The role of gastrointestinal pathogens in inflammatory bowel disease: a systematic review

The inflammatory bowel diseases (IBD), comprising Crohn’s disease (CD) and ulcerative colitis (UC), are chronic, progressive, inflammatory conditions of the gastrointestinal tract. Imbalance in the gut microbial community, or dysbiosis, and the subsequent immune response, represent the critical relationship between genetic susceptibility, microbes, and environment factors, that result in IBD. Gastrointestinal pathogens – a common cause of dysbiosis – have been implicated as an environmental trigger in new onset IBD, as well as flare of existing IBD. In this article, we systematically review clinical data regarding the association between specific gastrointestinal pathogens and IBD. Numerous bacteria, viruses, fungi, and parasites have been implicated in the pathogenesis of IBD, and exacerbations of existing disease. In this article, we will also specifically discuss the less recognized microbes that have an inverse association with IBD, including certain bacterial pathogens, such as Helicobacter pylori, and parasites, such as Trichuris species. Future prospective and experimental studies are required to establish causality and clarify potential mechanisms of enteric pathogens in modifying the risk and course of IBD.

[1]  Shannon Chang,et al.  Comparative Evaluation of Conventional Stool Testing and Multiplex Molecular Panel in Outpatients With Relapse of Inflammatory Bowel Disease. , 2021, Inflammatory bowel diseases.

[2]  A. Paterson,et al.  Increased Intestinal Permeability is Associated with Later Development of Crohn's Disease. , 2020, Gastroenterology.

[3]  K. Cadwell,et al.  Systematic review: gastrointestinal infection and incident inflammatory bowel disease , 2020, Alimentary pharmacology & therapeutics.

[4]  S. Shah,et al.  Friend or Foe in IBD Pathogenesis: Not All Infections are Equal. , 2019, Gastroenterology.

[5]  J. Hugot,et al.  Is Crohn Disease the price to pay today for having survived to the Black Death? , 2019, Journal of Crohn's & colitis.

[6]  R. Peek,et al.  Systematic review with meta‐analysis: association between Helicobacter pylori CagA seropositivity and odds of inflammatory bowel disease , 2019, Alimentary pharmacology & therapeutics.

[7]  J. Ludvigsson,et al.  Gastrointestinal Infection Increases Odds of Inflammatory Bowel Disease in a Nationwide Case-Control Study. , 2019, Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association.

[8]  S. Targan,et al.  Malassezia Is Associated with Crohn's Disease and Exacerbates Colitis in Mouse Models. , 2019, Cell host & microbe.

[9]  J. Hugot,et al.  Prevalence of Yersinia Species in the Ileum of Crohn's Disease Patients and Controls , 2018, Front. Cell. Infect. Microbiol..

[10]  K. Cadwell,et al.  Enteric Infections Are Common in Patients with Flares of Inflammatory Bowel Disease , 2018, The American Journal of Gastroenterology.

[11]  Feng Chen,et al.  Trichuris suis ova therapy in inflammatory bowel disease , 2018, Medicine.

[12]  J. Miyoshi,et al.  The evidence for fungus in Crohn’s disease pathogenesis , 2018, Clinical Journal of Gastroenterology.

[13]  J. del Valle-Mendoza,et al.  Helicobacter pylori and its relationship with variations of gut microbiota in asymptomatic children between 6 and 12 years , 2018, BMC Research Notes.

[14]  H. Sokol,et al.  Specificities of the intestinal microbiota in patients with inflammatory bowel disease and Clostridium difficile infection , 2018, Gut microbes.

[15]  V. Nizet,et al.  Recurrent infection progressively disables host protection against intestinal inflammation , 2017, Science.

[16]  Vanessa M. Hubbard-Lucey,et al.  Autophagy protein ATG16L1 prevents necroptosis in the intestinal epithelium , 2017, The Journal of experimental medicine.

[17]  Jana G Hashash,et al.  Lasting Impact of Clostridium difficile Infection in Inflammatory Bowel Disease: A Propensity Score Matched Analysis , 2017, Inflammatory bowel diseases.

[18]  X. Qiu,et al.  Alterations in the mucosa-associated fungal microbiota in patients with ulcerative colitis , 2017, Oncotarget.

[19]  S. Oka,et al.  PCR detection of human herpesviruses in colonic mucosa of individuals with inflammatory bowel disease: Comparison with individuals with immunocompetency and HIV infection , 2017, PloS one.

[20]  S. Ng,et al.  Global Prevalence of Helicobacter pylori Infection: Systematic Review and Meta-Analysis. , 2017, Gastroenterology.

[21]  Y. Nobel,et al.  Enteric Infection in Relapse of Inflammatory Bowel Disease: The Utility of Stool Microbial PCR Testing , 2017, Inflammatory bowel diseases.

[22]  W. Agace,et al.  Diversity and functions of intestinal mononuclear phagocytes , 2017, Mucosal Immunology.

[23]  J. Langhorst,et al.  A Randomised, Double-blind, Placebo-controlled Trial of Trichuris suis ova in Active Crohn’s Disease , 2016, Journal of Crohn's & colitis.

[24]  A. Bianchi,et al.  Gastric transposition as a valid surgical option for esophageal replacement in pediatric patients: experience from three Italian medical centers. , 2017, Gastroenterology report.

[25]  B. Shah,et al.  Clostridium difficile Infection in Inflammatory Bowel Disease: A Nursing-Based Quality Improvement Strategy , 2016, Journal for healthcare quality : official publication of the National Association for Healthcare Quality.

[26]  A. McGeer,et al.  Recurrence of Clostridium difficile Infection in Patients with Inflammatory Bowel Disease: The RECIDIVISM Study , 2016, The American Journal of Gastroenterology.

[27]  N. Zmora,et al.  The microbiome and innate immunity , 2016, Nature.

[28]  T. Lobaton,et al.  Bacterial Intestinal Superinfections in Inflammatory Bowel Diseases Beyond Clostridum difficile , 2016, Inflammatory bowel diseases.

[29]  H. Nielsen,et al.  Optimized cultivation of Campylobacter concisus from gut mucosal biopsies in inflammatory bowel disease , 2016, Gut Pathogens.

[30]  Ta-Chiang Liu,et al.  Genetics and Pathogenesis of Inflammatory Bowel Disease. , 2016, Annual review of pathology.

[31]  Martin J. Blaser,et al.  Helminth infection promotes colonization resistance via type 2 immunity , 2016, Science.

[32]  A. Roy,et al.  Clostridium difficile Infection: A Rarity in Patients Receiving Chronic Antibiotic Treatment for Crohn's Disease , 2016, Inflammatory bowel diseases.

[33]  G. Liguori,et al.  Fungal Dysbiosis in Mucosa-associated Microbiota of Crohn's Disease Patients. , 2016, Journal of Crohn's & colitis.

[34]  G. Daskalopoulos,et al.  The Association of Mycobacterium avium subsp. paratuberculosis with Inflammatory Bowel Disease , 2016, PloS one.

[35]  Hugues Aschard,et al.  Fungal microbiota dysbiosis in IBD , 2016, Gut.

[36]  Z. Arora,et al.  Risk factors and clinical implication of superimposed Campylobacter jejuni infection in patients with underlying ulcerative colitis , 2015, Gastroenterology report.

[37]  N. Kaakoush,et al.  Dual role of Helicobacter and Campylobacter species in IBD: a systematic review and meta-analysis , 2015, Gut.

[38]  Eric Z. Chen,et al.  Inflammation, Antibiotics, and Diet as Environmental Stressors of the Gut Microbiome in Pediatric Crohn's Disease. , 2015, Cell host & microbe.

[39]  Jonathan Braun,et al.  Diagnostic and Prognostic Microbial Biomarkers in Inflammatory Bowel Diseases. , 2015, Gastroenterology.

[40]  T. Monaghan,et al.  Pathogenesis of Clostridium difficile Infection and Its Potential Role in Inflammatory Bowel Disease , 2015, Inflammatory bowel diseases.

[41]  F. Bushman,et al.  Fungal Signature in the Gut Microbiota of Pediatric Patients With Inflammatory Bowel Disease , 2015, Inflammatory Bowel Diseases.

[42]  D. Littman,et al.  The functional impact of the intestinal microbiome on mucosal immunity and systemic autoimmunity , 2015, Current opinion in rheumatology.

[43]  J. Turner,et al.  Intestinal barrier loss as a critical pathogenic link between inflammatory bowel disease and graft-versus-host disease , 2015, Mucosal Immunology.

[44]  Fang-yu Wang,et al.  Helicobacter pylori infection and inflammatory bowel disease in Asians: a meta-analysis. , 2015, World journal of gastroenterology.

[45]  G. Liguori,et al.  Gut Fungal Microbiota: The Yin and Yang of Inflammatory Bowel Disease , 2015, Inflammatory bowel diseases.

[46]  M. Ghannoum,et al.  Mycobiota in gastrointestinal diseases , 2015, Nature Reviews Gastroenterology &Hepatology.

[47]  Jenny Sauk,et al.  Disease-Specific Alterations in the Enteric Virome in Inflammatory Bowel Disease , 2015, Cell.

[48]  E. Bouza,et al.  Listeria monocytogenes infection in inflammatory bowel disease patients: case series and review of the literature , 2014, European journal of gastroenterology & hepatology.

[49]  M. Yazdanbakhsh,et al.  Helminth therapy or elimination: epidemiological, immunological, and clinical considerations. , 2014, The Lancet. Infectious diseases.

[50]  Si Ming Man,et al.  Role of Emerging Campylobacter Species in Inflammatory Bowel Diseases , 2014, Inflammatory bowel diseases.

[51]  S. Naser,et al.  Mycobacterium avium subspecies paratuberculosis causes Crohn's disease in some inflammatory bowel disease patients. , 2014, World journal of gastroenterology.

[52]  A. Kostic,et al.  The microbiome in inflammatory bowel disease: current status and the future ahead. , 2014, Gastroenterology.

[53]  F. Carrat,et al.  The impact of cytomegalovirus reactivation and its treatment on the course of inflammatory bowel disease , 2014, Alimentary pharmacology & therapeutics.

[54]  P. Bager,et al.  Helminth therapy (worms) for induction of remission in inflammatory bowel disease. , 2014, The Cochrane database of systematic reviews.

[55]  Jie-shou Li,et al.  Dysbiosis of Gut Fungal Microbiota is Associated With Mucosal Inflammation in Crohn’s Disease , 2013, Journal of clinical gastroenterology.

[56]  K. Carroll,et al.  Clostridium difficile Carriage and Serum Antitoxin Responses in Children with Inflammatory Bowel Disease , 2013, Inflammatory bowel diseases.

[57]  R. Fedorak,et al.  Prevalence of Epstein–Barr Virus in a population of patients with inflammatory bowel disease: a prospective cohort study , 2013, Alimentary pharmacology & therapeutics.

[58]  A. Kalergis,et al.  Role of Salmonella enterica exposure in Chilean Crohn's disease patients. , 2013, World journal of gastroenterology.

[59]  H. Sewell,et al.  Circulating Antibody and Memory B-Cell Responses to C. difficile Toxins A and B in Patients with C. difficile-Associated Diarrhoea, Inflammatory Bowel Disease and Cystic Fibrosis , 2013, PloS one.

[60]  A. Ananthakrishnan,et al.  Genetic risk factors for Clostridium difficile infection in ulcerative colitis , 2013, Alimentary pharmacology & therapeutics.

[61]  M. Wilkins,et al.  Comparative genomics of Campylobacter concisus isolates reveals genetic diversity and provides insights into disease association , 2013, BMC Genomics.

[62]  O. Bulut,et al.  Pathogenic Yersinia DNA in Intestinal Specimens of Pediatric Patients with Crohn's Disease , 2013, Fetal and pediatric pathology.

[63]  S. Hanauer,et al.  Randomised clinical trial: the safety and tolerability of Trichuris suis ova in patients with Crohn's disease , 2013, Alimentary pharmacology & therapeutics.

[64]  E. El-Omar,et al.  The Microaerophilic Microbiota of De-Novo Paediatric Inflammatory Bowel Disease: The BISCUIT Study , 2013, PloS one.

[65]  Xuhang Li,et al.  Childhood Helminth Exposure Is Protective Against Inflammatory Bowel Disease: A Case Control Study in South Africa , 2013, Inflammatory bowel diseases.

[66]  P. Austin,et al.  Impact of Clostridium difficile colitis on 5‐year health outcomes in patients with ulcerative colitis , 2012, Alimentary pharmacology & therapeutics.

[67]  Y. Belkaid,et al.  Acute Gastrointestinal Infection Induces Long-Lived Microbiota-Specific T Cell Responses , 2012, Science.

[68]  U. Navaneethan,et al.  Clostridium difficile infection is associated with worse long term outcome in patients with ulcerative colitis. , 2012, Journal of Crohn's & colitis.

[69]  V. Villanacci,et al.  Intestinal superinfections in patients with inflammatory bowel diseases. , 2012, Journal of Crohn's & colitis.

[70]  P. Klemola,et al.  Enteric viral pathogens in children with inflammatory bowel disease , 2012, Journal of medical virology.

[71]  M. Wilkins,et al.  The Pathogenic Potential of Campylobacter concisus Strains Associated with Chronic Intestinal Diseases , 2011, PloS one.

[72]  J. Arola,et al.  Human herpesvirus 6 and cytomegalovirus in ileocolonic mucosa in inflammatory bowel disease , 2011, Scandinavian journal of gastroenterology.

[73]  S. Mazmanian,et al.  Pathobionts of the gastrointestinal microbiota and inflammatory disease. , 2011, Current opinion in immunology.

[74]  M. Riddle,et al.  Detection bias and the association between inflammatory bowel disease and Salmonella and Campylobacter infection , 2011, Gut.

[75]  E. El-Omar,et al.  Detection of Campylobacter concisus and Other Campylobacter Species in Colonic Biopsies from Adults with Ulcerative Colitis , 2011, PloS one.

[76]  A. Ananthakrishnan,et al.  Temporal trends in disease outcomes related to Clostridium difficile infection in patients with inflammatory bowel disease , 2011, Inflammatory bowel diseases.

[77]  U. Navaneethan,et al.  Impact of Clostridium difficile infection in patients with ulcerative colitis. , 2011, Journal of Crohn's & colitis.

[78]  I. Grishina,et al.  Epstein-Barr virus replication linked to B cell proliferation in inflamed areas of colonic mucosa of patients with inflammatory bowel disease. , 2011, Journal of clinical virology : the official publication of the Pan American Society for Clinical Virology.

[79]  E. Szigethy,et al.  Inflammatory bowel disease. , 2011, Pediatric clinics of North America.

[80]  K. T. Jørgensen,et al.  Enteric Salmonella or Campylobacter infections and the risk of inflammatory bowel disease , 2010, Gut.

[81]  Si Ming Man,et al.  Detection of Helicobacteraceae in Intestinal Biopsies of Children with Crohn’s Disease , 2010, Helicobacter.

[82]  M. Vatn,et al.  Paucity of mycobacteria in mucosal bowel biopsies from adults and children with early inflammatory bowel disease. , 2010, Journal of Crohn's & colitis.

[83]  M. Diebold,et al.  Low frequency of cytomegalovirus infection during exacerbations of inflammatory bowel diseases , 2010, Journal of medical virology.

[84]  A. Ananthakrishnan,et al.  Impact of Clostridium difficile on inflammatory bowel disease , 2010, Expert review of gastroenterology & hepatology.

[85]  R. Xavier,et al.  Virus-Plus-Susceptibility Gene Interaction Determines Crohn's Disease Gene Atg16L1 Phenotypes in Intestine , 2010, Cell.

[86]  Si Ming Man,et al.  Campylobacter concisus and other Campylobacter species in children with newly diagnosed Crohn's disease , 2010, Inflammatory bowel diseases.

[87]  M. Dave,et al.  Association between Helicobacter pylori infection and inflammatory bowel disease: A meta‐analysis and systematic review of the literature† , 2010, Inflammatory bowel diseases.

[88]  M. Abreu,et al.  Clinical Outcomes of Patients with Ulcerative Colitis and Co-existing Clostridium difficile Infection , 2010, Digestive Diseases and Sciences.

[89]  Thomas F. Tedder,et al.  Innate and Adaptive Immunity Cooperate Flexibly to Maintain Host-Microbiota Mutualism , 2009, Science.

[90]  R. P. Ross,et al.  The Vexed Relationship Between Clostridium Difficile and Inflammatory Bowel Disease: An Assessment of Carriage in an Outpatient Setting Among Patients in Remission , 2009, The American Journal of Gastroenterology.

[91]  J. Ellingson,et al.  Absence of mycobacterium avium subsp. paratuberculosis in Crohn's patients , 2009, Inflammatory bowel diseases.

[92]  D. Elliott,et al.  Helminths and the IBD hygiene hypothesis , 2009, Inflammatory bowel diseases.

[93]  M. I. Nassar,et al.  Acute Cytomegalovirus Infection Is a Risk Factor in Refractory and Complicated Inflammatory Bowel Disease , 2009, Digestive Diseases and Sciences.

[94]  Si Ming Man,et al.  Detection and Isolation of Campylobacter Species Other than C. jejuni from Children with Crohn's Disease , 2008, Journal of Clinical Microbiology.

[95]  G. Kaplan,et al.  A National Survey of the Prevalence and Impact of Clostridium difficile Infection Among Hospitalized Inflammatory Bowel Disease Patients , 2008, The American Journal of Gastroenterology.

[96]  W. Weichert,et al.  Fungi and inflammatory bowel diseases: Alterations of composition and diversity , 2008, Scandinavian journal of gastroenterology.

[97]  A. Ananthakrishnan,et al.  Excess hospitalisation burden associated with Clostridium difficile in patients with inflammatory bowel disease , 2007, Gut.

[98]  Kimberly A. Reske,et al.  Incidence of Clostridium difficile infection in inflammatory bowel disease. , 2007, Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association.

[99]  H. Ogata,et al.  Cytomegalovirus Is Frequently Reactivated and Disappears Without Antiviral Agents in Ulcerative Colitis Patients , 2007, The American Journal of Gastroenterology.

[100]  B. Lashner,et al.  Cytomegalovirus Colitis Complicating Inflammatory Bowel Disease , 2006, The American Journal of Gastroenterology.

[101]  H. Nagawa,et al.  Cytomegalovirus infection in ulcerative colitis , 2006, Scandinavian journal of gastroenterology.

[102]  T. Giese,et al.  High prevalence of Mycobacterium avium subspecies paratuberculosis IS900 DNA in gut tissues from individuals with Crohn’s disease , 2005, Gut.

[103]  Joel V Weinstock,et al.  Trichuris suis therapy for active ulcerative colitis: a randomized controlled trial. , 2005, Gastroenterology.

[104]  Robert W. Summers,et al.  Vomiting in the recently anticoagulated patient , 2004, Gut.

[105]  S. Finkelstein,et al.  Absence of Mycobacterium avium subsp. paratuberculosis in the microdissected granulomas of Crohn's disease , 2004, Modern Pathology.

[106]  D. Rampton,et al.  Enteric infection in relapse of inflammatory bowel disease: importance of microbiological examination of stool , 2004, European journal of gastroenterology & hepatology.

[107]  C. Bernstein,et al.  Study of Animal-Borne Infections in the Mucosas of Patients with Inflammatory Bowel Disease and Population-Based Controls , 2003, Journal of Clinical Microbiology.

[108]  M. Bronner,et al.  Pathogenic Yersinia DNA Is Detected in Bowel and Mesenteric Lymph Nodes From Patients With Crohn's Disease , 2003, The American journal of surgical pathology.

[109]  D. Elliott,et al.  The possible link between de-worming and the emergence of immunological disease. , 2002, The Journal of laboratory and clinical medicine.

[110]  P. Malfertheiner,et al.  Influence of anti‐Helicobacter triple‐therapy with metronidazole, omeprazole and clarithromycin on intestinal microflora , 2001, Alimentary pharmacology & therapeutics.

[111]  G. Pietrosi,et al.  Prevalence of cytomegalovirus infection in severe refractory ulcerative and Crohn's colitis , 2001, American Journal of Gastroenterology.

[112]  Wangxue Chen,et al.  Detection of Listeria monocytogenes by polymerase chain reaction in intestinal mucosal biopsies from patients with inflammatory bowel disease and controls , 2000, Journal of gastroenterology and hepatology.

[113]  A. West,et al.  Immunocytochemical evidence of Listeria, Escherichia coil, and Streptococcus antigens in Crohn's disease , 1995, Gastroenterology.

[114]  M. Scheurlen,et al.  Microbic Superinfection in Relapse of Inflammatory Bowel Disease , 1992, Journal of clinical gastroenterology.

[115]  R. Pounder,et al.  Clostridium difficile and inflammatory bowel disease. , 1983, Gut.