, Yuhua District, Shijiazhuang, 050000, Hebei, China
| | - David Q Shih
- Cedars-Sinai Inflammatory Bowel and Immunobiology Research Institute, Los Angeles, USA
| | - Xiaolan Zhang
- Department of Gastroenterology, The Second Hospital of Hebei Medical University, No. 80 Huanghe Road, Yuhua District, Shijiazhuang, 050000, Hebei, China.
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31
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Lee JG, Han DS, Jo SV, Lee AR, Park CH, Eun CS, Lee Y. Characteristics and pathogenic role of adherent-invasive Escherichia coli in inflammatory bowel disease: Potential impact on clinical outcomes. PLoS One 2019; 14:e0216165. [PMID: 31034508 PMCID: PMC6488085 DOI: 10.1371/journal.pone.0216165] [Citation(s) in RCA: 38] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2018] [Accepted: 04/15/2019] [Indexed: 12/29/2022] Open
Abstract
Adherent-invasive Escherichia coli (AIEC) has been reported as associated with the pathogenesis of inflammatory bowel disease (IBD). We aimed to investigate the characteristics of mucosa-associated E. coli and the clinical significance of AIEC in Korean IBD patients. E. coli strains were isolated from the mucosal tissues of 18 Crohn’s disease (CD) patients, 24 ulcerative colitis (UC) patients, and 9 healthy controls (HC). Adhesion, invasion, and survival assays were performed to evaluate phenotypic features of E. coli isolates and to identify AIEC. The presence of virulence genes and cytokine expression were examined using PCR. In addition, data on IBD-related hospitalization were collected. A total of 59 E. coli strains were isolated (25 from CD, 27 from UC, and 7 from HC). The average levels of adhesion, invasion, and survival were higher in E. coli strains from IBD patients than those from HC (adhesion: 1.65 vs. 0.71, p = 0.046; invasion: 1.68 vs. 0.52, p = 0.039; survival: 519.55 vs. 47.55, p = 0.363). Prevalence of AIEC in HC, CD and UC patients was 22.2%, 38.9% and 37.5%, respectively. E. coli isolates from IBD patients had various virulence genes and were associated with increased expression of TNF-α and IL-17. IBD-related hospitalization within 3 years was 18.8% in patients with AIEC and 11.5% in patients without AIEC. E. coli strains from IBD patients showed high levels of adhesion, invasion, and survival. AIEC strains were identified in both CD and UC patients at a similar rate. AIEC may be associated with sustaining inflammation in the pre-existing inflammatory mucosa.
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Affiliation(s)
- Jae Gon Lee
- Department of Internal Medicine, Hanyang University Guri Hospital, Hanyang University College of Medicine, Guri, Korea
| | - Dong Soo Han
- Department of Internal Medicine, Hanyang University Guri Hospital, Hanyang University College of Medicine, Guri, Korea
- * E-mail:
| | - Su Vin Jo
- Department of Internal Medicine, Hanyang University Guri Hospital, Hanyang University College of Medicine, Guri, Korea
| | - A. Reum Lee
- Department of Internal Medicine, Hanyang University Guri Hospital, Hanyang University College of Medicine, Guri, Korea
| | - Chan Hyuk Park
- Department of Internal Medicine, Hanyang University Guri Hospital, Hanyang University College of Medicine, Guri, Korea
| | - Chang Soo Eun
- Department of Internal Medicine, Hanyang University Guri Hospital, Hanyang University College of Medicine, Guri, Korea
| | - Yangsoon Lee
- Department of Laboratory Medicine, Hanyang University Hospital, Hanyang University College of Medicine, Seoul, Korea
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Camprubí-Font C, Ewers C, Lopez-Siles M, Martinez-Medina M. Genetic and Phenotypic Features to Screen for Putative Adherent-Invasive Escherichia coli. Front Microbiol 2019; 10:108. [PMID: 30846972 PMCID: PMC6393329 DOI: 10.3389/fmicb.2019.00108] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2018] [Accepted: 01/18/2019] [Indexed: 01/19/2023] Open
Abstract
To date no molecular tools are available to identify the adherent-invasive Escherichia coli (AIEC) pathotype, which has been associated with Crohn's disease and colonizes the intestine of different hosts. Current techniques based on phenotypic screening of isolates are extremely time-consuming. The aim of this work was to search for signature traits to assist in rapid AIEC identification. The occurrence of at least 54 virulence genes (VGs), the resistance to 30 antibiotics and the distribution of FimH and ChiA amino acid substitutions was studied in a collection of 48 AIEC and 56 non-AIEC isolated from the intestine of humans and animals. χ2 test was used to find frequency differences according to origin of isolation, AIEC phenotype and phylogroup. Mann-Whitney test was applied to test association with adhesion and invasion indices. Binary logistic regression was performed to search for variables of predictive value. Animal strains (N = 45) were enriched in 12 VGs while 7 VGs were more predominant in human strains (N = 59). The prevalence of 15 VGs was higher in AIEC (N = 49) than in non-AIEC (N = 56) strains, but only pic gene was still differentially distributed when analyzing human and animal strains separately. Among human strains, three additional VGs presented higher frequency in AIEC strains (papGII/III, iss and vat; N = 22) than in non-AIEC strains (N = 37). No differences between AIEC/non-AIEC were found in FimH variants. In contrast, the ChiA sequence of LF82 was shared with the 35.5% of AIEC studied (N = 31) and only with the 7.4% of non-AIEC strains (N = 27; p = 0.027). Binary logistic regression analysis, using as input variables all the VGs and antibiotic resistances tested, revealed that typifying E. coli isolates using pic gene and ampicillin resistance was useful to correctly classify strains according to the phenotype with a 75.5% of accuracy. Although there is not a molecular signature fully specific and sensitive to identify the AIEC pathotype, we propose two features easy to be tested that could assist in AIEC screening. Future work using additional strain collections would be required to assess the applicability of this method.
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Affiliation(s)
- Carla Camprubí-Font
- Laboratory of Molecular Microbiology, Department of Biology, Universitat de Girona, Girona, Spain
| | - Christa Ewers
- Institute of Hygiene and Infectious Diseases of Animals, Faculty of Veterinary Medicine, Justus-Liebig University Giessen, Giessen, Germany
| | - Mireia Lopez-Siles
- Laboratory of Molecular Microbiology, Department of Biology, Universitat de Girona, Girona, Spain
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Elhenawy W, Tsai CN, Coombes BK. Host-Specific Adaptive Diversification of Crohn's Disease-Associated Adherent-Invasive Escherichia coli. Cell Host Microbe 2019; 25:301-312.e5. [PMID: 30683582 DOI: 10.1016/j.chom.2018.12.010] [Citation(s) in RCA: 51] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2018] [Revised: 10/05/2018] [Accepted: 12/13/2018] [Indexed: 12/12/2022]
Abstract
Crohn's disease (CD) is an inflammatory bowel disease influenced by bacteria. Adherent-invasive E. coli (AIEC) is associated with CD, yet the adaptations facilitating AIEC gut colonization are unknown. AIEC isolates exhibit high genetic diversity, suggesting strains evolve independently across different gut environments. We tracked the adaptive evolution of AIEC in a murine model of chronic colonization across multiple hosts and transmission events. We detected evolved lineages that outcompeted the ancestral strain in the host through independent mechanisms. One lineage was hypermotile because of a mobile insertion sequence upstream of the master flagellar regulator, flhDC, which enhanced AIEC invasion and establishment of a mucosal niche. Another lineage outcompeted the ancestral strain through improved use of acetate, a short-chain fatty acid in the gut. The presence of hypermotile and acetate-consuming lineages discriminated E. coli isolated from CD patients from healthy controls, suggesting an evolutionary trajectory that distinguishes AIEC from commensal E. coli.
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Affiliation(s)
- Wael Elhenawy
- Michael G. DeGroote Institute for Infectious Disease Research, Hamilton, ON, Canada
| | - Caressa N Tsai
- Michael G. DeGroote Institute for Infectious Disease Research, Hamilton, ON, Canada
| | - Brian K Coombes
- Michael G. DeGroote Institute for Infectious Disease Research, Hamilton, ON, Canada; Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Hamilton, ON, Canada.
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Geng S, Cheng S, Li Y, Wen Z, Ma X, Jiang X, Wang Y, Han X. Faecal Microbiota Transplantation Reduces Susceptibility to Epithelial Injury and Modulates Tryptophan Metabolism of the Microbial Community in a Piglet Model. J Crohns Colitis 2018; 12:1359-1374. [PMID: 30010734 DOI: 10.1093/ecco-jcc/jjy103] [Citation(s) in RCA: 36] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
BACKGROUND AND AIMS Faecal microbiota transplantation [FMT] has shown promise as a treatment for inflammatory bowel disease [IBD]. Using a piglet model, our previous study indicated that exogenous faecal microbiota can increase the expressions of tight junction proteins, mucin and antimicrobial peptide in the intestinal mucosa, suggesting a beneficial effect of FMT on gut barrier and gastrointestinal health. However, specific connections between FMT-induced microbial changes and modulation of the intestinal barrier remain to be fully illustrated. Here, we aimed to determine the potential role of metabolic function of gut microbiota in the beneficial effects of FMT. METHODS The influence of FMT on the maintenance of intestinal homeostasis was assessed by early-life gut microbiota intervention on newborn piglets and subsequent lipopolysaccharide [LPS] challenge. Analysis of the gut microbiome and metabolome was carried out by 16S rRNA gene sequencing and multiple mass spectrometry platforms. RESULTS FMT modulated the diversity and composition of colonic microbiota and reduced the susceptibility to LPS-induced destruction of epithelial integrity and severe inflammatory response. Metabolomic analysis revealed functional changes of the gut metabolome along with a significant increase of the typical microbiota-derived tryptophan catabolite indole-3-acetic acid in the colonic lumen. In concordance with the metabolome data, metagenomics prediction analysis based on 16S rRNA gene sequencing also demonstrated that FMT modulated the metabolic functions of gut microbiota associated with indole alkaloid biosynthesis, cytochrome P450 and intestinal homeostasis, which coincided with up-regulation of cytokine interleukin-22 and enhanced activation of aryl hydrocarbon receptor in the recipient colon. CONCLUSIONS Our data reveal a regulatory effect of FMT on tryptophan metabolism of gut microbiota in the recipient colon, which may play a potential role in maintenance of the intestinal barrier.
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Affiliation(s)
- Shijie Geng
- The Key Laboratory of Animal Nutrition and Feed Science in East China of Ministry of Agriculture, College of Animal Science, Zhejiang University, Hangzhou, Zhejiang, China
| | - Saisai Cheng
- The Key Laboratory of Animal Nutrition and Feed Science in East China of Ministry of Agriculture, College of Animal Science, Zhejiang University, Hangzhou, Zhejiang, China
| | - Yuan Li
- The Key Laboratory of Animal Nutrition and Feed Science in East China of Ministry of Agriculture, College of Animal Science, Zhejiang University, Hangzhou, Zhejiang, China
| | - Zhengshun Wen
- School of Food Science and Pharmaceutics, Zhejiang Ocean University, Zhoushan, Zhejiang, China
| | - Xin Ma
- The Key Laboratory of Animal Nutrition and Feed Science in East China of Ministry of Agriculture, College of Animal Science, Zhejiang University, Hangzhou, Zhejiang, China
| | - Xuemei Jiang
- The Key Laboratory of Animal Nutrition and Feed Science in East China of Ministry of Agriculture, College of Animal Science, Zhejiang University, Hangzhou, Zhejiang, China
| | - Yizhen Wang
- The Key Laboratory of Animal Nutrition and Feed Science in East China of Ministry of Agriculture, College of Animal Science, Zhejiang University, Hangzhou, Zhejiang, China
| | - Xinyan Han
- The Key Laboratory of Animal Nutrition and Feed Science in East China of Ministry of Agriculture, College of Animal Science, Zhejiang University, Hangzhou, Zhejiang, China
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Fang X, Monk JM, Nurk S, Akseshina M, Zhu Q, Gemmell C, Gianetto-Hill C, Leung N, Szubin R, Sanders J, Beck PL, Li W, Sandborn WJ, Gray-Owen SD, Knight R, Allen-Vercoe E, Palsson BO, Smarr L. Metagenomics-Based, Strain-Level Analysis of Escherichia coli From a Time-Series of Microbiome Samples From a Crohn's Disease Patient. Front Microbiol 2018; 9:2559. [PMID: 30425690 PMCID: PMC6218438 DOI: 10.3389/fmicb.2018.02559] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2018] [Accepted: 10/08/2018] [Indexed: 12/12/2022] Open
Abstract
Dysbiosis of the gut microbiome, including elevated abundance of putative leading bacterial triggers such as E. coli in inflammatory bowel disease (IBD) patients, is of great interest. To date, most E. coli studies in IBD patients are focused on clinical isolates, overlooking their relative abundances and turnover over time. Metagenomics-based studies, on the other hand, are less focused on strain-level investigations. Here, using recently developed bioinformatic tools, we analyzed the abundance and properties of specific E. coli strains in a Crohns disease (CD) patient longitudinally, while also considering the composition of the entire community over time. In this report, we conducted a pilot study on metagenomic-based, strain-level analysis of a time-series of E. coli strains in a left-sided CD patient, who exhibited sustained levels of E. coli greater than 100X healthy controls. We: (1) mapped out the composition of the gut microbiome over time, particularly the presence of E. coli strains, and found that the abundance and dominance of specific E. coli strains in the community varied over time; (2) performed strain-level de novo assemblies of seven dominant E. coli strains, and illustrated disparity between these strains in both phylogenetic origin and genomic content; (3) observed that strain ST1 (recovered during peak inflammation) is highly similar to known pathogenic AIEC strains NC101 and LF82 in both virulence factors and metabolic functions, while other strains (ST2-ST7) that were collected during more stable states displayed diverse characteristics; (4) isolated, sequenced, experimentally characterized ST1, and confirmed the accuracy of the de novo assembly; and (5) assessed growth capability of ST1 with a newly reconstructed genome-scale metabolic model of the strain, and showed its potential to use substrates found abundantly in the human gut to outcompete other microbes. In conclusion, inflammation status (assessed by the blood C-reactive protein and stool calprotectin) is likely correlated with the abundance of a subgroup of E. coli strains with specific traits. Therefore, strain-level time-series analysis of dominant E. coli strains in a CD patient is highly informative, and motivates a study of a larger cohort of IBD patients.
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Affiliation(s)
- Xin Fang
- Department of Bioengineering, University of California, San Diego, La Jolla, CA, United States
| | - Jonathan M Monk
- Department of Bioengineering, University of California, San Diego, La Jolla, CA, United States
| | - Sergey Nurk
- Center for Algorithmic Biotechnology, Institute for Translational Biomedicine, St. Petersburg State University, St. Petersburg, Russia
| | - Margarita Akseshina
- St. Petersburg Academic University, Russian Academy of Sciences, St. Petersburg, Russia
| | - Qiyun Zhu
- Department of Pediatrics, University of California, San Diego, La Jolla, CA, United States
| | - Christopher Gemmell
- Department of Molecular and Cellular Biology, University of Guelph, Guelph, ON, Canada
| | - Connor Gianetto-Hill
- Department of Molecular and Cellular Biology, University of Guelph, Guelph, ON, Canada
| | - Nelly Leung
- Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada
| | - Richard Szubin
- Department of Bioengineering, University of California, San Diego, La Jolla, CA, United States
| | - Jon Sanders
- Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada
| | - Paul L Beck
- Division of Gastroenterology, University of Calgary, Calgary, AB, Canada
| | - Weizhong Li
- Human Longevity Inc., San Diego, CA, United States.,J. Craig Venter Institute, La Jolla, CA, United States
| | - William J Sandborn
- Department of Medicine, University of California, San Diego, La Jolla, CA, United States.,Inflammatory Bowel Disease Center, University of California, San Diego, La Jolla, CA, United States
| | - Scott D Gray-Owen
- Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada
| | - Rob Knight
- Department of Pediatrics, University of California, San Diego, La Jolla, CA, United States.,Department of Computer Science and Engineering, University of California, San Diego, La Jolla, CA, United States.,Center for Microbiome Innovation, University of California, San Diego, La Jolla, CA, United States
| | - Emma Allen-Vercoe
- Department of Molecular and Cellular Biology, University of Guelph, Guelph, ON, Canada
| | - Bernhard O Palsson
- Department of Bioengineering, University of California, San Diego, La Jolla, CA, United States.,Center for Algorithmic Biotechnology, Institute for Translational Biomedicine, St. Petersburg State University, St. Petersburg, Russia.,Center for Microbiome Innovation, University of California, San Diego, La Jolla, CA, United States.,The Novo Nordisk Foundation Center for Biosustainability, Technical University of Denmark, Lyngby, Denmark
| | - Larry Smarr
- Department of Computer Science and Engineering, University of California, San Diego, La Jolla, CA, United States.,Center for Microbiome Innovation, University of California, San Diego, La Jolla, CA, United States.,California Institute for Telecommunications and Information Technology, University of California, San Diego, La Jolla, CA, United States
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Khan S, Imran A, Malik A, Chaudhary AA, Rub A, Jan AT, Syed JB, Rolfo C. Bacterial imbalance and gut pathologies: Association and contribution of E. coli in inflammatory bowel disease. Crit Rev Clin Lab Sci 2018; 56:1-17. [DOI: 10.1080/10408363.2018.1517144] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Affiliation(s)
- Shahanavaj Khan
- Nanomedicine Research Unit, Department of Pharmaceutics, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia
- Department of Bioscience, Shri Ram Group of College (SRGC), Muzaffarnagar, India
| | - Ahamad Imran
- King Abdullah Institute for Nanotechnology, King Saud University, Riyadh, Saudi Arabia
| | - Abdul Malik
- Department of Clinical Laboratory Science, College of Applied Medical Sciences, King Saud University, Riyadh, Saudi Arabia
| | - Anis Ahmad Chaudhary
- Department of Pharmacology, College of Medicine, Al-Imam Mohammad Ibn Saud Islamic University, Riyadh, Saudi Arabia
| | - Abdur Rub
- Department of Medical Laboratory Sciences, College of Applied Medical Sciences, Majmaah University, Al Majmaah, Saudi Arabia
| | - Arif Tasleem Jan
- School of Biotechnology, Yeungnam University, Gyeongsan, Republic of Korea
| | - Jakeera Begum Syed
- King Abdullah Institute for Nanotechnology, King Saud University, Riyadh, Saudi Arabia
- College of Medicine and Dentistry, Dar Al Uloom University, Riyadh, Saudi Arabia
| | - Christian Rolfo
- Phase I-Early Clinical Trials Unit, Oncology Department and Multidisciplinary Oncology Center Antwerp (MOCA), Antwerp University Hospital, Edegem, Belgium
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Abstract
In the 21st century, urbanization represents a major demographic shift in developed and developing countries. Rapid urbanization in the developing world has been associated with an increasing incidence of several autoimmune diseases, including IBD. Patients with IBD exhibit a decrease in the diversity and richness of the gut microbiota, while urbanization attenuates the gut microbial diversity and might have a role in the pathogenesis of IBD. Environmental exposures during urbanization, including Westernization of diet, increased antibiotic use, pollution, improved hygiene status and early-life microbial exposure, have been shown to affect the gut microbiota. The disparate patterns of the gut microbiota composition in rural and urban areas offer an opportunity to understand the contribution of a 'rural microbiome' in potentially protecting against the development of IBD. This Perspective discusses the effect of urbanization and its surrogates on the gut microbiome (bacteriome, virome, mycobiome and helminths) in both human health and IBD and how such changes might be associated with the development of IBD.
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Palmela C, Chevarin C, Xu Z, Torres J, Sevrin G, Hirten R, Barnich N, Ng SC, Colombel JF. Adherent-invasive Escherichia coli in inflammatory bowel disease. Gut 2018; 67:574-587. [PMID: 29141957 DOI: 10.1136/gutjnl-2017-314903] [Citation(s) in RCA: 352] [Impact Index Per Article: 50.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/07/2017] [Revised: 09/20/2017] [Accepted: 10/28/2017] [Indexed: 02/06/2023]
Abstract
Intestinal microbiome dysbiosis has been consistently described in patients with IBD. In the last decades, Escherichia coli, and the adherent-invasive E coli (AIEC) pathotype in particular, has been implicated in the pathogenesis of IBD. Since the discovery of AIEC, two decades ago, progress has been made in unravelling these bacteria characteristics and its interaction with the gut immune system. The mechanisms of adhesion of AIEC to intestinal epithelial cells (via FimH and cell adhesion molecule 6) and its ability to escape autophagy when inside macrophages are reviewed here. We also explore the existing data on the prevalence of AIEC in patients with Crohn's disease and UC, and the association between the presence of AIEC and disease location, activity and postoperative recurrence. Finally, we highlight potential therapeutic strategies targeting AIEC colonisation of gut mucosa, including the use of phage therapy, bacteriocins and antiadhesive molecules. These strategies may open new avenues for the prevention and treatment of IBD in the future.
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Affiliation(s)
- Carolina Palmela
- Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York City, New York, USA.,Division of Gastroenterology, Hospital Beatriz Ângelo, Loures, Portugal
| | - Caroline Chevarin
- Université Clermont Auvergne, Inserm U1071, USC-INRA 2018, M2iSH, CRNH Auvergne, F-63000 Clermont-Ferrand, France
| | - Zhilu Xu
- Department of Medicine and Therapeutics, Institute of Digestive Diseases, LKS Institute of Health Science, State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong, China
| | - Joana Torres
- Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York City, New York, USA.,Division of Gastroenterology, Hospital Beatriz Ângelo, Loures, Portugal
| | - Gwladys Sevrin
- Université Clermont Auvergne, Inserm U1071, USC-INRA 2018, M2iSH, CRNH Auvergne, F-63000 Clermont-Ferrand, France
| | - Robert Hirten
- Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York City, New York, USA
| | - Nicolas Barnich
- Université Clermont Auvergne, Inserm U1071, USC-INRA 2018, M2iSH, CRNH Auvergne, F-63000 Clermont-Ferrand, France
| | - Siew C Ng
- Department of Medicine and Therapeutics, Institute of Digestive Diseases, LKS Institute of Health Science, State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong, China
| | - Jean-Frederic Colombel
- Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York City, New York, USA
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Vila J, Sáez-López E, Johnson JR, Römling U, Dobrindt U, Cantón R, Giske CG, Naas T, Carattoli A, Martínez-Medina M, Bosch J, Retamar P, Rodríguez-Baño J, Baquero F, Soto SM. Escherichia coli: an old friend with new tidings. FEMS Microbiol Rev 2018; 40:437-463. [PMID: 28201713 DOI: 10.1093/femsre/fuw005] [Citation(s) in RCA: 198] [Impact Index Per Article: 28.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Revised: 09/23/2015] [Accepted: 02/04/2016] [Indexed: 12/16/2022] Open
Abstract
Escherichia coli is one of the most-studied microorganisms worldwide but its characteristics are continually changing. Extraintestinal E. coli infections, such as urinary tract infections and neonatal sepsis, represent a huge public health problem. They are caused mainly by specialized extraintestinal pathogenic E. coli (ExPEC) strains that can innocuously colonize human hosts but can also cause disease upon entering a normally sterile body site. The virulence capability of such strains is determined by a combination of distinctive accessory traits, called virulence factors, in conjunction with their distinctive phylogenetic background. It is conceivable that by developing interventions against the most successful ExPEC lineages or their key virulence/colonization factors the associated burden of disease and health care costs could foreseeably be reduced in the future. On the other hand, one important problem worldwide is the increase of antimicrobial resistance shown by bacteria. As underscored in the last WHO global report, within a wide range of infectious agents including E. coli, antimicrobial resistance has reached an extremely worrisome situation that ‘threatens the achievements of modern medicine’. In the present review, an update of the knowledge about the pathogenicity, antimicrobial resistance and clinical aspects of this ‘old friend’ was presented.
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Affiliation(s)
- J Vila
- ISGlobal, Barcelona Ctr. Int. Health Res. (CRESIB), Hospital Clínic-Universitat de Barcelona, Barcelona, Spain
- Department of Clinical Microbiology, Hospital Clinic, Universitat de Barcelona, Barcelona, Spain
- Spanish Network for Research in Infectious Diseases (REIPI), Instituto de Salud Carlos III, Madrid, Spain
| | - E Sáez-López
- ISGlobal, Barcelona Ctr. Int. Health Res. (CRESIB), Hospital Clínic-Universitat de Barcelona, Barcelona, Spain
| | - J R Johnson
- VA Medical Center, Minneapolis, MN, USA, and University of Minnesota, Minneapolis, MN, USA
| | - U Römling
- Karolinska Institute, Stockholm, Sweden
| | - U Dobrindt
- Institute of Hygiene, University of Münster, Münster, Germany
| | - R Cantón
- Servicio de Microbiología, Hospital Universitario Ramón y Cajal and Instituto de Investigación Sanitaria (IRYCIS), Madrid, Spain
- Spanish Network for Research in Infectious Diseases (REIPI), Instituto de Salud Carlos III, Madrid, Spain
| | - C G Giske
- Karolinska Institute, Stockholm, Sweden
| | - T Naas
- Hôpital de Bicêtre, Université Paris Sud, Le Kremlin-Bicêtre, France
| | - A Carattoli
- Department of infectious, parasitic and immune-mediated diseases, Istituto Superiore di Sanità, Rome, Italy
| | - M Martínez-Medina
- Laboratory of Molecular Microbiology, Department of Biology, University of Girona, Girona, Spain
| | - J Bosch
- ISGlobal, Barcelona Ctr. Int. Health Res. (CRESIB), Hospital Clínic-Universitat de Barcelona, Barcelona, Spain
- Department of Clinical Microbiology, Hospital Clinic, Universitat de Barcelona, Barcelona, Spain
| | - P Retamar
- Unidad Clínica de Enfermedades Infecciosas, Microbiología y Medicina Preventiva, Hospitales Universitarios Virgen Macarena y Virgen del Rocío, Departamento de Medicina, Universidad de Sevilla, Seville, Spain
| | - J Rodríguez-Baño
- Unidad Clínica de Enfermedades Infecciosas, Microbiología y Medicina Preventiva, Hospitales Universitarios Virgen Macarena y Virgen del Rocío, Departamento de Medicina, Universidad de Sevilla, Seville, Spain
- Spanish Network for Research in Infectious Diseases (REIPI), Instituto de Salud Carlos III, Madrid, Spain
| | - F Baquero
- Servicio de Microbiología, Hospital Universitario Ramón y Cajal and Instituto de Investigación Sanitaria (IRYCIS), Madrid, Spain
| | - S M Soto
- ISGlobal, Barcelona Ctr. Int. Health Res. (CRESIB), Hospital Clínic-Universitat de Barcelona, Barcelona, Spain
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Serena G, Fasano A. Use of Probiotics to Prevent Celiac Disease and IBD in Pediatrics. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2018; 1125:69-81. [PMID: 30565165 DOI: 10.1007/5584_2018_317] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
The incidence of chronic inflammatory diseases (CIDs) is increasing worldwide. Their dramatic rise associated with limited effective strategies to slow down these epidemics calls for a better understanding of their pathophysiology in order to decrease the burdens on childhood. Several cross-sectional studies have demonstrated the association between intestinal dysbiosis and active diseases. Although informative, these studies do not mechanistically link alterations of the microflora with disease pathogenesis and, therefore, with potential therapeutic targets. More prospective studies are needed to determine whether intestinal dysbiosis plays a causative role in the onset and development of CIDs. Furthermore, given the complexity of the microflora interaction with the host, it is necessary to design a systems-level model of interactions between the host and the development of disease by integrating microbiome, metagenomics, metatranscriptomics, and metabolomics with either clinical either environmental data.In this chapter we will discuss the current knowledge regarding the microbiome's contribution to celiac disease and inflammatory bowel disease with a particular focus on how probiotics may be used as potential preventive therapy for CIDs.
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Affiliation(s)
- Gloria Serena
- Mucosal Immunology and Biology Research Center and Division of Pediatric Gastroenterology and Nutrition, Massachusetts General Hospital for Children - Harvard Medical School, Boston, MA, USA.
| | - Alessio Fasano
- Mucosal Immunology and Biology Research Center and Division of Pediatric Gastroenterology and Nutrition, Massachusetts General Hospital for Children - Harvard Medical School, Boston, MA, USA
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Mazzarella G, Perna A, Marano A, Lucariello A, Rotondi Aufiero V, Sorrentino A, Melina R, Guerra G, Taccone FS, Iaquinto G, De Luca A. Pathogenic Role of Associated Adherent-Invasive Escherichia coli in Crohn's Disease. J Cell Physiol 2017; 232:2860-2868. [PMID: 27925192 DOI: 10.1002/jcp.25717] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2016] [Accepted: 11/30/2016] [Indexed: 02/09/2025]
Abstract
Several lines of evidence suggest that adherent-invasive Escherichia coli (AIEC) strains play an important role in Crohn's disease (CD). The objective of this study was to investigate the pathogenic role of two AIEC strains, LF82 and O83:H1, in CD patients. Organ cultures of colonic biopsies from patients were set up to assess the effects of LF82 and O83:H1 on the expression of CEACAM6, LAMP1, HLA-DR, ICAM1 by immunohistochemistry and of IL-8, IFNʏ, and TNF-α genes by RT-PCR. Moreover, on Caco2 cells, we analyzed the cell cycle, the expression of MGMT and DNMT1 genes, and DNA damage induced by LF82 and O83:H1, by FACS, RT-PCR, and DAPI staining, respectively. Epithelial and lamina propria mononuclear cells (LPMNC) expression of CEACAM6 and LAMP1 were higher in biopsies cultured in the presence of both O83:H1 and LF82 than in biopsies cultured with non-pathogenic E. coli. Both AIEC strains induced increased expression of ICAM-1 on blood vessels and HLA-DR on LPMNC. We observed higher levels of TNF-α, IFN-γ, and IL-8 transcripts in biopsies cultured with both AIEC strains than in those cultured with NP. Both LF82 and O83:H1, block the cell cycle into S phase, inducing DNA damage, and modulate the expression of DNMT1 and MGMT genes. Our data suggest that LF82 and 083:H1 strains of E. coli are able to increase in CD colonic biopsies the expression of all the pro-inflammatory cytokines and all the mucosal immune markers investigated. J. Cell. Physiol. 232: 2860-2868, 2017. © 2016 Wiley Periodicals, Inc.
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Affiliation(s)
| | - Angelica Perna
- Department of Mental and Physical Health and Preventive Medicine, Section of Human Anatomy, Second University of Naples, Naples, Italy
| | - Angela Marano
- Institute of Food Sciences-CNR, Lab. Immuno-Morphology, Avellino, Italy
| | - Angela Lucariello
- Department of Mental and Physical Health and Preventive Medicine, Section of Human Anatomy, Second University of Naples, Naples, Italy
| | | | - Alida Sorrentino
- Institute of Food Sciences-CNR, Lab. Immuno-Morphology, Avellino, Italy
| | - Raffaele Melina
- Department of Gastroenterology, San G. Moscati Hospital, Avellino, Italy
| | - Germano Guerra
- Department of Medicine and Health Sciences, University of Molise, Molise, Italy
| | - Fabio Silvio Taccone
- Department of Intensive Care, Erasme Hospital, Université Libre de Bruxelles, Brussels, Belgium
| | - Gaetano Iaquinto
- Division of Gastroenterology, Santa Rita Hospital, Atripalda (Av), Italy
| | - Antonio De Luca
- Department of Mental and Physical Health and Preventive Medicine, Section of Human Anatomy, Second University of Naples, Naples, Italy
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Abstract
The human gut is home to trillions of bacteria and provides the scaffold for one of the most complex microbial ecosystems in nature. Inflammatory bowel diseases, such as Crohn's disease, involve a compositional shift in the microbial constituents of this ecosystem with a marked expansion of Enterobacteriaceae, particularly Escherichia coli. Adherent-invasive E. coli (AIEC) strains are frequently isolated from the biopsies of Crohn's patients, where their ability to elicit inflammation suggests a possible role in Crohn's pathology. Here, we consider the origins of the AIEC pathovar and discuss how risk factors associated with Crohn's disease might influence AIEC colonization dynamics within the host to alter the overall disease potential of the microbial community.
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Affiliation(s)
- Wael Elhenawy
- Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON, Canada,Michael G. DeGroote Institute for Infectious Disease Research, Hamilton, ON, Canada
| | - Alexander Oberc
- Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON, Canada,Michael G. DeGroote Institute for Infectious Disease Research, Hamilton, ON, Canada
| | - Brian K. Coombes
- Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON, Canada,Michael G. DeGroote Institute for Infectious Disease Research, Hamilton, ON, Canada,CONTACT Brian K. Coombes , Department of Biochemistry and Biomedical Sciences, McMaster University, MDCL 2319, Hamilton, ON Canada L8S 4K1
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Sivignon A, Bouckaert J, Bernard J, Gouin SG, Barnich N. The potential of FimH as a novel therapeutic target for the treatment of Crohn’s disease. Expert Opin Ther Targets 2017; 21:837-847. [DOI: 10.1080/14728222.2017.1363184] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Affiliation(s)
- Adeline Sivignon
- M2iSH, UMR 1071 Inserm, INRA USC-2018, Institut Universitaire Technologique, Université Clermont Auvergne, Clermont-Ferrand 63001, France
| | - Julie Bouckaert
- Univ. Lille, CNRS, UMR 8576 – UGSF – Unité de Glycobiologie Structurale et Fonctionnelle, 59000 Lille, France
| | - Julien Bernard
- Université de Lyon, Lyon, France ; INSA-Lyon, Ingénierie des Matériaux Polymères (IMP), Villeurbanne, France ; CNRS, UMR 5223, Ingénierie des Matériaux Polymères, Villeurbanne, France
- INSA-Lyon, IMP, Villeurbanne, France
- UMR 5223, Ingénierie des Matériaux Polymères, CNRS, Villeurbanne, France
| | - Sebastien G. Gouin
- CEISAM, Chimie Et Interdisciplinarité, Synthèse, Analyse, Modélisation, UMR CNRS 6230, UFR des Sciences et des Techniques, LUNAM Université, Nantes Cedex 3, France
| | - Nicolas Barnich
- M2iSH, UMR 1071 Inserm, INRA USC-2018, Institut Universitaire Technologique, Université Clermont Auvergne, Clermont-Ferrand 63001, France
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Kramer CD, Genco CA. Microbiota, Immune Subversion, and Chronic Inflammation. Front Immunol 2017; 8:255. [PMID: 28348558 PMCID: PMC5346547 DOI: 10.3389/fimmu.2017.00255] [Citation(s) in RCA: 48] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2016] [Accepted: 02/21/2017] [Indexed: 12/12/2022] Open
Abstract
Several host-adapted pathogens and commensals have evolved mechanisms to evade the host innate immune system inducing a state of low-grade inflammation. Epidemiological studies have also documented the association of a subset of these microorganisms with chronic inflammatory disorders. In this review, we summarize recent studies demonstrating the role of the microbiota in chronic inflammatory diseases and discuss how specific microorganisms subvert or inhibit protective signaling normally induced by toll-like receptors (TLRs). We highlight our work on the oral pathogen Porphyromonas gingivalis and discuss the role of microbial modulation of lipid A structures in evasion of TLR4 signaling and resulting systemic immunopathology associated with atherosclerosis. P. gingivalis intrinsically expresses underacylated lipid A moieties and can modify the phosphorylation of lipid A, leading to altered TLR4 signaling. Using P. gingivalis mutant strains expressing distinct lipid A moieties, we demonstrated that expression of antagonist lipid A was associated with P. gingivalis-mediated systemic inflammation and immunopathology, whereas strains expressing agonist lipid A exhibited modest systemic inflammation. Likewise, mice deficient in TLR4 were more susceptible to vascular inflammation after oral infection with P. gingivalis wild-type strain compared to mice possessing functional TLR4. Collectively, our studies support a role for P. gingivalis-mediated dysregulation of innate and adaptive responses resulting in immunopathology and systemic inflammation. We propose that anti-TLR4 interventions must be designed with caution, given the balance between the protective and destructive roles of TLR signaling in response to microbiota and associated immunopathologies.
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Affiliation(s)
- Carolyn D Kramer
- Department of Integrative Physiology and Pathobiology, Tufts University School of Medicine , Boston, MA , USA
| | - Caroline Attardo Genco
- Department of Integrative Physiology and Pathobiology, Tufts University School of Medicine , Boston, MA , USA
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Drago-Serrano ME, Campos-Rodríguez R, Carrero JC, de la Garza M. Lactoferrin: Balancing Ups and Downs of Inflammation Due to Microbial Infections. Int J Mol Sci 2017; 18:E501. [PMID: 28257033 PMCID: PMC5372517 DOI: 10.3390/ijms18030501] [Citation(s) in RCA: 96] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2017] [Revised: 02/13/2017] [Accepted: 02/22/2017] [Indexed: 02/07/2023] Open
Abstract
Lactoferrin (Lf) is a glycoprotein of the primary innate immune-defense system of mammals present in milk and other mucosal secretions. This protein of the transferrin family has broad antimicrobial properties by depriving pathogens from iron, or disrupting their plasma membranes through its highly cationic charge. Noteworthy, Lf also exhibits immunomodulatory activities performing up- and down-regulation of innate and adaptive immune cells, contributing to the homeostasis in mucosal surfaces exposed to myriad of microbial agents, such as the gastrointestinal and respiratory tracts. Although the inflammatory process is essential for the control of invasive infectious agents, the development of an exacerbated or chronic inflammation results in tissue damage with life-threatening consequences. In this review, we highlight recent findings in in vitro and in vivo models of the gut, lung, oral cavity, mammary gland, and liver infections that provide experimental evidence supporting the therapeutic role of human and bovine Lf in promoting some parameters of inflammation and protecting against the deleterious effects of bacterial, viral, fungal and protozoan-associated inflammation. Thus, this new knowledge of Lf immunomodulation paves the way to more effective design of treatments that include native or synthetic Lf derivatives, which may be useful to reduce immune-mediated tissue damage in infectious diseases.
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Affiliation(s)
- Maria Elisa Drago-Serrano
- Departamento de Sistemas Biológicos, Universidad Autónoma Metropolitana Unidad Xochimilco (UAM-X), CdMx 04960, Mexico.
| | - Rafael Campos-Rodríguez
- Sección de Estudios de Posgrado e Investigación, Escuela Superior de Medicina, Instituto Politécnico Nacional (ESM-IPN), CdMx 11340, Mexico.
| | - Julio César Carrero
- Departamento de Inmunología, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México (IIB-UNAM), CdMx 70228, Mexico.
| | - Mireya de la Garza
- Departamento de Biología Celular, Centro de Investigación y Estudios Avanzados del Instituto Politécnico Nacional (CINVESTAV-IPN), CdMx 07360, Mexico.
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46
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Bovine colostrum demonstrates anti-inflammatory and antibacterial activity in in vitro models of intestinal inflammation and infection. J Funct Foods 2017. [DOI: 10.1016/j.jff.2016.11.016] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023] Open
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Martin VJ, Leonard MM, Fiechtner L, Fasano A. Transitioning From Descriptive to Mechanistic Understanding of the Microbiome: The Need for a Prospective Longitudinal Approach to Predicting Disease. J Pediatr 2016; 179:240-248. [PMID: 27634626 PMCID: PMC5479769 DOI: 10.1016/j.jpeds.2016.08.049] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/03/2016] [Revised: 07/15/2016] [Accepted: 08/16/2016] [Indexed: 12/11/2022]
Affiliation(s)
| | | | | | - Alessio Fasano
- Department of Pediatric Gastroenterology and Nutrition, Massachusetts General Hospital for Children, Boston, MA.
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48
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Small CL, Xing L, McPhee JB, Law HT, Coombes BK. Acute Infectious Gastroenteritis Potentiates a Crohn's Disease Pathobiont to Fuel Ongoing Inflammation in the Post-Infectious Period. PLoS Pathog 2016; 12:e1005907. [PMID: 27711220 PMCID: PMC5053483 DOI: 10.1371/journal.ppat.1005907] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2016] [Accepted: 08/30/2016] [Indexed: 12/18/2022] Open
Abstract
Crohn’s disease (CD) is a chronic inflammatory condition of diverse etiology. Exposure to foodborne pathogens causing acute gastroenteritis produces a long-term risk of CD well into the post-infectious period but the mechanistic basis for this ongoing relationship to disease onset is unknown. We developed two novel models to study the comorbidity of acute gastroenteritis caused by Salmonella Typhimurium or Citrobacter rodentium in mice colonized with adherent-invasive Escherichia coli (AIEC), a bacterial pathobiont linked to CD. Here, we show that disease activity in the post-infectious period after gastroenteritis is driven by the tissue-associated expansion of the resident AIEC pathobiont, with an attendant increase in immunopathology, barrier defects, and delays in mucosal restitution following pathogen clearance. These features required AIEC resistance to host defense peptides and a fulminant inflammatory response to the enteric pathogen. Our results suggest that individuals colonized by AIEC at the time of acute infectious gastroenteritis may be at greater risk for CD onset. Importantly, our data identify AIEC as a tractable disease modifier, a finding that could be exploited in the development of therapeutic interventions following infectious gastroenteritis in at-risk individuals. Western societies have a disproportionately high rate of inflammatory bowel disease (IBD), with growing incidence especially in the adolescent population. A large body of evidence supports the view that bacteria in the gut participate in the pathophysiology of human bowel diseases. The unifying concept is chronic inflammation that is driven by microbial stimulation of the mucosal immune system. However, the mechanisms by which pathogenic or commensal microbes work in concert with each other and with host responses to perpetuate this inflammation is not well known. Adherent-invasive E. coli (AIEC) are Crohn’s disease (CD)-associated bacteria that are implicated in disease pathology. AIEC are pro-inflammatory and may play a central role in maintaining chronic inflammation in response to other CD risk factors, such as acute infectious gastroenteritis. Here, we show that indeed, acute infectious gastroenteritis creates an inflammatory environment in the gut that drives AIEC expansion and worsens disease severity. The increase in disease severity strictly correlates with this AIEC bloom because blocking this bloom by sensitizing AIEC to host defenses also improves the health status of the host. The long time period between recovery from acute gastroenteritis and new onset CD may allow for targeted interventions to mitigate the risk of CD in AIEC-positive individuals.
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Affiliation(s)
- Cherrie L. Small
- Michael G. DeGroote Institute for Infectious Disease Research, Hamilton, Ontario, Canada
| | - Lydia Xing
- Michael G. DeGroote Institute for Infectious Disease Research, Hamilton, Ontario, Canada
| | - Joseph B. McPhee
- Michael G. DeGroote Institute for Infectious Disease Research, Hamilton, Ontario, Canada
| | - Hong T. Law
- Michael G. DeGroote Institute for Infectious Disease Research, Hamilton, Ontario, Canada
| | - Brian K. Coombes
- Michael G. DeGroote Institute for Infectious Disease Research, Hamilton, Ontario, Canada
- Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario, Canada
- Farncombe Family Digestive Health Research Institute, Hamilton, Ontario, Canada
- * E-mail:
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NOD2 induces autophagy to control AIEC bacteria infectiveness in intestinal epithelial cells. Inflamm Res 2016; 65:803-13. [PMID: 27335178 DOI: 10.1007/s00011-016-0964-8] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2015] [Revised: 05/13/2016] [Accepted: 06/16/2016] [Indexed: 12/13/2022] Open
Abstract
OBJECTIVE The importance of autophagy in mechanisms underlying inflammation has been highlighted. Downstream effects of the bacterial sensor NOD2 include autophagy induction. Recently, a relationship between defects in autophagy and adherent/invasive Escherichia coli (AIEC) persistence has emerged. The present study aims at investigating the interplay between autophagy, NOD2 and AIEC bacteria and assessing the expression level of autophagic proteins in intestinal biopsies of pediatric patients with inflammatory bowel disease (IBD). METHODS A human epithelial colorectal adenocarcinoma (Caco2) cell line stably over-expressing NOD2 was produced (Caco2NOD2). ATG16L1, LC3 and NOD2 levels were analysed in the Caco2 cell line and Caco2NOD2 after exposure to AIEC strains, by western blot and immunofluorescence. AIEC survival inside cells and TNFα, IL-8 and IL-1βmRNA expression were analysed by gentamicin protection assay and real time PCR. ATG16L1 and LC3 expression was analyzed in the inflamed ileum and colon of 28 patients with Crohn's disease (CD), 14 with ulcerative colitis (UC) and 23 controls by western blot. RESULTS AIEC infection increased ATG16L1 and LC3 in Caco2 cells. Exposure to AIEC strains increased LC3 and ATG16L1 in Caco2 overexpressing NOD2, more than in Caco2 wild type, while a decrease of AIEC survival rate and cytokine expression was observed in the same cell line. LC3 expression was increased in the inflamed colon of CD and UC children. CONCLUSIONS The NOD2-mediated autophagy induction is crucial to hold the intramucosal bacterial burden, especially towards AIEC, and to limit the resulting inflammatory response. Autophagy is active in inflamed colonic tissues of IBD pediatric patients.
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50
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Shi Y, Dong Y, Huang W, Zhu D, Mao H, Su P. Fecal Microbiota Transplantation for Ulcerative Colitis: A Systematic Review and Meta-Analysis. PLoS One 2016; 11:e0157259. [PMID: 27295210 PMCID: PMC4905678 DOI: 10.1371/journal.pone.0157259] [Citation(s) in RCA: 73] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2016] [Accepted: 05/26/2016] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Fecal microbiota transplantation (FMT) has been recognized as a novel treatment for ulcerative colitis (UC). However, its efficacy and safety remain unclear. OBJECTIVE We conducted this systematic review to assess the efficacy and safety of FMT in UC. DATA SOURCES PubMed, EMBASE, Cochrane Central, Web of Science Core Collection, and three other Chinese databases were searched for reports of FMT in UC with clear outcomes. DATA EXTRACTION AND SYNTHESIS We estimated pooled rates [with 95% confidence interval (CI)] of clinical remission among 15 cohort studies and clinical response among 16 cohort studies. RESULTS Twenty five studies (2 randomized controlled trials, 15 cohort studies, and 8 case studies) with 234 UC patients were included. Overall, 41.58% (84/202) patients achieved clinical remission (CR) and 65.28% (126/193) achieved clinical response. Among the cohort studies, the pooled estimate of patients who achieved CR and clinical response were 40.5% (95% CI 24.7%-58.7%), and 66.1% (95% CI 43.7%-83.0%). Most adverse events were slight and self-resolving. The analyses of gut microbiota in 7 studies showed that FMT could increase microbiota diversity and richness, similarity, and certain change of bacterial composition. CONCLUSION FMT provides a promising effect for UC with few adverse events. Successful FMT may be associated with an increase in microbiota diversity and richness, similarity, and certain change of bacterial composition.
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Affiliation(s)
- Yanqiang Shi
- The Second Clinical Medical School, Southern Medical University, 510280, Guangzhou City, Guangdong Province, China
| | - Yiwei Dong
- The Second Clinical Medical School, Southern Medical University, 510280, Guangzhou City, Guangdong Province, China
| | - Wenhui Huang
- The Second Clinical Medical School, Southern Medical University, 510280, Guangzhou City, Guangdong Province, China
| | - Decong Zhu
- The Second Clinical Medical School, Southern Medical University, 510280, Guangzhou City, Guangdong Province, China
| | - Hua Mao
- Department of Gastroenterology, Zhujiang Hospital, Southern Medical University, 510280, Guangzhou City, Guangdong Province, China
| | - Peizhu Su
- Department of Gastroenterology, Zhujiang Hospital, Southern Medical University, 510280, Guangzhou City, Guangdong Province, China
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