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Lai J, Rigas Y, Kantor N, Cohen N, Tomlinson A, St. Leger AJ, Galor A. Living with your biome: how the bacterial microbiome impacts ocular surface health and disease. EXPERT REVIEW OF OPHTHALMOLOGY 2024; 19:89-103. [PMID: 38764699 PMCID: PMC11101146 DOI: 10.1080/17469899.2024.2306582] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/01/2023] [Accepted: 01/14/2024] [Indexed: 05/21/2024]
Abstract
Introduction Microbiome research has grown exponentially but the ocular surface microbiome (OSM) remains an area in need of further study. This review aims to explore its complexity, disease-related microbial changes, and immune interactions, and highlights the potential for its manipulation as a therapeutic for ocular surface diseases. Areas Covered We introduce the OSM by location and describe what constitutes a normal OSM. Second, we highlight aspects of the ocular immune system and discuss potential immune microbiome interactions in health and disease. Finally, we highlight how microbiome manipulation may have therapeutic potential for ocular surface diseases. Expert Opinion The ocular surface microbiome varies across its different regions, with a core phyla identified, but with genus variability. A few studies have linked microbiome composition to diseases like dry eye but more research is needed, including examining microbiome interactions with the host. Studies have noted that manipulating the microbiome may impact disease presentation. As such, microbiome manipulation via diet, oral and topical pre and probiotics, and hygienic measures may provide new therapeutic algorithms in ocular surface diseases.
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Affiliation(s)
- James Lai
- Bascom Palmer Eye Institute, University of Miami, Miami, Florida, USA
| | - Yannis Rigas
- University of Pittsburgh School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Nicole Kantor
- Bascom Palmer Eye Institute, University of Miami, Miami, Florida, USA
| | - Noah Cohen
- Bascom Palmer Eye Institute, University of Miami, Miami, Florida, USA
| | - Ana Tomlinson
- Bascom Palmer Eye Institute, University of Miami, Miami, Florida, USA
| | - Anthony J. St. Leger
- University of Pittsburgh School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Anat Galor
- Bascom Palmer Eye Institute, University of Miami, Miami, Florida, USA
- Miami Veterans Affairs Hospital, Miami, Florida, USA
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Caparrós E, Wiest R, Scharl M, Rogler G, Gutiérrez Casbas A, Yilmaz B, Wawrzyniak M, Francés R. Dysbiotic microbiota interactions in Crohn's disease. Gut Microbes 2021; 13:1949096. [PMID: 34313550 PMCID: PMC8320851 DOI: 10.1080/19490976.2021.1949096] [Citation(s) in RCA: 41] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023] Open
Abstract
Crohn's disease (CD) is a major form of inflammatory bowel disease characterized by transmural inflammation along the alimentary tract. Changes in the microbial composition and reduction in species diversity are recognized as pivotal hallmarks in disease dynamics, challenging the gut barrier function and shaping a pathological immune response in genetically influenced subjects. The purpose of this review is to delve into the modification of the gut microbiota cluster network during CD progression and to discuss how this shift compromises the gut barrier integrity, granting the translocation of microbes and their products. We then complete the scope of the review by retracing gut microbiota dysbiosis interactions with the main pathophysiologic factors of CD, starting from the host's genetic background to the immune inflammatory and fibrotic processes, providing a standpoint on the lifestyle/exogenous factors and the potential benefits of targeting a specific gut microbiota.
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Affiliation(s)
- Esther Caparrós
- Dpto Medicina Clínica, Universidad Miguel Hernández, San Juan De Alicante, Spain,Iis Isabial, Hospital General Universitario De Alicante, Alicante, Spain
| | - Reiner Wiest
- Department for Biomedical Research, Department of Visceral Surgery and Medicine, Bern University Hospital, University of Bern, Bern, Switzerland
| | - Michael Scharl
- Department of Gastroenterology and Hepatology, University Hospital of Zurich, University of Zurich, Zurich, Switzerland
| | - Gerhard Rogler
- Department of Gastroenterology and Hepatology, University Hospital of Zurich, University of Zurich, Zurich, Switzerland
| | - Ana Gutiérrez Casbas
- Iis Isabial, Hospital General Universitario De Alicante, Alicante, Spain,CIBERehd, Instituto De Salud Carlos III, Madrid, Spain
| | - Bahtiyar Yilmaz
- Department for Biomedical Research, Department of Visceral Surgery and Medicine, Bern University Hospital, University of Bern, Bern, Switzerland
| | - Marcin Wawrzyniak
- Department of Gastroenterology and Hepatology, University Hospital of Zurich, University of Zurich, Zurich, Switzerland
| | - Rubén Francés
- Dpto Medicina Clínica, Universidad Miguel Hernández, San Juan De Alicante, Spain,Iis Isabial, Hospital General Universitario De Alicante, Alicante, Spain,CIBERehd, Instituto De Salud Carlos III, Madrid, Spain,CONTACT Rubén Francés Hepatic and Intestinal Immunobiology Group. Departamento De Medicina Clínica, Universidad Miguel Hernández De Elche. Carretera Alicante-Valencia, Km 8,703550San Juan De Alicante
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3
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Extended graphical lasso for multiple interaction networks for high dimensional omics data. PLoS Comput Biol 2021; 17:e1008794. [PMID: 34669695 PMCID: PMC8528283 DOI: 10.1371/journal.pcbi.1008794] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2021] [Accepted: 09/03/2021] [Indexed: 11/19/2022] Open
Abstract
There has been a spate of interest in association networks in biological and medical research, for example, genetic interaction networks. In this paper, we propose a novel method, the extended joint hub graphical lasso (EDOHA), to estimate multiple related interaction networks for high dimensional omics data across multiple distinct classes. To be specific, we construct a convex penalized log likelihood optimization problem and solve it with an alternating direction method of multipliers (ADMM) algorithm. The proposed method can also be adapted to estimate interaction networks for high dimensional compositional data such as microbial interaction networks. The performance of the proposed method in the simulated studies shows that EDOHA has remarkable advantages in recognizing class-specific hubs than the existing comparable methods. We also present three applications of real datasets. Biological interpretations of our results confirm those of previous studies and offer a more comprehensive understanding of the underlying mechanism in disease.
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Ditto MC, Parisi S, Landolfi G, Borrelli R, Realmuto C, Finucci A, Caviglia GP, Ribaldone DG, Astegiano M, Zanetti A, Carrara G, Scirè CA, Antivalle M, Sarzi-Puttini P, Fusaro E. Intestinal microbiota changes induced by TNF-inhibitors in IBD-related spondyloarthritis. RMD Open 2021; 7:e001755. [PMID: 34489323 PMCID: PMC8422478 DOI: 10.1136/rmdopen-2021-001755] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2021] [Accepted: 07/30/2021] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND The close relationship between joints and gut inflammation has long been known and several data suggest that dysbiosis could link spondyloarthritis (SpA) to inflammatory bowel diseases (IBD). The introduction of biological drugs, in particular tumour necrosis factor inhibitors (TNFi), revolutionised the management of both these diseases. While the impact of conventional drugs on gut microbiota is well known, poor data are available about TNFi. AIM To investigate the impact of TNFi on gut microbiota. METHODS We evaluated 20 patients affected by enteropathic arthritis, naïve for biological drugs, treated with TNFi at baseline and after 6 months of therapy. All patients followed a Mediterranean diet. Patients performed self-sampling of a faecal sample at baseline and after 6 months of therapy. NGS-based ITS and 16S rRNA gene sequencing was performed, followed by the taxonomic bioinformatics analysis. RESULTS After 6 months of therapy, we detected a remarkable increase in Lachnospiraceae family (Δ +10.3, p=0.04) and Coprococcus genus (Δ +2.8, p=0.003). We also noted a decreasing trend in Proteobacteria (Δ -8.0, p=0.095) and Gammaproteobacteria (Δ -9, p=0.093) and an increasing trend in Clostridia (Δ +8.2, p=0.083). We did not find differences between TNFi responders (SpA improvement or IBD remission achieved) and non-responders in terms of alpha and beta diversity. CONCLUSIONS Our findings are consistent with the hypothesis that TNFi therapy tends to restore the intestinal eubiosis.
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Affiliation(s)
- Maria Chiara Ditto
- Rheumatology Unit, Azienda Ospedaliero Universitaria Città della Salute e della Scienza di Torino, Turin, Italy
| | - Simone Parisi
- Rheumatology Unit, Azienda Ospedaliero Universitaria Città della Salute e della Scienza di Torino, Turin, Italy
| | | | - Richard Borrelli
- Rheumatology Unit, Azienda Ospedaliero Universitaria Città della Salute e della Scienza di Torino, Turin, Italy
| | - Cristina Realmuto
- Rheumatology Unit, Azienda Ospedaliero Universitaria Città della Salute e della Scienza di Torino, Turin, Italy
| | - Annacarla Finucci
- Rheumatology Unit, Azienda Ospedaliero Universitaria Città della Salute e della Scienza di Torino, Turin, Italy
| | - Gian Paolo Caviglia
- Gastroenterology Unit, University of Turin Department of Medical Sciences, Turin, Italy
| | - Davide Giuseppe Ribaldone
- Gastroenterology Unit, Azienda Ospedaliero Universitaria Città della Salute e della Scienza di Torino, Turin, Italy
| | - Marco Astegiano
- Gastroenterology Unit, Azienda Ospedaliero Universitaria Città della Salute e della Scienza di Torino, Turin, Italy
| | - Anna Zanetti
- Epidemiology Unit, Italian Society of Rheumatology, Milan, Italy
| | - Greta Carrara
- Epidemiology Unit, Italian Society of Rheumatology, Milan, Italy
| | | | | | | | - Enrico Fusaro
- Rheumatology Unit, Azienda Ospedaliero Universitaria Città della Salute e della Scienza di Torino, Turin, Italy
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Tong Y, Gao H, Qi Q, Liu X, Li J, Gao J, Li P, Wang Y, Du L, Wang C. High fat diet, gut microbiome and gastrointestinal cancer. Theranostics 2021; 11:5889-5910. [PMID: 33897888 PMCID: PMC8058730 DOI: 10.7150/thno.56157] [Citation(s) in RCA: 115] [Impact Index Per Article: 28.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2020] [Accepted: 03/09/2021] [Indexed: 12/12/2022] Open
Abstract
Gastrointestinal cancer is currently one of the main causes of cancer death, with a large number of cases and a wide range of lesioned sites. A high fat diet, as a public health problem, has been shown to be correlated with various digestive system diseases and tumors, and can accelerate the occurrence of cancer due to inflammation and altered metabolism. The gut microbiome has been the focus of research in recent years, and associated with cell damage or tumor immune microenvironment changes via direct or extra-intestinal effects; this may facilitate the occurrence and development of gastrointestinal tumors. Based on research showing that both a high fat diet and gut microbes can promote the occurrence of gastrointestinal tumors, and that a high fat diet imbalances intestinal microbes, we propose that a high fat diet drives gastrointestinal tumors by changing the composition of intestinal microbes.
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Affiliation(s)
- Yao Tong
- Department of Clinical Laboratory, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
| | - Huiru Gao
- Department of Clinical Laboratory, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
| | - Qiuchen Qi
- Department of Clinical Laboratory, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
| | - Xiaoyan Liu
- Department of Clinical Laboratory, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
| | - Juan Li
- Department of Clinical Laboratory, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
| | - Jie Gao
- Department of Clinical Laboratory, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
| | - Peilong Li
- Department of Clinical Laboratory, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
| | - Yunshan Wang
- Department of Clinical Laboratory, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
| | - Lutao Du
- Department of Clinical Laboratory, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
| | - Chuanxin Wang
- Department of Clinical Laboratory, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
- Shandong Engineering & Technology Research Center for Tumor Marker Detection, Jinan, Shandong, China
- Shandong Provincial Clinical Medicine Research Center for Clinical Laboratory, Jinan, Shandong, China
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6
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Guo H, Gibson SA, Ting JPY. Gut microbiota, NLR proteins, and intestinal homeostasis. J Exp Med 2021; 217:152098. [PMID: 32941596 PMCID: PMC7537383 DOI: 10.1084/jem.20181832] [Citation(s) in RCA: 36] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2020] [Revised: 08/10/2020] [Accepted: 08/14/2020] [Indexed: 12/21/2022] Open
Abstract
The gastrointestinal tract harbors a highly complex microbial community, which is referred to as gut microbiota. With increasing evidence suggesting that the imbalance of gut microbiota plays a significant role in the pathogenesis of multiple diseases, interactions between the host immune system and the gut microbiota are now attracting emerging interest. Nucleotide-binding and leucine-rich repeat–containing receptors (NLRs) encompass a large number of innate immune sensors and receptors, which mediate the activation of Caspase-1 and the subsequent release of mature interleukin-1β and interleukin-18. Several family members have been found to restrain rather than activate inflammatory cytokines and immune signaling. NLR family members are central regulators of pathogen recognition, host immunity, and inflammation with utmost importance in human diseases. In this review, we focus on the potential roles played by NLRs in controlling and shaping the microbiota community and discuss how the functional axes interconnecting gut microbiota with NLRs impact the modulation of colitis, inflammatory bowel diseases, and colorectal cancer.
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Affiliation(s)
- Hao Guo
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC
| | - Sara A Gibson
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC.,Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC
| | - Jenny P Y Ting
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC.,Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC.,Department of Microbiology-Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC
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7
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Hu S, Vich Vila A, Gacesa R, Collij V, Stevens C, Fu JM, Wong I, Talkowski ME, Rivas MA, Imhann F, Bolte L, van Dullemen H, Dijkstra G, Visschedijk MC, Festen EA, Xavier RJ, Fu J, Daly MJ, Wijmenga C, Zhernakova A, Kurilshikov A, Weersma RK. Whole exome sequencing analyses reveal gene-microbiota interactions in the context of IBD. Gut 2021; 70:285-296. [PMID: 32651235 PMCID: PMC7815889 DOI: 10.1136/gutjnl-2019-319706] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/23/2019] [Revised: 04/08/2020] [Accepted: 04/20/2020] [Indexed: 12/18/2022]
Abstract
OBJECTIVE Both the gut microbiome and host genetics are known to play significant roles in the pathogenesis of IBD. However, the interaction between these two factors and its implications in the aetiology of IBD remain underexplored. Here, we report on the influence of host genetics on the gut microbiome in IBD. DESIGN To evaluate the impact of host genetics on the gut microbiota of patients with IBD, we combined whole exome sequencing of the host genome and whole genome shotgun sequencing of 1464 faecal samples from 525 patients with IBD and 939 population-based controls. We followed a four-step analysis: (1) exome-wide microbial quantitative trait loci (mbQTL) analyses, (2) a targeted approach focusing on IBD-associated genomic regions and protein truncating variants (PTVs, minor allele frequency (MAF) >5%), (3) gene-based burden tests on PTVs with MAF <5% and exome copy number variations (CNVs) with site frequency <1%, (4) joint analysis of both cohorts to identify the interactions between disease and host genetics. RESULTS We identified 12 mbQTLs, including variants in the IBD-associated genes IL17REL, MYRF, SEC16A and WDR78. For example, the decrease of the pathway acetyl-coenzyme A biosynthesis, which is involved in short chain fatty acids production, was associated with variants in the gene MYRF (false discovery rate <0.05). Changes in functional pathways involved in the metabolic potential were also observed in participants carrying rare PTVs or CNVs in CYP2D6, GPR151 and CD160 genes. These genes are known for their function in the immune system. Moreover, interaction analyses confirmed previously known IBD disease-specific mbQTLs in TNFSF15. CONCLUSION This study highlights that both common and rare genetic variants affecting the immune system are key factors in shaping the gut microbiota in the context of IBD and pinpoints towards potential mechanisms for disease treatment.
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Affiliation(s)
- Shixian Hu
- Department of Gastroenterology and Hepatology, University of Groningen and University Medical Center Groningen, Groningen, The Netherlands
- Department of Genetics, University of Groningen and University Medical Center Groningen, Groningen, The Netherlands
| | - Arnau Vich Vila
- Department of Gastroenterology and Hepatology, University of Groningen and University Medical Center Groningen, Groningen, The Netherlands
- Department of Genetics, University of Groningen and University Medical Center Groningen, Groningen, The Netherlands
| | - Ranko Gacesa
- Department of Gastroenterology and Hepatology, University of Groningen and University Medical Center Groningen, Groningen, The Netherlands
- Department of Genetics, University of Groningen and University Medical Center Groningen, Groningen, The Netherlands
| | - Valerie Collij
- Department of Gastroenterology and Hepatology, University of Groningen and University Medical Center Groningen, Groningen, The Netherlands
- Department of Genetics, University of Groningen and University Medical Center Groningen, Groningen, The Netherlands
| | - Christine Stevens
- Program in Medical and Population Genetics, Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusetts, USA
| | - Jack M Fu
- Program in Medical and Population Genetics, Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, Massachusetts, USA
- Center for Genomic Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA
- Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA
| | - Isaac Wong
- Program in Medical and Population Genetics, Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, Massachusetts, USA
- Center for Genomic Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - Michael E Talkowski
- Program in Medical and Population Genetics, Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, Massachusetts, USA
- Center for Genomic Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA
- Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA
- Division of Medical Sciences, Harvard Medical School, Boston, Massachusetts, USA
- Stanley Center for Psychiatric Research, Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusetts, USA
| | - Manuel A Rivas
- Department of Biomedical Data Science, Stanford University, Stanford, California, USA
| | - Floris Imhann
- Department of Gastroenterology and Hepatology, University of Groningen and University Medical Center Groningen, Groningen, The Netherlands
- Department of Genetics, University of Groningen and University Medical Center Groningen, Groningen, The Netherlands
| | - Laura Bolte
- Department of Gastroenterology and Hepatology, University of Groningen and University Medical Center Groningen, Groningen, The Netherlands
- Department of Genetics, University of Groningen and University Medical Center Groningen, Groningen, The Netherlands
| | - Hendrik van Dullemen
- Department of Gastroenterology and Hepatology, University of Groningen and University Medical Center Groningen, Groningen, The Netherlands
| | - Gerard Dijkstra
- Department of Gastroenterology and Hepatology, University of Groningen and University Medical Center Groningen, Groningen, The Netherlands
| | - Marijn C Visschedijk
- Department of Gastroenterology and Hepatology, University of Groningen and University Medical Center Groningen, Groningen, The Netherlands
| | - Eleonora A Festen
- Department of Gastroenterology and Hepatology, University of Groningen and University Medical Center Groningen, Groningen, The Netherlands
| | - Ramnik J Xavier
- Center for Microbiome Informatics and Therapeutic, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA
- Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, Massachusetts, USA
| | - Jingyuan Fu
- Department of Genetics, University of Groningen and University Medical Center Groningen, Groningen, The Netherlands
- Department of Pediatrics, University of Groningen and University Medical Center Groningen, Groningen, The Netherlands
| | - Mark J Daly
- Program in Medical and Population Genetics, Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusetts, USA
| | - Cisca Wijmenga
- Department of Genetics, University of Groningen and University Medical Center Groningen, Groningen, The Netherlands
| | - Alexandra Zhernakova
- Department of Genetics, University of Groningen and University Medical Center Groningen, Groningen, The Netherlands
| | - Alexander Kurilshikov
- Department of Genetics, University of Groningen and University Medical Center Groningen, Groningen, The Netherlands
| | - Rinse K Weersma
- Department of Gastroenterology and Hepatology, University of Groningen and University Medical Center Groningen, Groningen, The Netherlands
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Lee M, Chang EB. Inflammatory Bowel Diseases (IBD) and the Microbiome-Searching the Crime Scene for Clues. Gastroenterology 2021; 160:524-537. [PMID: 33253681 PMCID: PMC8098834 DOI: 10.1053/j.gastro.2020.09.056] [Citation(s) in RCA: 363] [Impact Index Per Article: 90.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/27/2020] [Revised: 09/25/2020] [Accepted: 09/28/2020] [Indexed: 02/07/2023]
Abstract
Inflammatory bowel diseases (IBD) develop via convergence of environmental, microbial, immunological, and genetic factors. Alterations in the gut microbiota have been associated with development and progression of IBD, but it is not clear which populations of microbes are involved or how they might contribute to IBD. We review the genetic and environmental factors affecting the gut microbiota, the roles of gut microbes and their bioproducts in the development and clinical course of IBD, and strategies by which microbiome-based therapies can be used to prevent, manage, and eventually cure IBD. We discuss research findings that help bridge the gap between the basic sciences and clinical application.
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Affiliation(s)
| | - Eugene B Chang
- Department of Medicine, University of Chicago, Chicago, Illinois.
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Xue AJ, Miao SJ, Sun H, Qiu XX, Wang SN, Wang L, Ye ZQ, Zheng CF, Huang ZH, Wang YH, Huang Y. Intestinal dysbiosis in pediatric Crohn's disease patients with IL10RA mutations. World J Gastroenterol 2020; 26:3098-3109. [PMID: 32587451 PMCID: PMC7304104 DOI: 10.3748/wjg.v26.i22.3098] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/06/2020] [Revised: 03/30/2020] [Accepted: 05/28/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Several studies have employed animal models to explore the association between microbiota and interleukin (IL) 10 signaling; however, limited information is available about the human microbiome.
AIM To characterize the microbiome in patients with IL10RA mutations and to explore the association between gut dysbiosis and disease severity.
METHODS Fecal samples were collected from patients who were diagnosed with loss-of-function mutations in the IL10RA gene between January 2017 and July 2018 at the Children's Hospital of Fudan University. Age-matched volunteer children were recruited as healthy controls. Patients with Crohn's disease (CD) were used as disease controls to standardize the antibiotic exposure. Microbial DNA was extracted from the fecal samples. All analyses were based on the 16S rRNA gene sequencing data.
RESULTS Seventeen patients with IL10RA mutations (IL10RA group), 17 patients with pediatric CD, and 26 healthy children were included. Both patients with IL10RA mutations and those with CD exhibited a reduced diversity of gut microbiome with increased variability. The relative abundance of Firmicutes was substantially increased in the IL10RA group (P = 0.02). On further comparison of the relative abundance of taxa between patients with IL10RA mutations and healthy children, 13 taxa showed significant differences. The IL10RA-specific dysbiosis indices exhibited a significant positive correlation with weighted pediatric CD activity index and simple endoscopic score for CD.
CONCLUSION In patients with IL10RA mutations and early onset inflammatory bowel disease, gut dysbiosis shows a moderate association with disease severity.
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Affiliation(s)
- Ai-Juan Xue
- Department of Gastroenterology, Children’s Hospital of Fudan University, Shanghai 201102, China
| | - Shi-Jian Miao
- Department of Gastroenterology, Children’s Hospital of Fudan University, Shanghai 201102, China
| | - Hua Sun
- Department of Gastroenterology, Children’s Hospital of Fudan University, Shanghai 201102, China
| | - Xiao-Xia Qiu
- Department of Gastroenterology, Children’s Hospital of Fudan University, Shanghai 201102, China
| | - Sheng-Nan Wang
- Department of Gastroenterology, Children’s Hospital of Fudan University, Shanghai 201102, China
| | - Lin Wang
- Department of Gastroenterology, Children’s Hospital of Fudan University, Shanghai 201102, China
| | - Zi-Qing Ye
- Department of Gastroenterology, Children’s Hospital of Fudan University, Shanghai 201102, China
| | - Cui-Fang Zheng
- Department of Gastroenterology, Children’s Hospital of Fudan University, Shanghai 201102, China
| | - Zhi-Heng Huang
- Department of Gastroenterology, Children’s Hospital of Fudan University, Shanghai 201102, China
| | - Yu-Huan Wang
- Department of Gastroenterology, Children’s Hospital of Fudan University, Shanghai 201102, China
| | - Ying Huang
- Department of Gastroenterology, Children’s Hospital of Fudan University, Shanghai 201102, China
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10
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Zatorski H, Nakov R. Faecal Microbiota Transplantation in Inflammatory Bowel Disease: Current Concepts and Future Challenges. Curr Drug Targets 2020; 21:1440-1447. [PMID: 32484770 DOI: 10.2174/1389450121666200602125507] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2020] [Revised: 04/08/2020] [Accepted: 04/09/2020] [Indexed: 12/26/2022]
Abstract
Dysbiosis has been repeatedly observed in inflammatory bowel disease (IBD) and is now recognized as an essential factor in the gut inflammatory process. IBD is a significant burden to health-care systems, mainly due to treatment-related costs. Available treatments have several limitations: up to 30% of patients are primary non-responders, and between 10 and 20% lose response per year, requiring a dose-escalation or a switch to another biologic. Hence, the current IBD treatment is not sufficient, and there is an urgent need to introduce new therapies in the management of these patients. Recently, the correction of dysbiosis has become an attractive approach from a therapeutic point of view. Faecal microbiota transplantation (FMT) appears as a reliable and potentially beneficial therapy in IBD patients. There is developing data that FMT for mild-to-moderately active UC is a safe and efficient therapy for the induction of remission. However, the current studies have different designs and have a short follow up, which makes clinical interpretation significantly difficult. There is a need for RCTs with a well-defined study cohort using FMT for the therapy of CD patients. The location, behavior, and severity of the disease should be taken into account. The goal of this manuscript is to review the data currently available on FMT and IBD, to explain FMT principles and methodology in IBD patients and to discuss some unresolved issues.
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Affiliation(s)
- Hubert Zatorski
- Department of Digestive Tract Diseasesx,Department of Biochemistry, Faculty of Medicine, Medical University of Lodz, Lodz, Poland
| | - Radislav Nakov
- Clinic of Gastroenterology, Tsaritsa Yoanna University Hospital, Medical University of Sofia, Sofia, Bulgaria
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11
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Moltzau Anderson J, Lipinski S, Sommer F, Pan WH, Boulard O, Rehman A, Falk-Paulsen M, Stengel ST, Aden K, Häsler R, Bharti R, Künzel S, Baines JF, Chamaillard M, Rosenstiel P. NOD2 Influences Trajectories of Intestinal Microbiota Recovery After Antibiotic Perturbation. Cell Mol Gastroenterol Hepatol 2020; 10:365-389. [PMID: 32289499 PMCID: PMC7327897 DOI: 10.1016/j.jcmgh.2020.03.008] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/23/2018] [Revised: 03/31/2020] [Accepted: 03/31/2020] [Indexed: 12/12/2022]
Abstract
BACKGROUND & AIMS Loss-of-function variants in nucleotide-binding oligomerization domain-containing protein 2 (NOD2) impair the recognition of the bacterial cell wall component muramyl-dipeptide and are associated with an increased risk for developing Crohn's disease. Likewise, exposure to antibiotics increases the individual risk for developing inflammatory bowel disease. Here, we studied the long-term impact of NOD2 on the ability of the gut bacterial and fungal microbiota to recover after antibiotic treatment. METHODS Two cohorts of 20-week-old and 52-week-old wild-type (WT) C57BL/6J and NOD2 knockout (Nod2-KO) mice were treated with broad-spectrum antibiotics and fecal samples were collected to investigate temporal dynamics of the intestinal microbiota (bacteria and fungi) using 16S ribosomal RNA and internal transcribed spacer 1 sequencing. In addition, 2 sets of germ-free WT mice were colonized with either WT or Nod2-KO after antibiotic donor microbiota and the severity of intestinal inflammation was monitored in the colonized mice. RESULTS Antibiotic exposure caused long-term shifts in the bacterial and fungal community composition. Genetic ablation of NOD2 was associated with delayed body weight gain after antibiotic treatment and an impaired recovery of the bacterial gut microbiota. Transfer of the postantibiotic fecal microbiota of Nod2-KO mice induced an intestinal inflammatory response in the colons of germ-free recipient mice compared with respective microbiota from WT controls based on histopathology and gene expression analyses. CONCLUSIONS Our data show that the bacterial sensor NOD2 contributes to intestinal microbial community composition after antibiotic treatment and may add to the explanation of how defects in the NOD2 signaling pathway are involved in the etiology of Crohn's disease.
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Affiliation(s)
| | | | - Felix Sommer
- Institute of Clinical Molecular Biology, Kiel, Germany
| | - Wei-Hung Pan
- Institute of Clinical Molecular Biology, Kiel, Germany
| | - Olivier Boulard
- University of Lille, Centre national de la recherche scientifique, Inserm, Centre Hospitalier Universitaire de Lille Lille, Institut Pasteur de Lille, Centre d'Infection et d'Immunité de Lille, Lille, France
| | | | | | | | - Konrad Aden
- Institute of Clinical Molecular Biology, Kiel, Germany,First Medical Department, University Hospital Schleswig-Holstein, Kiel, Germany
| | - Robert Häsler
- Institute of Clinical Molecular Biology, Kiel, Germany
| | - Richa Bharti
- Institute of Clinical Molecular Biology, Kiel, Germany
| | - Sven Künzel
- Evolutionary Genomics, Max-Planck-Institute for Evolutionary Biology, Plön, Germany
| | - John F. Baines
- Institute for Experimental Medicine, Christian-Albrechts-University, Kiel, Germany,Evolutionary Genomics, Max-Planck-Institute for Evolutionary Biology, Plön, Germany
| | - Mathias Chamaillard
- University of Lille, Centre national de la recherche scientifique, Inserm, Centre Hospitalier Universitaire de Lille Lille, Institut Pasteur de Lille, Centre d'Infection et d'Immunité de Lille, Lille, France
| | - Philip Rosenstiel
- Institute of Clinical Molecular Biology, Kiel, Germany,Correspondence Address correspondence to: Philip Rosenstiel, MD, Institute of Clinical Molecular Biology, Christian-Albrechts-University Kiel, Rosalind-Franklin-Str. 12, Kiel D-24105, Germany. fax: (49) 4315971842.
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12
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Umiker B, Lee HH, Cope J, Ajami NJ, Laine JP, Fregeau C, Ferguson H, Alves SE, Sciammetta N, Kleinschek M, Salmon M. The NLRP3 inflammasome mediates DSS-induced intestinal inflammation in Nod2 knockout mice. Innate Immun 2020; 25:132-143. [PMID: 30774010 PMCID: PMC6830860 DOI: 10.1177/1753425919826367] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023] Open
Abstract
Crohn’s disease (CD) is a chronic disorder of the gastrointestinal tract
characterized by inflammation and intestinal epithelial injury. Loss of function
mutations in the intracellular bacterial sensor NOD2 are major risk factors for
the development of CD. In the absence of robust bacterial recognition by NOD2 an
inflammatory cascade is initiated through alternative PRRs leading to CD. In the
present study, MCC950, a specific small molecule inhibitor of NLR pyrin
domain-containing protein 3 (NLRP3), abrogated dextran sodium sulfate
(DSS)-induced intestinal inflammation in Nod2−/−
mice. NLRP3 inflammasome formation was observed at a higher rate in
NOD2-deficient small intestinal lamina propria cells after insult by DSS. NLRP3
complex formation led to an increase in IL-1β secretion in both the small
intestine and colon of Nod2ko mice. This increase in IL-1β
secretion in the intestine was attenuated by MCC950 leading to decreased disease
severity in Nod2ko mice. Our work suggests that NLRP3
inflammasome activation may be a key driver of intestinal inflammation in the
absence of functional NOD2. NLRP3 pathway inhibition can prevent intestinal
inflammation in the absence of robust NOD2 signaling.
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Affiliation(s)
| | | | | | - Nadim J Ajami
- 2 Diversigen, Inc. Houston, TX, USA.,3 Alkek Center for Metagenomics and Microbiome Research, Baylor College of Medicine, Houston, TX, USA
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13
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De Musis C, Granata L, Dallio M, Miranda A, Gravina AG, Romano M. Inflammatory Bowel Diseases: The Role of Gut Microbiota. Curr Pharm Des 2020; 26:2951-2961. [PMID: 32310042 DOI: 10.2174/1381612826666200420144128] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2020] [Accepted: 04/13/2020] [Indexed: 12/12/2022]
Abstract
Inflammatory bowel diseases (IBD) are chronic multifactorial diseases characterized by partially unclear pathogenic mechanisms including changes in intestinal microbiota. Despite the microbiota, alteration is well established in IBD patients, as reported by 16RNA sequencing analysis, an important goal is to define if it is just a consequence of the disease progression or a trigger factor of the disease itself. To date, gut microbiota composition and gut microbiota-related metabolites seem to affect the host healthy state both by modulating metabolic pathways or acting on the expression of different genes through epigenetic effects. Because of this, it has been suggested that intestinal microbiota might represent a promising therapeutic target for IBD patients. The aim of this review is to summarize both the most recent acquisitions in the field of gut microbiota and its involvement in intestinal inflammation together with the available strategies for the modulation of microbiota, such as prebiotics and/or probiotics administration or fecal microbiota transplantation.
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Affiliation(s)
- Cristiana De Musis
- Departments of Precision Medicine and Polyspecialistic Internal Medicine, University of Campania ''Luigi Vanvitelli'' and University Hospital, Naples, Italy
| | - Lucia Granata
- Departments of Precision Medicine and Polyspecialistic Internal Medicine, University of Campania ''Luigi Vanvitelli'' and University Hospital, Naples, Italy
| | - Marcello Dallio
- Departments of Precision Medicine and Polyspecialistic Internal Medicine, University of Campania ''Luigi Vanvitelli'' and University Hospital, Naples, Italy
| | - Agnese Miranda
- Departments of Precision Medicine and Polyspecialistic Internal Medicine, University of Campania ''Luigi Vanvitelli'' and University Hospital, Naples, Italy
| | - Antonietta G Gravina
- Departments of Precision Medicine and Polyspecialistic Internal Medicine, University of Campania ''Luigi Vanvitelli'' and University Hospital, Naples, Italy
| | - Marco Romano
- Departments of Precision Medicine and Polyspecialistic Internal Medicine, University of Campania ''Luigi Vanvitelli'' and University Hospital, Naples, Italy
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14
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Waldschmitt N, Kitamoto S, Secher T, Zacharioudaki V, Boulard O, Floquet E, Delacre M, Lamas B, Pham HP, Six A, Richard ML, Dagorn JC, Eberl G, Langella P, Chatel JM, Ryffel B, Iovanna JL, Poulin LF, Sokol H, Kamada N, Chamaillard M. The regenerating family member 3 β instigates IL-17A-mediated neutrophil recruitment downstream of NOD1/2 signalling for controlling colonisation resistance independently of microbiota community structure. Gut 2019; 68:1190-1199. [PMID: 30279238 DOI: 10.1136/gutjnl-2018-316757] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/07/2018] [Revised: 08/08/2018] [Accepted: 08/29/2018] [Indexed: 01/01/2023]
Abstract
OBJECTIVE Loss of the Crohn's disease predisposing NOD2 gene results in an intestinal microenvironment conducive for colonisation by attaching-and-effacing enteropathogens. However, it remains elusive whether it relies on the intracellular recruitment of the serine-threonine kinase RIPK2 by NOD2, a step that is required for its activation of the transcription factor NF-κB. DESIGN Colonisation resistance was evaluated in wild type and mutant mice, as well as in ex-germ-free (ex-GF) mice which were colonised either with faeces from Ripk2-deficient mice or with bacteria with similar preferences for carbohydrates to those acquired by the pathogen. The severity of the mucosal pathology was quantified at several time points postinfection by using a previously established scoring. The community resilience in response to infection was evaluated by 16S ribosomal RNA gene sequence analysis. The control of pathogen virulence was evaluated by monitoring the secretion of Citrobacter-specific antibody response in the faeces. RESULTS Primary infection was similarly outcompeted in ex-GF Ripk2-deficient and control mice, demonstrating that the susceptibility to infection resulting from RIPK2 deficiency cannot be solely attributed to specific microbiota community structures. In contrast, delayed clearance of Citrobacter rodentium and exacerbated histopathology were preceded by a weakened propensity of intestinal macrophages to afford innate lymphoid cell activation. This tissue protection unexpectedly required the regenerating family member 3β by instigating interleukin (IL) 17A-mediated neutrophil recruitment to the intestine and subsequent phosphorylation of signal transducer and activator of transcription 3. CONCLUSIONS These results unveil a previously unrecognised mechanism that efficiently protects from colonisation by diarrhoeagenic bacteria early in infection.
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Affiliation(s)
- Nadine Waldschmitt
- CIIL - Centre d'Infection et d'Immunité de Lille, Université de Lille, CNRS, Inserm, CHRU Lille, Institut Pasteur de Lille, U1019 - UMR 8204, F-59000, Lille, France
| | - Sho Kitamoto
- Division of Gastroenterology, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan, USA
| | - Thomas Secher
- INEM, Orléans University, CNRS UMR 7355, F-45071, Orléans, France
| | - Vassiliki Zacharioudaki
- CIIL - Centre d'Infection et d'Immunité de Lille, Université de Lille, CNRS, Inserm, CHRU Lille, Institut Pasteur de Lille, U1019 - UMR 8204, F-59000, Lille, France
| | - Olivier Boulard
- CIIL - Centre d'Infection et d'Immunité de Lille, Université de Lille, CNRS, Inserm, CHRU Lille, Institut Pasteur de Lille, U1019 - UMR 8204, F-59000, Lille, France
| | - Emilie Floquet
- CIIL - Centre d'Infection et d'Immunité de Lille, Université de Lille, CNRS, Inserm, CHRU Lille, Institut Pasteur de Lille, U1019 - UMR 8204, F-59000, Lille, France
| | - Myriam Delacre
- CIIL - Centre d'Infection et d'Immunité de Lille, Université de Lille, CNRS, Inserm, CHRU Lille, Institut Pasteur de Lille, U1019 - UMR 8204, F-59000, Lille, France
| | - Bruno Lamas
- Laboratoire des Biomolécules (LBM), SorbonneUniversités, UPMC Univ. Paris 06, École normale supérieure, PSL ResearchUniversity, CNRS, INSERM, APHP, Paris, France.,Commensals and Probiotics-Host Interactions Laboratory, INRA, UMR1319Micalis & AgroParisTech, Jouy-en-Josas, France
| | - Hang-Phuong Pham
- ILTOO Pharma, iPEPS ICM, Hôpital Pitié Salpêtrière, Paris, France
| | - Adrien Six
- Department of Immunology-Immunopathology-Immunotherapy (I3), Sorbonne Universités, UPMC Univ Paris 06, Inserm UMRS959, Paris, France
| | - Mathias L Richard
- Commensals and Probiotics-Host Interactions Laboratory, INRA, UMR1319Micalis & AgroParisTech, Jouy-en-Josas, France
| | - Jean-Charles Dagorn
- Centre de Recherche en Cancérologie de Marseille, Aix-Marseille Université, Inserm U1068, CNRS UMR 7258 and Institut Paoli-Calmettes, Parc Scientifique et Technologique de Luminy, Marseille, France
| | - Gérard Eberl
- Microenvironment and Immunity Unit, Institut Pasteur, Paris, France
| | - Philippe Langella
- Commensals and Probiotics-Host Interactions Laboratory, INRA, UMR1319Micalis & AgroParisTech, Jouy-en-Josas, France
| | - Jean-Marc Chatel
- Commensals and Probiotics-Host Interactions Laboratory, INRA, UMR1319Micalis & AgroParisTech, Jouy-en-Josas, France
| | - Bernhard Ryffel
- INEM, Orléans University, CNRS UMR 7355, F-45071, Orléans, France
| | - Juan Lucio Iovanna
- Centre de Recherche en Cancérologie de Marseille, Aix-Marseille Université, Inserm U1068, CNRS UMR 7258 and Institut Paoli-Calmettes, Parc Scientifique et Technologique de Luminy, Marseille, France
| | - Lionel F Poulin
- CIIL - Centre d'Infection et d'Immunité de Lille, Université de Lille, CNRS, Inserm, CHRU Lille, Institut Pasteur de Lille, U1019 - UMR 8204, F-59000, Lille, France
| | - Harry Sokol
- Laboratoire des Biomolécules (LBM), SorbonneUniversités, UPMC Univ. Paris 06, École normale supérieure, PSL ResearchUniversity, CNRS, INSERM, APHP, Paris, France.,Commensals and Probiotics-Host Interactions Laboratory, INRA, UMR1319Micalis & AgroParisTech, Jouy-en-Josas, France.,Department of Gastroenterology, Saint Antoine Hospital, AP-HP, UPMC Univ Paris 06, Paris, France
| | - Nobuhiko Kamada
- Division of Gastroenterology, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan, USA
| | - Mathias Chamaillard
- CIIL - Centre d'Infection et d'Immunité de Lille, Université de Lille, CNRS, Inserm, CHRU Lille, Institut Pasteur de Lille, U1019 - UMR 8204, F-59000, Lille, France
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15
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Cohen LJ, Cho JH, Gevers D, Chu H. Genetic Factors and the Intestinal Microbiome Guide Development of Microbe-Based Therapies for Inflammatory Bowel Diseases. Gastroenterology 2019; 156:2174-2189. [PMID: 30880022 PMCID: PMC6568267 DOI: 10.1053/j.gastro.2019.03.017] [Citation(s) in RCA: 133] [Impact Index Per Article: 22.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/09/2018] [Revised: 02/28/2019] [Accepted: 03/02/2019] [Indexed: 12/22/2022]
Abstract
The intestinal microbiota is a dynamic community of bacteria, fungi, and viruses that mediates mucosal homeostasis and physiology. Imbalances in the microbiome and aberrant immune responses to gut bacteria can disrupt homeostasis and are associated with inflammatory bowel diseases (IBDs) in humans and colitis in mice. We review genetic variants associated with IBD and their effects on the intestinal microbiome, the immune response, and disease pathogenesis. The intestinal microbiome, which includes microbial antigens, adjuvants, and metabolic products, affects the development and function of the intestinal mucosa, influencing inflammatory responses in the gut. Therefore, strategies to manipulate the microbiome might be used in treatment of IBD. We review microbe-based therapies for IBD and the potential to engineer patients' intestinal microbiota. We discuss how studies of patients with IBD and mouse models have advanced our understanding of the interactions between genetic factors and the gut microbiome, and challenges to the development of microbe-based therapies for IBD.
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Affiliation(s)
- Louis J. Cohen
- Division of Gastroenterology, Department of Medicine, Icahn
School of Medicine at Mount Sinai, New York, New York, 10029, USA.,Correspondence:
(L.J.C.),
(H.C.)
| | - Judy H. Cho
- Division of Gastroenterology, Department of Medicine, Icahn
School of Medicine at Mount Sinai, New York, New York, 10029, USA.,Department of Genetics and Genomic Sciences, Icahn School
of Medicine at Mount Sinai; The Charles Bronfman Institute for Personalized
Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, 10029,
USA
| | - Dirk Gevers
- Janssen Human Microbiome Institute, Janssen Research &
Development, Cambridge, MA, 02142, USA
| | - Hiutung Chu
- Department of Pathology, University of California-San Diego, La Jolla, California; Chiba University and University of California-San Diego Center for Mucosal Immunology, Allergy, and Vaccines (CU-UCSD cMAV), La Jolla, California.
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16
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Aschard H, Laville V, Tchetgen ET, Knights D, Imhann F, Seksik P, Zaitlen N, Silverberg MS, Cosnes J, Weersma RK, Xavier R, Beaugerie L, Skurnik D, Sokol H. Genetic effects on the commensal microbiota in inflammatory bowel disease patients. PLoS Genet 2019; 15:e1008018. [PMID: 30849075 PMCID: PMC6426259 DOI: 10.1371/journal.pgen.1008018] [Citation(s) in RCA: 36] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2018] [Revised: 03/20/2019] [Accepted: 02/13/2019] [Indexed: 12/16/2022] Open
Abstract
Several bacteria in the gut microbiota have been shown to be associated with inflammatory bowel disease (IBD), and dozens of IBD genetic variants have been identified in genome-wide association studies. However, the role of the microbiota in the etiology of IBD in terms of host genetic susceptibility remains unclear. Here, we studied the association between four major genetic variants associated with an increased risk of IBD and bacterial taxa in up to 633 IBD cases. We performed systematic screening for associations, identifying and replicating associations between NOD2 variants and two taxa: the Roseburia genus and the Faecalibacterium prausnitzii species. By exploring the overall association patterns between genes and bacteria, we found that IBD risk alleles were significantly enriched for associations concordant with bacteria-IBD associations. To understand the significance of this pattern in terms of the study design and known effects from the literature, we used counterfactual principles to assess the fitness of a few parsimonious gene-bacteria-IBD causal models. Our analyses showed evidence that the disease risk of these genetic variants were likely to be partially mediated by the microbiome. We confirmed these results in extensive simulation studies and sensitivity analyses using the association between NOD2 and F. prausnitzii as a case study.
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Affiliation(s)
- Hugues Aschard
- Centre de Bioinformatique, Biostatistique et Biologie Intégrative (C3BI), Institut Pasteur, Paris, France
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, United States of America
- * E-mail: (HA); (DS); (HS)
| | - Vincent Laville
- Centre de Bioinformatique, Biostatistique et Biologie Intégrative (C3BI), Institut Pasteur, Paris, France
| | - Eric Tchetgen Tchetgen
- Department of Statistics, The Wharton School at the University of Pennsylvania, Philadelphia, Pennsylvania, United States of America
| | - Dan Knights
- Department of Computer Science and Engineering, University of Minnesota, Minneapolis, Minnesota, United States of America
- Broad Institute of Harvard and MIT, Cambridge, Massachusetts, United States of America
- Center for Computational and Integrative Biology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United States of America
- Biotechnology Institute, University of Minnesota, St. Paul, Minnesota, United States of America
| | - Floris Imhann
- Department of Gastroenterology and Hepatology, University of Groningen and University Medical Center Groningen, Groningen, the Netherlands
| | - Philippe Seksik
- Department of Gastroenterology, Saint Antoine Hospital, Paris, France
| | - Noah Zaitlen
- Department of Medicine, University of California, San Francisco, California, United States of America
| | - Mark S. Silverberg
- Zane Cohen Centre for Digestive Diseases, Mount Sinai Hospital, Toronto, Ontario, Canada
| | - Jacques Cosnes
- Department of Gastroenterology, Saint Antoine Hospital, Paris, France
- Sorbonne Université, Paris, France
| | - Rinse K. Weersma
- Department of Gastroenterology and Hepatology, University of Groningen and University Medical Center Groningen, Groningen, the Netherlands
| | - Ramnik Xavier
- Broad Institute of Harvard and MIT, Cambridge, Massachusetts, United States of America
- Center for Computational and Integrative Biology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United States of America
- Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, United States of America
| | - Laurent Beaugerie
- Department of Gastroenterology, Saint Antoine Hospital, Paris, France
- Sorbonne Université, Paris, France
| | - David Skurnik
- Division of Infectious Diseases, Harvard Medical School, Boston, Massachusetts, United States of America
- Massachusetts Technology and Analytics, Brookline, Massachusetts, United States of America
- Department of Microbiology, Necker Hospital and University Paris Descartes, Paris, France
- INSERM U1151-Equipe 11, Institut Necker-Enfants Malades, Paris, France
- * E-mail: (HA); (DS); (HS)
| | - Harry Sokol
- Department of Gastroenterology, Saint Antoine Hospital, Paris, France
- Sorbonne Université, Paris, France
- Micalis Institute, AgroParisTech, Jouy-en-Josas, France
- INSERM CRSA UMRS U938, Paris, France
- * E-mail: (HA); (DS); (HS)
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17
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King SJ, McCole DF. Epithelial-microbial diplomacy: escalating border tensions drive inflammation in inflammatory bowel disease. Intest Res 2019; 17:177-191. [PMID: 30836737 PMCID: PMC6505084 DOI: 10.5217/ir.2018.00170] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/24/2018] [Accepted: 02/01/2019] [Indexed: 02/07/2023] Open
Abstract
Inflammatory bowel diseases (IBD) are chronic conditions of the gastrointestinal tract-the main site of host-microbial interaction in the body. Development of IBD is not due to a single event but rather is a multifactorial process where a patient’s genetic background, behavioral habits, and environmental exposures contribute to disease pathogenesis. IBD patients exhibit alterations to gut bacterial populations “dysbiosis” due to the inflammatory microenvironment, however whether this alteration of the gut microbiota precedes inflammation has not been confirmed. Emerging evidence has highlighted the important role of gut microbes in developing measured immune responses and modulating other host responses such as metabolism. Much of the work on the gut microbiota has been correlative and there is an increasing need to understand the intimate relationship between host and microbe. In this review, we highlight how commensal and pathogenic bacteria interact with host intestinal epithelial cells and explore how altered microenvironments impact these connections.
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Affiliation(s)
- Stephanie J King
- Division of Biomedical Sciences, University of California, Riverside, CA, USA
| | - Declan F McCole
- Division of Biomedical Sciences, University of California, Riverside, CA, USA
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18
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NOD2 Expression in Intestinal Epithelial Cells Protects Toward the Development of Inflammation and Associated Carcinogenesis. Cell Mol Gastroenterol Hepatol 2018; 7:357-369. [PMID: 30704984 PMCID: PMC6357788 DOI: 10.1016/j.jcmgh.2018.10.009] [Citation(s) in RCA: 36] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/28/2018] [Revised: 10/11/2018] [Accepted: 10/15/2018] [Indexed: 12/12/2022]
Abstract
Nucleotide-binding oligomerization domain 2 (NOD2) is an intracellular pattern recognition receptor that senses bacterial peptidoglycan-conserved motifs in cytosol and stimulates host immune response including epithelial and immune cells. The association of NOD2 mutations with a number of inflammatory pathologies including Crohn's disease (CD), graft-versus-host diseases, or Blau syndrome, highlights its pivotal role in inflammatory response and the associated-carcinogenesis development. Since its identification in 2001 and its association with CD, the role of NOD2 in epithelial cells and immune cells has been investigated extensively but the precise mechanism by which NOD2 mutations lead to CD and the associated carcinogenesis development is largely unknown. In this review, we present and discuss recent developments about the role of NOD2 inside epithelial cells on the control of the inflammatory process and its linked carcinogenesis development.
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19
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Butera A, Di Paola M, Pavarini L, Strati F, Pindo M, Sanchez M, Cavalieri D, Boirivant M, De Filippo C. Nod2 Deficiency in mice is Associated with Microbiota Variation Favouring the Expansion of mucosal CD4+ LAP+ Regulatory Cells. Sci Rep 2018; 8:14241. [PMID: 30250234 PMCID: PMC6155205 DOI: 10.1038/s41598-018-32583-z] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2018] [Accepted: 06/29/2018] [Indexed: 02/07/2023] Open
Abstract
Nucleotide-binding Oligomerization Domain-2 (NOD2) mutations are associated with an increased risk to develop Crohn's Disease. In previous studies, we have shown that Nod2-/- mice manifest increased proportion of Lamina Propria (LP) CD4+ LAP+ Foxp3- regulatory cells, when compared with Nod2+/+ mice, while CD4+ Foxp3 + regulatory cells were not affected. Here, we investigated the Nod2 gut microbiota, by 16S rRNA pyrosequencing, at steady state and after TNBS-colitis induction in mice reared separately or in cohousing, correlating the microbial profiles with LP regulatory T cells proportion and tissue cytokines content. We found that enrichment of Rikenella and Alistipes (Rikenellaceae) in Nod2-/- mice at 8 weeks of age reared separately was associated with increased proportion of CD4+ LAP+ Foxp3- cells and less severe TNBS-colitis. In co-housed mice the acquisition of Rickenellaceae by Nod2+/+ mice was associated with increased CD4+ LAP+ Foxp3- proportion and less severe colitis. Severe colitis was associated with enrichment of gram-negative pathobionts (Escherichia and Enterococcus), while less severe colitis with protective bacteria (Barnesiella, Odoribacter and Clostridium IV). Environmental factors acting on genetic background with different outcomes according to their impact on microbiota, predispose in different ways to inflammation. These results open a new scenario for therapeutic attempt to re-establish eubiosis in Inflammatory Bowel Disease patients with NOD2 polymorphisms.
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Affiliation(s)
- A Butera
- Pharmacological Research and Experimental Therapy Section, National Center for Drug Research and Evaluation, Istituto Superiore di Sanità, Rome, Italy
| | - M Di Paola
- Department of Neuroscience, Psychology, Drug Research and Child Health (NEUROFARBA), University of Florence, Meyer Children Hospital, Florence, Italy.,Department of Biology, University of Florence, Sesto Fiorentino, Florence, Italy
| | - L Pavarini
- Research and Innovation Centre, Fondazione E. Mach, S. Michele all'Adige, Trento, Italy
| | - F Strati
- Institute for Research in Biomedicine (IRB), Università della Svizzera italiana, Bellinzona, Switzerland
| | - M Pindo
- Research and Innovation Centre, Fondazione E. Mach, S. Michele all'Adige, Trento, Italy
| | - M Sanchez
- Cytometry Unit - Core Facilities, Istituto Superiore di Sanità, Rome, Italy
| | - D Cavalieri
- Department of Biology, University of Florence, Sesto Fiorentino, Florence, Italy
| | - M Boirivant
- Pharmacological Research and Experimental Therapy Section, National Center for Drug Research and Evaluation, Istituto Superiore di Sanità, Rome, Italy.
| | - C De Filippo
- Institute of Biology and Agrarian Biotechnology (IBBA), National Research Council (CNR), Pisa, Italy.
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20
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Bretin A, Lucas C, Larabi A, Dalmasso G, Billard E, Barnich N, Bonnet R, Nguyen HTT. AIEC infection triggers modification of gut microbiota composition in genetically predisposed mice, contributing to intestinal inflammation. Sci Rep 2018; 8:12301. [PMID: 30120269 PMCID: PMC6098085 DOI: 10.1038/s41598-018-30055-y] [Citation(s) in RCA: 50] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2018] [Accepted: 07/21/2018] [Indexed: 12/12/2022] Open
Abstract
A high prevalence of adherent-invasive E. coli (AIEC) in the intestinal mucosa of Crohn's disease patients has been shown. AIEC colonize the intestine and induce inflammation in genetically predisposed mouse models including CEABAC10 transgenic (Tg) mice expressing human CEACAM6-receptor for AIEC and eif2ak4-/- mice exhibiting autophagy defect in response to AIEC infection. Here, we aimed at investigating whether gut microbiota modification contributes to AIEC-induced intestinal inflammation in these mouse models. For this, eif2ak4+/+ and eif2ak4-/- mice or CEABAC10 Tg mice invalidated for Eif2ak4 gene (Tg/eif2ak4-/-) or not (Tg/eif2ak4+/+) were infected with the AIEC reference strain LF82 or the non-pathogenic E. coli K12 MG1655 strain. In all mouse groups, LF82 colonized the gut better and longer than MG1655. No difference in fecal microbiota composition was observed in eif2ak4+/+ and eif2ak4-/- mice before infection and at day 1 and 4 post-infection. LF82-infected eif2ak4-/- mice exhibited altered fecal microbiota composition at day 14 and 21 post-infection and increased fecal lipocalin-2 level at day 21 post-infection compared to other groups, indicating that intestinal inflammation developed after microbiota modification. Similar results were obtained for LF82-infected Tg/eif2ak4-/- mice. These results suggest that in genetically predisposed hosts, AIEC colonization might induce chronic intestinal inflammation by altering the gut microbiota composition.
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Affiliation(s)
- Alexis Bretin
- M2iSH (Microbes, intestine, inflammation and Susceptibility of the Host), UMR 1071 Inserm, Université Clermont Auvergne, INRA USC 2018, Clermont-Ferrand, 63001, France
| | - Cécily Lucas
- M2iSH (Microbes, intestine, inflammation and Susceptibility of the Host), UMR 1071 Inserm, Université Clermont Auvergne, INRA USC 2018, Clermont-Ferrand, 63001, France
| | - Anaïs Larabi
- M2iSH (Microbes, intestine, inflammation and Susceptibility of the Host), UMR 1071 Inserm, Université Clermont Auvergne, INRA USC 2018, Clermont-Ferrand, 63001, France
| | - Guillaume Dalmasso
- M2iSH (Microbes, intestine, inflammation and Susceptibility of the Host), UMR 1071 Inserm, Université Clermont Auvergne, INRA USC 2018, Clermont-Ferrand, 63001, France
| | - Elisabeth Billard
- M2iSH (Microbes, intestine, inflammation and Susceptibility of the Host), UMR 1071 Inserm, Université Clermont Auvergne, INRA USC 2018, Clermont-Ferrand, 63001, France
| | - Nicolas Barnich
- M2iSH (Microbes, intestine, inflammation and Susceptibility of the Host), UMR 1071 Inserm, Université Clermont Auvergne, INRA USC 2018, Clermont-Ferrand, 63001, France
| | - Richard Bonnet
- M2iSH (Microbes, intestine, inflammation and Susceptibility of the Host), UMR 1071 Inserm, Université Clermont Auvergne, INRA USC 2018, Clermont-Ferrand, 63001, France
- Centre Hospitalier Universitaire (CHU), Clermont-Ferrand, 63001, France
| | - Hang Thi Thu Nguyen
- M2iSH (Microbes, intestine, inflammation and Susceptibility of the Host), UMR 1071 Inserm, Université Clermont Auvergne, INRA USC 2018, Clermont-Ferrand, 63001, France.
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21
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Kennedy NA, Lamb CA, Berry SH, Walker AW, Mansfield J, Parkes M, Simpkins R, Tremelling M, Nutland S, UK IBD Genetics Consortium, Parkhill J, Probert C, Hold GL, Lees CW. The Impact of NOD2 Variants on Fecal Microbiota in Crohn's Disease and Controls Without Gastrointestinal Disease. Inflamm Bowel Dis 2018; 24:583-592. [PMID: 29462388 PMCID: PMC6176884 DOI: 10.1093/ibd/izx061] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/04/2018] [Indexed: 12/12/2022]
Abstract
BACKGROUND/AIMS Current models of Crohn's disease (CD) describe an inappropriate immune response to gut microbiota in genetically susceptible individuals. NOD2 variants are strongly associated with development of CD, and NOD2 is part of the innate immune response to bacteria. This study aimed to identify differences in fecal microbiota in CD patients and non-IBD controls stratified by NOD2 genotype. METHODS Patients with CD and non-IBD controls of known NOD2 genotype were identified from patients in previous UK IBD genetics studies and the Cambridge bioresource (genotyped/phenotyped volunteers). Individuals with known CD-associated NOD2 mutations were matched to those with wild-type genotype. We obtained fecal samples from patients in clinical remission with low fecal calprotectin (<250 µg/g) and controls without gastrointestinal disease. After extracting DNA, the V1-2 region of 16S rRNA genes were polymerase chain reaction (PCR)-amplified and sequenced. Analysis was undertaken using the mothur package. Volatile organic compounds (VOC) were also measured. RESULTS Ninety-one individuals were in the primary analysis (37 CD, 30 bioresource controls, and 24 household controls). Comparing CD with nonIBD controls, there were reductions in bacterial diversity, Ruminococcaceae, Rikenellaceae, and Christensenellaceae and an increase in Enterobacteriaceae. No significant differences could be identified in microbiota by NOD2 genotype, but fecal butanoic acid was higher in Crohn's patients carrying NOD2 mutations. CONCLUSIONS In this well-controlled study of NOD2 genotype and fecal microbiota, we identified no significant genotype-microbiota associations. This suggests that the changes associated with NOD2 genotype might only be seen at the mucosal level, or that environmental factors and prior inflammation are the predominant determinant of the observed dysbiosis in gut microbiota.
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Affiliation(s)
- Nicholas A Kennedy
- GI Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK,IBD Pharmacogenetics Group, University of Exeter, UK,Address correspondence to: Dr Nicholas Kennedy, IBD Pharmacogenetics Group, RILD South, Royal Devon and Exeter Hospital, Barrack Road, Exeter EX2 5DW. E-mail:
| | | | - Susan H Berry
- Gastrointestinal Research Group, University of Aberdeen, Aberdeen, UK
| | - Alan W Walker
- Pathogen Genomics Group, Wellcome Trust Sanger Institute, Hinxton, Cambridgeshire, UK,Microbiology Group, The Rowett Institute, University of Aberdeen, Aberdeen, UK
| | - John Mansfield
- Dept of Gastroenterology, Royal Victoria Infirmary, Newcastle, UK
| | - Miles Parkes
- Dept of Gastroenterology, Addenbrookes Hospital, Cambridge, UK
| | | | - Mark Tremelling
- Department of Gastroenterology, Norfolk and Norwich University Hospital, Norwich, UK
| | | | | | - Julian Parkhill
- Pathogen Genomics Group, Wellcome Trust Sanger Institute, Hinxton, Cambridgeshire, UK
| | - Chris Probert
- Institute of Translational Medicine, University of Liverpool, UK
| | - Georgina L Hold
- Gastrointestinal Research Group, University of Aberdeen, Aberdeen, UK
| | - Charlie W Lees
- GI Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK,Gastrointestinal Research Group, University of Aberdeen, Aberdeen, UK
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22
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Abstract
The innate immune system recognizes microbial products using germline-encoded receptors that initiate inflammatory responses to infection. The bacterial cell wall component peptidoglycan is a prime example of a conserved pathogen-associated molecular pattern (PAMP) for which the innate immune system has evolved sensing mechanisms. Peptidoglycan is a direct target for innate immune receptors and also regulates the accessibility of other PAMPs to additional innate immune receptors. Subtle structural modifications to peptidoglycan can influence the ability of the innate immune system to detect bacteria and can allow bacteria to evade or alter host defences. This Review focuses on the mechanisms of peptidoglycan recognition that are used by mammalian cells and discusses new insights into the role of peptidoglycan recognition in inflammation, metabolism, immune homeostasis and disease.
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Affiliation(s)
- Andrea J Wolf
- Research Division of Immunology, Department of Biomedical Sciences, Cedars-Sinai Medical Center
| | - David M Underhill
- Research Division of Immunology, Department of Biomedical Sciences, Cedars-Sinai Medical Center.,Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, 8700 Beverly Blvd., Los Angeles, California 90048, USA
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23
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de Bruyn M, Vermeire S. NOD2 and bacterial recognition as therapeutic targets for Crohn’s disease. Expert Opin Ther Targets 2017; 21:1123-1139. [DOI: 10.1080/14728222.2017.1397627] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Affiliation(s)
- Magali de Bruyn
- Translational Research in GastroIntestinal Disorders, Department of Chronic Diseases, Metabolism and Ageing (CHROMETA), KU Leuven, Leuven, Belgium
| | - Séverine Vermeire
- Translational Research in GastroIntestinal Disorders, Department of Chronic Diseases, Metabolism and Ageing (CHROMETA), KU Leuven, Leuven, Belgium
- University Hospitals Leuven, Department of Gastroenterology and Hepatology, Leuven, Belgium
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24
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Nicolas S, Blasco-Baque V, Fournel A, Gilleron J, Klopp P, Waget A, Ceppo F, Marlin A, Padmanabhan R, Iacovoni JS, Tercé F, Cani PD, Tanti JF, Burcelin R, Knauf C, Cormont M, Serino M. Transfer of dysbiotic gut microbiota has beneficial effects on host liver metabolism. Mol Syst Biol 2017; 13:921. [PMID: 28302863 PMCID: PMC5371731 DOI: 10.15252/msb.20167356] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022] Open
Abstract
Gut microbiota dysbiosis has been implicated in a variety of systemic disorders, notably metabolic diseases including obesity and impaired liver function, but the underlying mechanisms are uncertain. To investigate this question, we transferred caecal microbiota from either obese or lean mice to antibiotic-free, conventional wild-type mice. We found that transferring obese-mouse gut microbiota to mice on normal chow (NC) acutely reduces markers of hepatic gluconeogenesis with decreased hepatic PEPCK activity, compared to non-inoculated mice, a phenotypic trait blunted in conventional NOD2 KO mice. Furthermore, transferring of obese-mouse microbiota changes both the gut microbiota and the microbiome of recipient mice. We also found that transferring obese gut microbiota to NC-fed mice then fed with a high-fat diet (HFD) acutely impacts hepatic metabolism and prevents HFD-increased hepatic gluconeogenesis compared to non-inoculated mice. Moreover, the recipient mice exhibit reduced hepatic PEPCK and G6Pase activity, fed glycaemia and adiposity. Conversely, transfer of lean-mouse microbiota does not affect markers of hepatic gluconeogenesis. Our findings provide a new perspective on gut microbiota dysbiosis, potentially useful to better understand the aetiology of metabolic diseases.
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Affiliation(s)
- Simon Nicolas
- Institut National de la Santé et de la Recherche Médicale (INSERM), Toulouse, France.,Unité Mixte de Recherche (UMR) 1048, Institut de Maladies Métaboliques et Cardiovasculaires (I2MC), Université Paul Sabatier (UPS), Toulouse Cedex 4, France
| | - Vincent Blasco-Baque
- Institut National de la Santé et de la Recherche Médicale (INSERM), Toulouse, France.,Unité Mixte de Recherche (UMR) 1048, Institut de Maladies Métaboliques et Cardiovasculaires (I2MC), Université Paul Sabatier (UPS), Toulouse Cedex 4, France.,Faculté de Chirurgie Dentaire de Toulouse, Université Paul Sabatier, Toulouse Cedex, France
| | - Audren Fournel
- Toulouse III, Institut de Recherche en Santé Digestive (IRSD) Team 3, "Intestinal Neuroimmune Interactions" INSERM U1220, Université Paul Sabatier, Toulouse Cedex 3, France.,European Associated Laboratory NeuroMicrobiota (INSERM/UCL), Bâtiment B - Pavillon Lefebvre, Toulouse Cedex 3, France
| | - Jerome Gilleron
- INSERM Unité 1065/Centre Méditerranéen de Médecine Moléculaire (C3M), Université Côte d'Azur, Nice, France
| | - Pascale Klopp
- Institut National de la Santé et de la Recherche Médicale (INSERM), Toulouse, France.,Unité Mixte de Recherche (UMR) 1048, Institut de Maladies Métaboliques et Cardiovasculaires (I2MC), Université Paul Sabatier (UPS), Toulouse Cedex 4, France
| | - Aurelie Waget
- Institut National de la Santé et de la Recherche Médicale (INSERM), Toulouse, France.,Unité Mixte de Recherche (UMR) 1048, Institut de Maladies Métaboliques et Cardiovasculaires (I2MC), Université Paul Sabatier (UPS), Toulouse Cedex 4, France
| | - Franck Ceppo
- INSERM Unité 1065/Centre Méditerranéen de Médecine Moléculaire (C3M), Université Côte d'Azur, Nice, France
| | - Alysson Marlin
- Toulouse III, Institut de Recherche en Santé Digestive (IRSD) Team 3, "Intestinal Neuroimmune Interactions" INSERM U1220, Université Paul Sabatier, Toulouse Cedex 3, France.,European Associated Laboratory NeuroMicrobiota (INSERM/UCL), Bâtiment B - Pavillon Lefebvre, Toulouse Cedex 3, France
| | - Roshan Padmanabhan
- Institut National de la Santé et de la Recherche Médicale (INSERM), Toulouse, France.,Unité Mixte de Recherche (UMR) 1048, Institut de Maladies Métaboliques et Cardiovasculaires (I2MC), Université Paul Sabatier (UPS), Toulouse Cedex 4, France
| | - Jason S Iacovoni
- Institut National de la Santé et de la Recherche Médicale (INSERM), Toulouse, France.,Unité Mixte de Recherche (UMR) 1048, Institut de Maladies Métaboliques et Cardiovasculaires (I2MC), Université Paul Sabatier (UPS), Toulouse Cedex 4, France
| | - François Tercé
- Institut National de la Santé et de la Recherche Médicale (INSERM), Toulouse, France.,Unité Mixte de Recherche (UMR) 1048, Institut de Maladies Métaboliques et Cardiovasculaires (I2MC), Université Paul Sabatier (UPS), Toulouse Cedex 4, France
| | - Patrice D Cani
- Walloon Excellence in Life Sciences and BIOtechnology (WELBIO), Metabolism and Nutrition Research Group, Louvain Drug Research Institute, Université catholique de Louvain, Brussels, Belgium
| | - Jean-François Tanti
- INSERM Unité 1065/Centre Méditerranéen de Médecine Moléculaire (C3M), Université Côte d'Azur, Nice, France
| | - Remy Burcelin
- Institut National de la Santé et de la Recherche Médicale (INSERM), Toulouse, France.,Unité Mixte de Recherche (UMR) 1048, Institut de Maladies Métaboliques et Cardiovasculaires (I2MC), Université Paul Sabatier (UPS), Toulouse Cedex 4, France
| | - Claude Knauf
- Toulouse III, Institut de Recherche en Santé Digestive (IRSD) Team 3, "Intestinal Neuroimmune Interactions" INSERM U1220, Université Paul Sabatier, Toulouse Cedex 3, France.,European Associated Laboratory NeuroMicrobiota (INSERM/UCL), Bâtiment B - Pavillon Lefebvre, Toulouse Cedex 3, France
| | - Mireille Cormont
- INSERM Unité 1065/Centre Méditerranéen de Médecine Moléculaire (C3M), Université Côte d'Azur, Nice, France
| | - Matteo Serino
- Institut National de la Santé et de la Recherche Médicale (INSERM), Toulouse, France .,Unité Mixte de Recherche (UMR) 1048, Institut de Maladies Métaboliques et Cardiovasculaires (I2MC), Université Paul Sabatier (UPS), Toulouse Cedex 4, France
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25
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Abstract
Nucleotide-binding oligomerization domain 2 (NOD2) is an intracellular pattern recognition receptor that senses bacterial peptidoglycan (PGN)-conserved motifs in cytosol and stimulates host immune response. The association of NOD2 mutations with a number of inflammatory pathologies, including Crohn disease (CD), Graft-versus-host disease (GVHD), and Blau syndrome, highlights its pivotal role in host–pathogen interactions and inflammatory response. Stimulation of NOD2 by its ligand (muramyl dipeptide) activates pro-inflammatory pathways such as nuclear factor-κB (NF-κB), mitogen-activated protein kinases (MAPKs), and Caspase-1. A loss of NOD2 function may result in a failure in the control of microbial infection, thereby initiating systemic responses and aberrant inflammation. Because the ligand of Nod2 is conserved in both gram-positive and gram-negative bacteria, NOD2 detects a wide variety of microorganisms. Furthermore, current literature evidences that NOD2 is also able to control viruses’ and parasites’ infections. In this review, we present and discuss recent developments about the role of NOD2 in shaping the gut commensal microbiota and pathogens, including bacteria, viruses, and parasites, and the mechanisms by which Nod2 mutations participate in disease occurrence.
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Affiliation(s)
- Ziad Al Nabhani
- Laboratoire Inflamex, Université Paris-Diderot Sorbonne Paris-Cité, Paris, France
- INSERM, UMR 1149, Paris, France
| | - Gilles Dietrich
- IRSD, Université de Toulouse, INSERM, INRA, ENVT, UPS, Toulouse, France
| | - Jean-Pierre Hugot
- Laboratoire Inflamex, Université Paris-Diderot Sorbonne Paris-Cité, Paris, France
- INSERM, UMR 1149, Paris, France
- Assistance Publique Hôpitaux de Paris, Hôpital Robert Debré, Paris, France
- * E-mail: (JPH); (FB)
| | - Frederick Barreau
- IRSD, Université de Toulouse, INSERM, INRA, ENVT, UPS, Toulouse, France
- * E-mail: (JPH); (FB)
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26
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Weingarden AR, Vaughn BP. Intestinal microbiota, fecal microbiota transplantation, and inflammatory bowel disease. Gut Microbes 2017; 8:238-252. [PMID: 28609251 PMCID: PMC5479396 DOI: 10.1080/19490976.2017.1290757] [Citation(s) in RCA: 322] [Impact Index Per Article: 40.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/03/2023] Open
Abstract
Inflammatory bowel disease (IBD) is a complex set of diseases that lead to chronic inflammation in the gastrointestinal tract. Although the etiology of IBD is not fully understood, it is well-known that the intestinal microbiota is associated with the development and maintenance of IBD. Manipulation of the gut microbiota, therefore, may represent a target for IBD therapy. Fecal microbiota transplantation (FMT), where fecal microbiota from a healthy donor is transplanted into a patient's GI tract, is already a successful therapy for Clostridium difficile infection. FMT is currently being explored as a potential therapy for IBD as well. In this review, the associations between the gut microbiota and IBD and the emerging data on FMT for IBD will be discussed.
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Affiliation(s)
- Alexa R. Weingarden
- Division of Gastroenterology, Hepatology and Nutrition, University of Minnesota, Minneapolis, MN, USA
| | - Byron P. Vaughn
- Division of Gastroenterology, Hepatology and Nutrition, University of Minnesota, Minneapolis, MN, USA,CONTACT Byron P. Vaughn 420 Delaware street SE, MMC36, Minneapolis, MN 55455
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27
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Al Nabhani Z, Lepage P, Mauny P, Montcuquet N, Roy M, Le Roux K, Dussaillant M, Berrebi D, Hugot JP, Barreau F. Nod2 Deficiency Leads to a Specific and Transmissible Mucosa-associated Microbial Dysbiosis Which Is Independent of the Mucosal Barrier Defect. J Crohns Colitis 2016; 10:1428-1436. [PMID: 27147452 DOI: 10.1093/ecco-jcc/jjw095] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/11/2015] [Revised: 02/25/2016] [Accepted: 03/22/2016] [Indexed: 02/07/2023]
Abstract
BACKGROUND AND AIMS Crohn's disease [CD] is a complex disorder characterised by an inappropriate immune response, impaired barrier function and microbial dysbiosis. Mutations in nucleotide oligomeriation domain 2 [NOD2] are CD risk factors. Increase of intestinal permeability, CD4+ T cell infiltration, and bacterial dysbiosis are also seen in Nod2-knockout [Nod2 KO] mice. However, the specificity and relationship between these Nod2-associated abnormalities remain largely unexplored. METHODS Wild-type [WT], Nod1-knockout [Nod1 KO] and Nod2 KO mice were analysed in parallel. Microbial composition was defined by 454-pyrosequencing of bacterial 16S rRNA genes. Mucin and antimicrobial peptide expression was assessed by RT-PCR. Cell populations from Peyer's patches were determined by flow cytometry. Ussing chambers were used to measure intestinal permeability and bacterial translocation. Finally, to explore the impact of colonisation with mother's microbiota at birth, analyses were also performed in Nod2 KO and WT mice born from WT surrogate mothers after embryo transfer. RESULTS Nod2 KO mice exhibited colonic bacterial dysbiosis different from WT and Nod1 KO mice. Altered expression of antimicrobial peptides and mucins in ileum and colon was associated with the microbial composition. Bacterial composition of Nod2 KO and WT mice obtained by embryo transfer was similar to that observed in Nod2 KO mice, arguing for a dominant effect of Nod2 KO-associated dysbiosis. In contrast, increased levels of CD4+ T cells and gut barrier defects across Peyer's patches were specific to Nod2 deficiency and independent of Microbial dysbiosis. CONCLUSIONS Nod2 deficiency is associated with a specific dominant dysbiosis which does not drive mucosal tissue and immune alterations.
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Affiliation(s)
- Ziad Al Nabhani
- Laboratoire d'excellence Inflamex, Université Paris-Diderot Sorbonne Paris-Cité, France.,INSERM, UMR 1149, F-75018 Paris, France.,INRA, MICALIS-UMR1319, Jouy-en-Josas, France.,AgroParisTech, MICALIS-UMR1319, Jouy-en-Josas, France
| | - Patricia Lepage
- INRA, MICALIS-UMR1319, Jouy-en-Josas, France.,AgroParisTech, MICALIS-UMR1319, Jouy-en-Josas, France
| | | | - Nicolas Montcuquet
- INSERM, UMR 989, F-75015 Paris, France.,Université Paris Descartes - Sorbonne Paris Cité, Institut IMAGINE, Paris, France
| | - Maryline Roy
- Laboratoire d'excellence Inflamex, Université Paris-Diderot Sorbonne Paris-Cité, France.,INSERM, UMR 1149, F-75018 Paris, France
| | - Karine Le Roux
- INRA, MICALIS-UMR1319, Jouy-en-Josas, France.,AgroParisTech, MICALIS-UMR1319, Jouy-en-Josas, France
| | - Monique Dussaillant
- Laboratoire d'excellence Inflamex, Université Paris-Diderot Sorbonne Paris-Cité, France.,INSERM, UMR 1149, F-75018 Paris, France
| | - Dominique Berrebi
- Services d'anatomie et de cytologie pathologiques, Hôpital Robert Debré, Université Paris-Diderot Sorbonne Paris-Cité, Paris, France.,UMR996, Cytokines, chimiokines et immunopathologie, Clamart, France
| | - Jean-Pierre Hugot
- Laboratoire d'excellence Inflamex, Université Paris-Diderot Sorbonne Paris-Cité, France.,INSERM, UMR 1149, F-75018 Paris, France.,Services des maladies digestives et respiratoires de l'enfant et service d'anatomie pathologique, Hôpital Robert Debré, Paris, France
| | - Frédérick Barreau
- Laboratoire d'excellence Inflamex, Université Paris-Diderot Sorbonne Paris-Cité, France .,INSERM, UMR 1149, F-75018 Paris, France.,Institut de Recherche en Santé Digestive, Université de Toulouse, Toulouse, France
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28
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Abstract
The pathophysiology of Crohn's disease (CD), a chronic inflammatory bowel disease, remains imperfectly elucidated. Consequently, the therapeutic armamentarium remains limited and has not changed the natural history of CD hitherto. Accordingly, physicians need to identify new therapeutic targets to be able to alter the intestinal damage. The most recent hypothesis considered CD as resulting from an abnormal interaction between microbiota and host immune system influenced by genetics and environmental factors. Several experimental and genetic evidence point out intestinal macrophages in CD etiology. An increase of macrophages number and the presence of granulomas are especially observed in the intestinal mucosa of patients with CD. These macrophages could be defective and particularly in responses to infectious agents like CD-associated Escherichia coli. This review focuses on, what is currently known regarding the role of macrophages, macrophages/E. coli interaction, and the impact of CD therapies on macrophages in CD. We also speculate that macrophages modulation could lead to important translational implications in CD with the end goal of promoting gut health.
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29
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Uniken Venema WT, Voskuil MD, Dijkstra G, Weersma RK, Festen EA. The genetic background of inflammatory bowel disease: from correlation to causality. J Pathol 2016; 241:146-158. [PMID: 27785786 DOI: 10.1002/path.4817] [Citation(s) in RCA: 76] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2016] [Revised: 09/13/2016] [Accepted: 09/27/2016] [Indexed: 12/12/2022]
Abstract
Recent studies have greatly improved our insight into the genetic background of inflammatory bowel disease (IBD). New high-throughput technologies and large-scale international collaborations have contributed to the identification of 200 independent genetic risk loci for IBD. However, in most of these loci, it is unclear which gene conveys the risk for IBD. More importantly, it is unclear which variant within or near the gene is causal to the disease. Using targeted GWAS, imputation, resequencing of risk loci, and in silico fine-mapping of densely typed loci, several causal variants have been identified in IBD risk genes, and various pathological pathways have been uncovered. Current research in the field of IBD focuses on the effect of these causal variants on gene expression and protein function. However, more elements than only the genome must be taken into account to disentangle the multifactorial pathology of IBD. The genetic risk loci identified to date only explain a small part of genetic variance in disease risk. Currently, large multi-omics studies are incorporating factors ranging from the gut microbiome to the environment. In this review, we present the progress that has been made in IBD genetic research and stress the importance of studying causality to increase our understanding of the pathogenesis of IBD. We highlight important causal genetic variants in the candidate genes NOD2, ATG16L1, IRGM, IL23R, CARD9, RNF186, and PRDM1. We describe their downstream effects on protein function and their direct effects on the gut immune system. Furthermore, we discuss the future role of genetics in unravelling disease mechanisms in IBD. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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Affiliation(s)
- Werna Tc Uniken Venema
- Department of Gastroenterology and Hepatology, University of Groningen and University Medical Center Groningen, Groningen, The Netherlands
| | - Michiel D Voskuil
- Department of Gastroenterology and Hepatology, University of Groningen and University Medical Center Groningen, Groningen, The Netherlands
| | - Gerard Dijkstra
- Department of Gastroenterology and Hepatology, University of Groningen and University Medical Center Groningen, Groningen, The Netherlands
| | - Rinse K Weersma
- Department of Gastroenterology and Hepatology, University of Groningen and University Medical Center Groningen, Groningen, The Netherlands
| | - Eleonora Am Festen
- Department of Gastroenterology and Hepatology, University of Groningen and University Medical Center Groningen, Groningen, The Netherlands.,Department of Genetics, University of Groningen and University Medical Center Groningen, Groningen, The Netherlands
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30
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Sidiq T, Yoshihama S, Downs I, Kobayashi KS. Nod2: A Critical Regulator of Ileal Microbiota and Crohn's Disease. Front Immunol 2016; 7:367. [PMID: 27703457 PMCID: PMC5028879 DOI: 10.3389/fimmu.2016.00367] [Citation(s) in RCA: 76] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2016] [Accepted: 09/06/2016] [Indexed: 12/19/2022] Open
Abstract
The human intestinal tract harbors large bacterial community consisting of commensal, symbiotic, and pathogenic strains, which are constantly interacting with the intestinal immune system. This interaction elicits a non-pathological basal level of immune responses and contributes to shaping both the intestinal immune system and bacterial community. Recent studies on human microbiota are revealing the critical role of intestinal bacterial community in the pathogenesis of both systemic and intestinal diseases, including Crohn’s disease (CD). NOD2 plays a key role in the regulation of microbiota in the small intestine. NOD2 is highly expressed in ileal Paneth cells that provide critical mechanism for the regulation of ileal microbiota through the secretion of anti-bacterial compounds. Genome mapping of CD patients revealed that loss of function mutations in NOD2 are associated with ileal CD. Genome-wide association studies further demonstrated that NOD2 is one of the most critical genetic factor linked to ileal CD. The bacterial community in the ileum is indeed dysregulated in Nod2-deficient mice. Nod2-deficient ileal epithelia exhibit impaired ability of killing bacteria. Thus, altered interactions between ileal microbiota and mucosal immunity through NOD2 mutations play significant roles in the disease susceptibility and pathogenesis in CD patients, thereby depicting NOD2 as a critical regulator of ileal microbiota and CD.
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Affiliation(s)
- Tabasum Sidiq
- Department of Microbial Pathogenesis and Immunology, College of Medicine, Texas A&M University , College Station, TX , USA
| | - Sayuri Yoshihama
- Department of Microbial Pathogenesis and Immunology, College of Medicine, Texas A&M University , College Station, TX , USA
| | - Isaac Downs
- Department of Microbial Pathogenesis and Immunology, College of Medicine, Texas A&M University , College Station, TX , USA
| | - Koichi S Kobayashi
- Department of Microbial Pathogenesis and Immunology, College of Medicine, Texas A&M University , College Station, TX , USA
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Multifaceted Functions of NOD-Like Receptor Proteins in Myeloid Cells at the Intersection of Innate and Adaptive Immunity. Microbiol Spectr 2016; 4. [DOI: 10.1128/microbiolspec.mchd-0021-2015] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022] Open
Abstract
NOD-like receptor (NLR) proteins, as much as Toll-like receptor proteins, play a major role in modulating myeloid cells in their immune functions. There is still, however, limited knowledge on the expression and function of several of the mammalian NLR proteins in myeloid lineages. Still, the function of pyrin domain-containing NLR proteins and NLRC4/NAIP as inflammasome components that drive interleukin-1β (IL-1β) and IL-18 maturation and secretion upon pathogen stimulation is well established. NOD1, NOD2, NLRP3, and NLRC4/NAIP act as bona fide pattern recognition receptors (PRRs) that sense microbe-associated molecular patterns (MAMPs) but also react to endogenous danger-associated molecular patterns (DAMPs). Ultimately, activation of these receptors achieves macrophage activation and maturation of dendritic cells to drive antigen-specific adaptive immune responses. Upon infection, sensing of invading pathogens and likely of DAMPs that are released in response to tissue injury is a process that involves multiple PRRs in both myeloid and epithelial cells, and these act in concert to design tailored, pathogen-adapted immune responses by induction of different cytokine profiles, giving rise to appropriate lymphocyte polarization.
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Intact Regulatory T-Cell Function but Defective Generation of IL-17A-Producing CD4+ T Cells in XIAP Deficiency. J Pediatr Gastroenterol Nutr 2016; 63:218-25. [PMID: 26825770 DOI: 10.1097/mpg.0000000000001122] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/10/2022]
Abstract
OBJECTIVE X-linked inhibitor of apoptosis (xIAP) deficiency is a primary immune deficiency disorder associated with hemophagocytic lymphohistiocytosis. About 17% of xIAP-deficient patients present with very early onset severe colitis with high mortality. We hypothesized that xIAP deficiency leads to defective generation and/or survival of T regulatory cells (Treg) through its involvement in transforming growth factor-β signaling. METHODS AND RESULTS We used a T-cell transfer model of chronic colitis and observed a mild increase in colitis severity induced by naïve CD4 T cells from xIAP mice compared with colitis induced by naïve CD4 T cells from WT mice. We did not observe any significant difference in the induction of Treg cells in these studies. We next tested whether xIAP is required for Treg cell function by co-transferring xIAP or WT Treg cells with naïve WT CD4 cells in this model. We demonstrate that XIAP-deficient Treg cells were able to prevent disease similarly to WT Treg cells. In these experiments we, however, found a significantly decreased percentage of IL-17A-producing CD4 T cells in mice receiving Tregs from xIAP mice. CONCLUSIONS xIAP appears dispensable for the generation of induced Treg cells as well as function of natural Treg cells. There appeared to be a role of xIAP in generation of IL-17-producing cells from either naïve CD4 T cells or Treg cells. Further research is needed to explore the role of xIAP in generation of IL-17-producing cells.
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Mondot S, Lepage P, Seksik P, Allez M, Tréton X, Bouhnik Y, Colombel JF, Leclerc M, Pochart P, Doré J, Marteau P, the GETAID. Structural robustness of the gut mucosal microbiota is associated with Crohn's disease remission after surgery. Gut 2016; 65:954-62. [PMID: 26628508 PMCID: PMC4893116 DOI: 10.1136/gutjnl-2015-309184] [Citation(s) in RCA: 108] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/13/2015] [Accepted: 11/01/2015] [Indexed: 12/13/2022]
Abstract
OBJECTIVES Preventing postoperative recurrence after ileocolonic resection (ICR) for Crohn's disease (CD) is challenging. Defining the disturbances of the microbial composition and community structure after ICR and their link with early disease recurrence is crucial. DESIGN Microbiota composition (fingerprinting and 16S rDNA sequencing) and community structure (correlation networks of bacterial species) were assessed from ileal mucosa sampled in 20 patients undergoing ICR and 6 months later during endoscopy from above (neoterminal ileum) and below (subanastomotic colon) the surgical anastomosis. RESULTS ICR had a dramatic effect on gut microbial ecosystem. At surgery, CD mucosa harboured a dysbiotic microbiota with high proportions of α/β Proteobacteria and Bacilli. Six months later, half of the patients had recurrent lesions at ileocolonoscopy and presented higher numbers of Lachnospiraceae. Recurrence of endoscopic lesions was associated with enrichment in Enterococcus durans while patients in remission had increased proportions of Dorea longicatena and Bacteroides plebeius. Structural differences were striking between recurrence and remission microbiota; while the microbiota of patients with CD recurrence exhibited a loose community structure, the microbiota of patients in remission displayed communities that were robustly correlated to each other. Microbiota colonising the neoterminal ileum and subanastomotic colon 6 months after ICR only differed in patients with recurrence. CONCLUSIONS ICR modifies the gut microbiome. Remission after 6 months was associated with homogenous bacterial distribution around the anastomosis. Community structure and bacterial networks highlight target species, including Faecalibacterium prausnitzii and Ruminococcus gnavus, which may allow precise modulations of the overall microbial ecosystem towards remission pattern.
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Affiliation(s)
- S Mondot
- INRA, Micalis UMR1319, Jouy-en-Josas, France,AgroParisTech, Micalis UMR1319, Jouy-en-Josas, France,Institut Curie, U932, Paris, France
| | - P Lepage
- INRA, Micalis UMR1319, Jouy-en-Josas, France,AgroParisTech, Micalis UMR1319, Jouy-en-Josas, France
| | - P Seksik
- Sorbonne Universités—UPMC Univ Paris 06, INSERM ERL 1157, AP-HP, Hôpital Saint Antoine, CNRS UMR 7203 LBM, CHU Saint-Antoine, Paris, France
| | - M Allez
- Gastroenterology Department, Hôpital Saint Louis, APHP, INSERM U1160, Université Paris 7, GETAID, Paris, France
| | - X Tréton
- Gastroenterology Department, Hôpital Beaujon, Clichy, Université Paris 7, GETAID, Paris, France
| | - Y Bouhnik
- Gastroenterology Department, Hôpital Beaujon, Clichy, Université Paris 7, GETAID, Paris, France
| | - J F Colombel
- Department of Gastroenterology, Icahn School of Medicine, New York, New York, USA
| | - M Leclerc
- INRA, Micalis UMR1319, Jouy-en-Josas, France,AgroParisTech, Micalis UMR1319, Jouy-en-Josas, France
| | - P Pochart
- EA Laboratoire de Biologie, Conservatoire national des arts et métiers, Paris, France,EA4065 Université Paris V, Paris, France
| | - J Doré
- INRA, Micalis UMR1319, Jouy-en-Josas, France,AgroParisTech, Micalis UMR1319, Jouy-en-Josas, France
| | - P Marteau
- Gastroenterology Department, Hôpital Lariboisière & Université Denis Diderot—Paris 7, Sorbonne Paris Cité & GETAID, Paris, France
| | - the GETAID
- GETAID, Groupe d'Etude des Traitements des Affections Inflammatoires Digestives, Paris, France
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Respective Roles of Hematopoietic and Nonhematopoietic Nod2 on the Gut Microbiota and Mucosal Homeostasis. Inflamm Bowel Dis 2016; 22:763-73. [PMID: 26963567 DOI: 10.1097/mib.0000000000000749] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND NOD2 mutations are associated with Crohn's disease (CD). Both CD (in human) and Nod2 deficiency (in mice) are characterized by increased mucosal CD4 T-cells, an altered permeability and a microbial dysbiosis. However, the respective roles of the gut epithelial and immune compartments on the phenotype are not known. METHODS Microbial composition, epithelial peptide secretion, intestinal permeability, and immune cell composition of Peyer patches were studied in Nod2 knock-out mice transplanted with wild-type bone marrow cells and vice versa. RESULTS The nonhematopoietic cells control the microbiota composition and epithelial secretion of mucins and antimicrobial peptides. These parameters are correlated with recurrent associations between bacterial species and luminal products. In contrast, Nod2 in the hematopoietic compartment regulates the epithelial permeability and the gut-associated lymphoid tissue independently of the bacterial composition. CONCLUSIONS The immune system and the gut permeability in one hand and the microbial and epithelial peptide compositions in the other hand are separate couples of interdependent parameters, both controlled by Nod2 in either the hematopoietic or nonhematopoietic lineages.
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Lauro ML, Burch JM, Grimes CL. The effect of NOD2 on the microbiota in Crohn's disease. Curr Opin Biotechnol 2016; 40:97-102. [PMID: 27035071 DOI: 10.1016/j.copbio.2016.02.028] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2015] [Revised: 02/17/2016] [Accepted: 02/23/2016] [Indexed: 02/07/2023]
Abstract
Recent advancements toward the treatment of Crohn's disease (CD) indicate great promise for long-term remission. CD patients suffer from a complex host of dysregulated interactions between their innate immune system and microbiome. The most predominant link to the onset of CD is a genetic mutation in the innate immune receptor nucleotide-binding oligomerization domain-containing 2 (NOD2). NOD2 responds to the presence of bacteria and stimulates the immune response. Mutations to NOD2 promote low diversity and dysbiosis in the microbiome, leading to impaired mucosal barrier function. Current treatments suppress the immune response rather than enhancing the function of this critical protein. New progress toward stabilizing NOD2 signaling through its interactions with chaperone proteins holds potential in the development of novel CD therapeutics.
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Affiliation(s)
- Mackenzie L Lauro
- University of Delaware, Department of Chemistry & Biochemistry, Newark, DE 19716, United States
| | - Jason M Burch
- University of Delaware, Department of Chemistry & Biochemistry, Newark, DE 19716, United States
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36
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Schaubeck M, Clavel T, Calasan J, Lagkouvardos I, Haange SB, Jehmlich N, Basic M, Dupont A, Hornef M, von Bergen M, Bleich A, Haller D. Dysbiotic gut microbiota causes transmissible Crohn's disease-like ileitis independent of failure in antimicrobial defence. Gut 2016; 65:225-37. [PMID: 25887379 PMCID: PMC4752651 DOI: 10.1136/gutjnl-2015-309333] [Citation(s) in RCA: 293] [Impact Index Per Article: 32.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/06/2015] [Accepted: 03/21/2015] [Indexed: 12/12/2022]
Abstract
OBJECTIVES Dysbiosis of the intestinal microbiota is associated with Crohn's disease (CD). Functional evidence for a causal role of bacteria in the development of chronic small intestinal inflammation is lacking. Similar to human pathology, TNF(deltaARE) mice develop a tumour necrosis factor (TNF)-driven CD-like transmural inflammation with predominant ileal involvement. DESIGN Heterozygous TNF(deltaARE) mice and wildtype (WT) littermates were housed under conventional (CONV), specific pathogen-free (SPF) and germ-free (GF) conditions. Microbial communities were analysed by high-throughput 16S ribosomal RNA gene sequencing. Metaproteomes were measured using LC-MS. Temporal and spatial resolution of disease development was followed after antibiotic treatment and transfer of microbial communities into GF mice. Granulocyte infiltration and Paneth cell function was assessed by immunofluorescence and gene expression analysis. RESULTS GF-TNF(deltaARE) mice were free of inflammation in the gut and antibiotic treatment of CONV-TNF(deltaARE) mice attenuated ileitis but not colitis, demonstrating that disease severity and location are microbiota-dependent. SPF-TNF(deltaARE) mice developed distinct ileitis-phenotypes associated with gradual loss of antimicrobial defence. 16S analysis and metaproteomics revealed specific compositional and functional alterations of bacterial communities in inflamed mice. Transplantation of disease-associated but not healthy microbiota transmitted CD-like ileitis to GF-TNF(deltaARE) recipients and triggered loss of lysozyme and cryptdin-2 expression. Monoassociation of GF-TNF(deltaARE) mice with the human CD-related Escherichia coli LF82 did not induce ileitis. CONCLUSIONS We provide clear experimental evidence for the causal role of gut bacterial dysbiosis in the development of chronic ileal inflammation with subsequent failure of Paneth cell function.
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Affiliation(s)
- Monika Schaubeck
- Chair of Nutrition and Immunology, Technische Universität München, Freising-Weihenstephan, Germany
| | - Thomas Clavel
- ZIEL-Institute for Food and Health, Technische Universität München, Freising-Weihenstephan, Germany
| | - Jelena Calasan
- Chair of Nutrition and Immunology, Technische Universität München, Freising-Weihenstephan, Germany
| | - Ilias Lagkouvardos
- ZIEL-Institute for Food and Health, Technische Universität München, Freising-Weihenstephan, Germany
| | - Sven Bastiaan Haange
- Department of Proteomics, Helmholtz-Centre for Environmental Research—UFZ, Leipzig, Germany
| | - Nico Jehmlich
- Department of Proteomics, Helmholtz-Centre for Environmental Research—UFZ, Leipzig, Germany
| | - Marijana Basic
- Institut for Medical Microbiology, RWTH University, Aachen, Germany
| | - Aline Dupont
- Institute of Medical Microbiology and Hospital Epidemiology, Hannover Medical School, Hannover, Germany,Institute for Laboratory Animal Science, Hannover Medical School, Hannover, Germany
| | - Mathias Hornef
- Institute of Medical Microbiology and Hospital Epidemiology, Hannover Medical School, Hannover, Germany,Institute for Laboratory Animal Science, Hannover Medical School, Hannover, Germany
| | - Martin von Bergen
- Department of Proteomics, Helmholtz-Centre for Environmental Research—UFZ, Leipzig, Germany,UFZ, Department of Metabolomics, Helmholtz-Centre for Environmental Research, Leipzig, Germany,Department of Biotechnology, Chemistry and Environmental Engineering, University of Aalborg, Aalborg, Denmark
| | - André Bleich
- Institute for Laboratory Animal Science, Hannover Medical School, Hannover, Germany
| | - Dirk Haller
- Chair of Nutrition and Immunology, Technische Universität München, Freising-Weihenstephan, Germany,ZIEL-Institute for Food and Health, Technische Universität München, Freising-Weihenstephan, Germany
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Buttó LF, Schaubeck M, Haller D. Mechanisms of Microbe-Host Interaction in Crohn's Disease: Dysbiosis vs. Pathobiont Selection. Front Immunol 2015; 6:555. [PMID: 26635787 PMCID: PMC4652232 DOI: 10.3389/fimmu.2015.00555] [Citation(s) in RCA: 52] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2015] [Accepted: 10/16/2015] [Indexed: 12/11/2022] Open
Abstract
Crohn’s disease (CD) is a systemic chronic inflammatory condition mainly characterized by discontinuous transmural pathology of the gastrointestinal tract and frequent extraintestinal manifestations with intermittent episodes of remission and relapse. Genome-wide association studies identified a number of risk loci that, catalyzed by environmental triggers, result in the loss of tolerance toward commensal bacteria based on dysregulated innate effector functions and antimicrobial defense, leading to exacerbated adaptive immune responses responsible for chronic immune-mediated tissue damage. In this review, we discuss the inter-related role of changes in the intestinal microbiota, epithelial barrier integrity, and immune cell functions on the pathogenesis of CD, describing the current approaches available to investigate the molecular mechanisms underlying the disease. Substantial effort has been dedicated to define disease-associated changes in the intestinal microbiota (dysbiosis) and to link pathobionts to the etiology of inflammatory bowel diseases. A cogent definition of dysbiosis is lacking, as well as an agreement of whether pathobionts or complex shifts in the microbiota trigger inflammation in the host. Among the rarely available animal models, SAMP/Yit and TNFdeltaARE mice are the best known displaying a transmural CD-like phenotype. New hypothesis-driven mouse models, e.g., epithelial-specific Caspase8−/−, ATG16L1−/−, and XBP1−/− mice, validate pathway-focused function of specific CD-associated risk genes highlighting the role of Paneth cells in antimicrobial defense. To study the causal role of bacteria in initiating inflammation in the host, the use of germ-free mouse models is indispensable. Unraveling the interactions of genes, immune cells and microbes constitute a criterion for the development of safe, reliable, and effective treatment options for CD.
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Affiliation(s)
- Ludovica F Buttó
- Chair of Nutrition and Immunology, Technische Universität München , Freising-Weihenstephan , Germany
| | - Monika Schaubeck
- Chair of Nutrition and Immunology, Technische Universität München , Freising-Weihenstephan , Germany
| | - Dirk Haller
- Chair of Nutrition and Immunology, Technische Universität München , Freising-Weihenstephan , Germany
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38
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Ray A, Dittel BN. Interrelatedness between dysbiosis in the gut microbiota due to immunodeficiency and disease penetrance of colitis. Immunology 2015. [PMID: 26211540 DOI: 10.1111/imm.12511] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
The composition of the microbiome in health and disease has only recently become a major research focus. Although it is clear that an imbalance or dysbiosis in the microbiota is associated with disease, its interrelatedness to disease penetrance is largely unknown. Inflammatory bowel disease (IBD) is an excellent disease in which to explore these questions because of the extensive genetic studies identifying disease susceptibility loci and the ability to easily sample the intestinal microbiota in IBD patients due to the accessibility of stool samples. In addition, mouse models of IBD have contributed to our understanding of the interrelatedness of the gut microbiota and genes associated with IBD. The power of the mouse studies is that multiple colitis models exist that can be used in combination with genetically modified mice that harbour deficiencies in IBD susceptibility genes. Collectively, these studies revealed that bacterial dysbiosis does occur in human IBD and in mouse colitis models. In addition, with an emphasis on immune genes, the mouse studies provided evidence that specific immune regulatory proteins associated with IBD influence the gut microbiota in a manner consistent with disease penetrance. In this review, we will discuss studies in both humans and mice that demonstrate the impact of immunodeficiences in interleukin-10, interleukin-17, nucleotide-binding oligomerization domain (NOD) 2, NOD-like receptor proteins 3 and 6, Toll-like receptor or IgA have on the interrelatedness between the composition of the gut microbiota and disease penetrance of IBD and its mouse models.
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Affiliation(s)
- Avijit Ray
- BloodCenter of Wisconsin, Blood Research Institute, Milwaukee, WI, USA
| | - Bonnie N Dittel
- BloodCenter of Wisconsin, Blood Research Institute, Milwaukee, WI, USA
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Intestinal barrier loss as a critical pathogenic link between inflammatory bowel disease and graft-versus-host disease. Mucosal Immunol 2015; 8:720-30. [PMID: 25943273 DOI: 10.1038/mi.2015.40] [Citation(s) in RCA: 100] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2015] [Accepted: 04/08/2015] [Indexed: 02/04/2023]
Abstract
Compromised intestinal barrier function is a prominent feature of inflammatory bowel disease (IBD). However, links between intestinal barrier loss and disease extend much further, including documented associations with celiac disease, type I diabetes, rheumatoid arthritis, and multiple sclerosis. Intestinal barrier loss has also been proposed to have a critical role in the pathogenesis of graft-versus-host disease (GVHD), a serious, potentially fatal consequence of hematopoietic stem cell transplantation. Experimental evidence has begun to support this view, as barrier loss and its role in initiating and establishing a pathogenic inflammatory cycle in GVHD is emerging. Here we discuss similarities between IBD and GVHD, mechanisms of intestinal barrier loss in these diseases, and the crosstalk between barrier loss and the immune system, with a special focus on natural killer (NK) cells. Unanswered questions and future research directions on the topic are discussed along with implications for treatment.
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Abstract
This review explores our current understanding of the complex interaction between environmental risk factors, genetic traits and the development of inflammatory bowel disease. The primacy of environmental risk factors is illustrated by the rapid increase in the incidence of the disease worldwide. We discuss how the gut microbiota is the proximate environmental risk factor for subsequent development of inflammatory bowel disease. The evolving fields of virome and mycobiome studies will further our understanding of the full potential of the gut microbiota in disease pathogenesis. Manipulating the gut microbiota is a promising therapeutic avenue.
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Pseudomonas fluorescens alters the intestinal barrier function by modulating IL-1β expression through hematopoietic NOD2 signaling. Inflamm Bowel Dis 2015; 21:543-55. [PMID: 25659087 DOI: 10.1097/mib.0000000000000291] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
BACKGROUND Ileal Crohn's disease is related to NOD2 mutations and to a gut barrier dysfunction. Pseudomonas fluorescens has also been associated with ileal Crohn's disease. The aim of this study was to determine the impact of P. fluorescens on the paracellular permeability in ileum and Peyer's patches. METHODS To explore this question, in vivo and ex vivo experiments were performed in wild-type, Nod2, Nod2, and IL-1R mice together with in vitro analyses using the Caco-2 (epithelial) and the THP-1 (monocyte) human cell lines. RESULTS Pseudomonas fluorescens increased the paracellular permeability of the intestinal mucosa through the secretion of IL-1β by the immune cell populations and the activation of myosin light chain kinase in the epithelial cells. Induction of the IL-1β pathway required the expression of Nod2 in the hematopoietic compartment, and muramyl dipeptide (a Nod2 ligand) had an inhibitory effect. CONCLUSIONS Pseudomonas fluorescens thus alters the homeostasis of the epithelial barrier function by a mechanism similar to that previously observed for Yersinia pseudotuberculosis. This work further documents a putative role of psychrotrophic bacteria in Crohn's disease.
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Burcelin R, Courtney M, Amar J. Gut Microbiota and Metabolic Diseases: From Pathogenesis to Therapeutic Perspective. MOLECULAR AND INTEGRATIVE TOXICOLOGY 2015:199-234. [DOI: 10.1007/978-1-4471-6539-2_11] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2025]
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Xu X, Zhang X. Effects of cyclophosphamide on immune system and gut microbiota in mice. Microbiol Res 2014; 171:97-106. [PMID: 25553830 DOI: 10.1016/j.micres.2014.11.002] [Citation(s) in RCA: 122] [Impact Index Per Article: 11.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2014] [Revised: 11/17/2014] [Accepted: 11/22/2014] [Indexed: 02/07/2023]
Abstract
Cyclophosphamide (CP) is the most commonly used drug in autoimmune disease, cancer, blood and marrow transplantation. Recent data revealed that therapy efficacy of CP is gut microbiota-dependent. So, it is very important to understand how CP affects intestinal microbiota and immune function. In this study, the effects of CP on mice immuno-activity were firstly evaluated, then, the fecal microbiota from normal and CP-treated mice was compared, and the characteristic bacterial diversity and compositions were identified, using 454 pyrosequencing technology. The results showed that CP reduced the diversity and shifted the fecal microbiota composition. Specifically, CP treatment decreased the proportion of Bacteroidetes while increased the proportion of Firmictutes in the microbial community. Most importantly, specific microbiota signatures belonging to Bacteroides acidifaciens, Streptococcaceae and Alistipes were also identified, which would provide new insight into the efficacy and side effects in clinical usage of CP. This should be helpful for further demonstration of CP's action mechanism, development of personalized therapy strategies, and prediction of potential side effects related to various treatment regimens of CP.
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Affiliation(s)
- Xiaofei Xu
- College of Light Industry and Food Sciences, South China University of Technology, 381 Wushan Road, Guangzhou 510640, China
| | - Xuewu Zhang
- College of Light Industry and Food Sciences, South China University of Technology, 381 Wushan Road, Guangzhou 510640, China.
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Jing X, Zulfiqar F, Park SY, Núñez G, Dziarski R, Gupta D. Peptidoglycan recognition protein 3 and Nod2 synergistically protect mice from dextran sodium sulfate-induced colitis. THE JOURNAL OF IMMUNOLOGY 2014; 193:3055-69. [PMID: 25114103 DOI: 10.4049/jimmunol.1301548] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Aberrant immune response and changes in the gut microflora are the main causes of inflammatory bowel disease (IBD). Peptidoglycan recognition proteins (Pglyrp1, Pglyrp2, Pglyrp3, and Pglyrp4) are bactericidal innate immunity proteins that maintain normal gut microbiome, protect against experimental colitis, and are associated with IBD in humans. Nucleotide-binding oligomerization domain 2 (Nod2) is an intracellular bacterial sensor and may be required for maintaining normal gut microbiome. Mutations in Nod2 are strongly associated with Crohn's disease, but the causative mechanism is not understood, and the role of Nod2 in ulcerative colitis is not known. Because IBD is likely caused by variable multiple mutations in different individuals, in this study, we examined the combined role of Pglyrp3 and Nod2 in the development of experimental colitis in mice. We demonstrate that a combined deficiency of Pglyrp3 and Nod2 results in higher sensitivity to dextran sodium sulfate-induced colitis compared with a single deficiency. Pglyrp3(-/-)Nod2(-/-) mice had decreased survival and higher loss of body weight, increased intestinal bleeding, higher apoptosis of colonic mucosa, elevated expression of cytokines and chemokines, altered gut microbiome, and increased levels of ATP in the colon. Increased sensitivity to dextran sodium sulfate-induced colitis in Pglyrp3(-/-)Nod2(-/-) mice depended on increased apoptosis of intestinal epithelium, changed gut microflora, and elevated ATP. Pglyrp3 deficiency contributed colitis-predisposing intestinal microflora and increased intestinal ATP, whereas Nod2 deficiency contributed higher apoptosis and responsiveness to increased level of ATP. In summary, Pglyrp3 and Nod2 are both required for maintaining gut homeostasis and protection against colitis, but their protective mechanisms differ.
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Affiliation(s)
- Xuefang Jing
- Indiana University School of Medicine-Northwest, Gary, IN 46408; and
| | - Fareeha Zulfiqar
- Indiana University School of Medicine-Northwest, Gary, IN 46408; and
| | - Shin Yong Park
- Indiana University School of Medicine-Northwest, Gary, IN 46408; and
| | - Gabriel Núñez
- Department of Pathology and Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, MI 48109
| | - Roman Dziarski
- Indiana University School of Medicine-Northwest, Gary, IN 46408; and
| | - Dipika Gupta
- Indiana University School of Medicine-Northwest, Gary, IN 46408; and
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Ramanan D, Tang MS, Bowcutt R, Loke P, Cadwell K. Bacterial sensor Nod2 prevents inflammation of the small intestine by restricting the expansion of the commensal Bacteroides vulgatus. Immunity 2014; 41:311-24. [PMID: 25088769 DOI: 10.1016/j.immuni.2014.06.015] [Citation(s) in RCA: 217] [Impact Index Per Article: 19.7] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2014] [Accepted: 06/23/2014] [Indexed: 12/16/2022]
Abstract
UNLABELLED Nod2 has been extensively characterized as a bacterial sensor that induces an antimicrobial and inflammatory gene expression program. Therefore, it is unclear why Nod2 mutations that disrupt bacterial recognition are paradoxically among the highest risk factors for Crohn's disease, which involves an exaggerated immune response directed at intestinal bacteria. Here, we identified several abnormalities in the small-intestinal epithelium of Nod2(-/-) mice including inflammatory gene expression and goblet cell dysfunction, which were associated with excess interferon-γ production by intraepithelial lymphocytes and Myd88 activity. Remarkably, these abnormalities were dependent on the expansion of a common member of the intestinal microbiota Bacteroides vulgatus, which also mediated exacerbated inflammation in Nod2(-/-) mice upon small-intestinal injury. These results indicate that Nod2 prevents inflammatory pathologies by controlling the microbiota and support a multihit disease model involving specific gene-microbe interactions. VIDEO ABSTRACT
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Affiliation(s)
- Deepshika Ramanan
- Kimmel Center for Biology and Medicine at the Skirball Institute, New York University School of Medicine, New York, NY 10016, USA; Sackler Institute of Graduate Biomedical Science, New York University School of Medicine, New York, NY 10016, USA
| | - Mei San Tang
- Department of Microbiology, New York University School of Medicine, New York, NY 10016, USA
| | - Rowann Bowcutt
- Department of Microbiology, New York University School of Medicine, New York, NY 10016, USA
| | - P'ng Loke
- Department of Microbiology, New York University School of Medicine, New York, NY 10016, USA
| | - Ken Cadwell
- Kimmel Center for Biology and Medicine at the Skirball Institute, New York University School of Medicine, New York, NY 10016, USA; Department of Microbiology, New York University School of Medicine, New York, NY 10016, USA.
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Strober W, Asano N, Fuss I, Kitani A, Watanabe T. Cellular and molecular mechanisms underlying NOD2 risk-associated polymorphisms in Crohn's disease. Immunol Rev 2014; 260:249-260. [PMID: 24942694 DOI: 10.1111/imr.12193] [Citation(s) in RCA: 83] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
The discovery that polymorphisms in the NOD2 (nucleotide-binding oligomerization domain containing 2) gene are associated with a greatly increased risk for the development of Crohn's disease has provided a means to achieve a deeper understanding of the dysregulation of mucosal immune responses to the commensal intestinal organisms that is thought to underlie this disease. NOD2 is a NOD-like receptor (NLR) family member that senses and responds to bacterial wall peptides; thus, the most widely held view of the relation of the NOD2 polymorphisms with Crohn's disease is that these polymorphisms lead to deficient immune responses to gut bacteria, and these, in turn, lead to quantitative or qualitative changes in the bacterial population in the gut lumen or lamina propria that cause inflammation at this site. Initially, this view was based mainly on the observation that defective NOD2 function can result in reduced α-defensin production by intestinal Paneth cells and that such impairment leads to loss of host defense against gut bacteria. In this review, we reconsider this possibility and marshal evidence that it is not in fact likely to be a prime element of Crohn's disease causation. More recently, evidence has been accumulating that the NOD2 dysfunction leads to Crohn's inflammation by inducing changes in the gut microbiome that influence immune effector or regulatory function. We review the strengths and weaknesses of this emerging hypothesis. Finally, we consider the possibility that NOD2 dysfunction can lead to inflammation because of a second and somewhat overlooked aspect of its function, that as an immunoregulator of innate immune responses. In particular, we review the body of evidence that NOD2 stimulation activates a cross-tolerance response that downregulates and thus prevents excessive TLR responses that cause Crohn's inflammation.
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Affiliation(s)
- Warren Strober
- Mucosal Immunity Section, LHD, NIAID, NIH, Bethesda, MD, USA
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Shanahan MT, Carroll IM, Grossniklaus E, White A, von Furstenberg RJ, Barner R, Fodor AA, Henning SJ, Sartor RB, Gulati AS. Mouse Paneth cell antimicrobial function is independent of Nod2. Gut 2014; 63:903-10. [PMID: 23512834 PMCID: PMC3844066 DOI: 10.1136/gutjnl-2012-304190] [Citation(s) in RCA: 82] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
OBJECTIVE Although polymorphisms of the NOD2 gene predispose to the development of ileal Crohn's disease, the precise mechanisms of this increased susceptibility remain unclear. Previous work has shown that transcript expression of the Paneth cell (PC) antimicrobial peptides (AMPs) α-defensin 4 and α-defensin-related sequence 10 are selectively decreased in Nod2(-/-) mice. However, the specific mouse background used in this previous study is unclear. In light of recent evidence suggesting that mouse strain strongly influences PC antimicrobial activity, we sought to characterise PC AMP function in commercially available Nod2(-/-) mice on a C57BL/6 (B6) background. Specifically, we hypothesised that Nod2(-/-) B6 mice would display reduced AMP expression and activity. DESIGN Wild-type (WT) and Nod2(-/-) B6 ileal AMP expression was assessed via real-time PCR, acid urea polyacrylamide gel electrophoresis and mass spectrometry. PCs were enumerated using flow cytometry. Functionally, α-defensin bactericidal activity was evaluated using a gel-overlay antimicrobial assay. Faecal microbial composition was determined using 454-sequencing of the bacterial 16S gene in cohoused WT and Nod2(-/-) littermates. RESULTS WT and Nod2(-/-) B6 mice displayed similar PC AMP expression patterns, equivalent α-defensin profiles, and identical antimicrobial activity against commensal and pathogenic bacterial strains. Furthermore, minimal differences in gut microbial composition were detected between the two cohoused, littermate mouse groups. CONCLUSIONS Our data reveal that Nod2 does not directly regulate PC antimicrobial activity in B6 mice. Moreover, we demonstrate that previously reported Nod2-dependent influences on gut microbial composition may be overcome by environmental factors, such as cohousing with WT littermates.
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Affiliation(s)
- Michael T Shanahan
- Department of Medicine, Division of Gastroenterology and Hepatology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
| | - Ian M Carroll
- Department of Medicine, Division of Gastroenterology and Hepatology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
| | - Emily Grossniklaus
- Department of Medicine, Division of Gastroenterology and Hepatology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
| | - Andrew White
- Department of Medicine, Division of Gastroenterology and Hepatology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
| | - Richard J von Furstenberg
- Department of Medicine, Division of Gastroenterology and Hepatology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
| | - Roshonda Barner
- Department of Bioinformatics and Genomics, University of North Carolina at Charlotte, Charlotte, North Carolina, USA
| | - Anthony A Fodor
- Department of Bioinformatics and Genomics, University of North Carolina at Charlotte, Charlotte, North Carolina, USA
| | - Susan J Henning
- Department of Medicine, Division of Gastroenterology and Hepatology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
| | - R Balfour Sartor
- Department of Medicine, Division of Gastroenterology and Hepatology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
| | - Ajay S Gulati
- Department of Pediatrics, Division of Gastroenterology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
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Hasegawa M, Inohara N. Regulation of the gut microbiota by the mucosal immune system in mice. Int Immunol 2014; 26:481-7. [PMID: 24792038 DOI: 10.1093/intimm/dxu049] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023] Open
Abstract
The benefits of commensal bacteria to the health of the host have been well documented, such as providing stimulation to potentiate host immune responses, generation of useful metabolites, and direct competition with pathogens. However, the ability of the host immune system to control the microbiota remains less well understood. Recent microbiota analyses in mouse models have revealed detailed structures and diversities of microbiota at different sites of the digestive tract in mouse populations. The contradictory findings of previous studies on the role of host immune responses in overall microbiota composition are likely attributable to the high β-diversity in mouse populations as well as technical limitations of the methods to analyze microbiota. The host employs multiple systems to strictly regulate their interactions with the microbiota. A spatial segregation between the host and microbiota is achieved with the mucosal epithelium, which is further fortified with a mucus layer on the luminal side and Paneth cells that produce antimicrobial peptides. When commensal bacteria or pathogens breach the epithelial barrier and translocate to peripheral tissues, the host immune system is activated to eliminate them. Defective segregation and tissue elimination of commensals result in exaggerated inflammatory responses and possibly death of the host. In this review, we discuss the current understanding of mouse microbiota, its common features with human microbiota, the technologies utilized to analyze microbiota, and finally the challenges faced to delineate the role of host immune responses in the composition of the luminal microbiota.
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Affiliation(s)
- Mizuho Hasegawa
- Department of Pathology, University of Michigan Medical School, 1150W. Medical Center Drive, Ann Arbor, MI 48109, USA
| | - Naohiro Inohara
- Department of Pathology, University of Michigan Medical School, 1150W. Medical Center Drive, Ann Arbor, MI 48109, USA
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Abstract
Although a causing viral infectious agent remains untraceable in Crohn's disease, most recent genome-wide association studies have linked the FUT2 W143X mutation (resulting in asymptomatic norovirus infection) with the pathogenesis of Crohn's ileitis and with vitamin B12 deficiency (i.e., a known risk factor for Crohn's disease with ileal involvement). In line with these findings, host variations in additional genes involved in host response to norovirus infection (such as ATG16L1 and NOD2) predispose humans to Crohn's ileitis. One may therefore presume that asymptomatic norovirus infection may contribute to disruption of the stability of the gut microbiota leading to Crohn's ileitis. These paradigms highlight not only the need to revisit the potential transmissibility of Crohn's disease, but also potential safety issues of forthcoming clinical trials on human probiotic infusions in Crohn's ileitis by rigorous donors screening program.
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Affiliation(s)
- Mathias Chamaillard
- *Institut Pasteur de Lille, Center for Infection and Immunity of Lille, Lille, France; †CNRS, UMR 8204, Lille, France; ‡Institut National de la Santé et de la Recherche Médicale, U1019, Team 7, Equipe FRM, Lille, France; §Univ Lille Nord de France, Lille, France; and ‖Université Lille 2, Faculté de Médecine, CHRU de Lille, Laboratoire de Virologie EA3610, Loos-lez-Lille, France
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Relationship between gut microbiota and development of T cell associated disease. FEBS Lett 2014; 588:4195-206. [PMID: 24681103 DOI: 10.1016/j.febslet.2014.03.019] [Citation(s) in RCA: 74] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2014] [Revised: 03/11/2014] [Accepted: 03/11/2014] [Indexed: 12/11/2022]
Abstract
The interplay between the immune response and the gut microbiota is complex. Although it is well-established that the gut microbiota is essential for the proper development of the immune system, recent evidence indicates that the cells of the immune system also influence the composition of the gut microbiota. This interaction can have important consequences for the development of inflammatory diseases, including autoimmune diseases and allergy, and the specific mechanisms by which the gut commensals drive the development of different types of immune responses are beginning to be understood. Furthermore, sex hormones are now thought to play a novel role in this complex relationship, and collaborate with both the gut microbiota and immune system to influence the development of autoimmune disease. In this review, we will focus on recent studies that have transformed our understanding of the importance of the gut microbiota in inflammatory responses.
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