Pathobionts in Inflammatory Bowel Disease: Origins, Underlying Mechanisms, and Implications for Clinical Care

Abstract

The gut microbiota plays a significant role in the pathogenesis of both forms of inflammatory bowel disease (IBD), namely, Crohn’s disease (CD) and ulcerative colitis (UC). Although evidence suggests dysbiosis and loss of beneficial microbial species can exacerbate IBD, many new studies have identified microbes with pathogenic qualities, termed “pathobionts,” within the intestines of patients with IBD. The concept of pathobionts initiating or driving the chronicity of IBD has largely focused on the putative aggravating role that adherent invasive Escherichia coli may play in CD. However, recent studies have identified additional bacterial and fungal pathobionts in patients with CD and UC. This review will highlight the characteristics of these pathobionts and their implications for IBD treatment. Beyond exploring the origins of pathobionts, we discuss those associated with specific clinical features and the potential mechanisms involved, such as creeping fat (Clostridium innocuum) and impaired wound healing (Debaryomyces hansenii) in patients with CD as well as the increased fecal proteolytic activity (Bacteroides vulgatus) seen as a biomarker for UC severity. Finally, we examine the potential impact of pathobionts on current IBD therapies, and several new approaches to target pathobionts currently in the early stages of development. Despite recognizing that pathobionts likely contribute to the pathogenesis of IBD, more work is needed to define their modes of action. Determining whether causal relationships exist between pathobionts and specific disease characteristics could pave the way for improved care for patients, particularly for those not responding to current IBD therapies. The gut microbiota plays a significant role in the pathogenesis of both forms of inflammatory bowel disease (IBD), namely, Crohn’s disease (CD) and ulcerative colitis (UC). Although evidence suggests dysbiosis and loss of beneficial microbial species can exacerbate IBD, many new studies have identified microbes with pathogenic qualities, termed “pathobionts,” within the intestines of patients with IBD. The concept of pathobionts initiating or driving the chronicity of IBD has largely focused on the putative aggravating role that adherent invasive Escherichia coli may play in CD. However, recent studies have identified additional bacterial and fungal pathobionts in patients with CD and UC. This review will highlight the characteristics of these pathobionts and their implications for IBD treatment. Beyond exploring the origins of pathobionts, we discuss those associated with specific clinical features and the potential mechanisms involved, such as creeping fat (Clostridium innocuum) and impaired wound healing (Debaryomyces hansenii) in patients with CD as well as the increased fecal proteolytic activity (Bacteroides vulgatus) seen as a biomarker for UC severity. Finally, we examine the potential impact of pathobionts on current IBD therapies, and several new approaches to target pathobionts currently in the early stages of development. Despite recognizing that pathobionts likely contribute to the pathogenesis of IBD, more work is needed to define their modes of action. Determining whether causal relationships exist between pathobionts and specific disease characteristics could pave the way for improved care for patients, particularly for those not responding to current IBD therapies. The incidence of inflammatory bowel diseases (IBD; Crohn’s disease [CD] and ulcerative colitis [UC]), is increasing in most industrialized countries.1Ng S.C. Shi H.Y. Hamidi N. et al.Worldwide incidence and prevalence of inflammatory bowel disease in the 21st century: a systematic review of population-based studies.Lancet. 2017; 390: 2769-2778Abstract Full Text Full Text PDF PubMed Scopus (3342) Google Scholar Although the etiology of IBD is complex, it is thought to reflect dysregulated immunity that develops in genetically susceptible individuals after exposure to noxious environmental stimuli, including gut microbes. Genome-wide association studies have identified more than 200 IBD genes2Ye B.D. McGovern D.P.B. Genetic variation in IBD: progress, clues to pathogenesis and possible clinical utility.Expert Rev Clin Microbiol. 2017; 12: 1091-1107Google Scholar,3Peters L.A. Perrigoue J. Mortha A. et al.A functional genomics predictive network model identifies regulators of inflammatory bowel disease.Nat Genet. 2017; 49: 1437-1449Crossref PubMed Scopus (151) Google Scholar (eg, NOD2, ATG16L1), many encoding key proteins underlying host processes aimed at controlling or eliminating invading microbes, including autophagy, oxidative stress, epithelial barrier integrity, and Paneth and immune cell functions.4Hampe J. Franke A. Rosenstiel P. et al.A genome-wide association scan of nonsynonymous SNPs identifies a susceptibility variant for Crohn disease in ATG16L1.Nat Genet. 2007; 39: 207-211Crossref PubMed Scopus (1596) Google Scholar,5Hugot J. Chamaillard M. Zouali H. et al.Association of NOD2 leucine-rich repeat variants with susceptibility to Crohn’s disease.Nature. 2001; 411: 599-603Crossref PubMed Scopus (4813) Google Scholar Only 19%–26% of IBD heritability is explained by genetics,3Peters L.A. Perrigoue J. Mortha A. et al.A functional genomics predictive network model identifies regulators of inflammatory bowel disease.Nat Genet. 2017; 49: 1437-1449Crossref PubMed Scopus (151) Google Scholar suggesting that environmental factors, such as bacteria, can promote IBD even without genetic susceptibility. Interestingly, prior acute infection by enteric pathogens and related antibiotic exposures have been repeatedly shown to be risk factors for IBD.6Faye A.S. Allin K.H. Iversen A.T. et al.Antibiotic use as a risk factor for inflammatory bowel disease across the ages: a population-based cohort study.Gut. 2023; 72: 663-670Crossref PubMed Scopus (16) Google Scholar However, they are unlikely to be directly causal because they typically precede IBD development by several years. Intestinal microbial dysbiosis is a well-established feature of IBD.7Gevers D. Kugathasan S. Knights D. et al.A Microbiome Foundation for the Study of Crohn’s Disease.Cell Host Microbe. 2017; 21: 301-304Abstract Full Text Full Text PDF PubMed Scopus (37) Google Scholar,8Michail S. Durbin M. Turner D. et al.Alterations in the gut microbiome of children with severe ulcerative colitis.Inflamm Bowel Dis. 2013; 18: 1799-1808Google Scholar Previously defined as “compositional and functional alterations in the microbiota [driven by] environmental and host-related factors,”9Levy M. Kolodziejczyk A.A. Thaiss C.A. et al.Dysbiosis and the immune system.Nat Rev Immunol. 2017; 17: 219-232Crossref PubMed Scopus (947) Google Scholar dysbiosis is caused by factors such as inflammation, infection, genetics, and dietary habits and is typically characterized by one or more of the following: a loss of beneficial microbes, blooms in potentially pathogenic microbes, or an overall loss of microbial diversity.9Levy M. Kolodziejczyk A.A. Thaiss C.A. et al.Dysbiosis and the immune system.Nat Rev Immunol. 2017; 17: 219-232Crossref PubMed Scopus (947) Google Scholar,10Tiffany C.R. Bäumler A.J. Dysbiosis: to PubMed Scopus Google Scholar Although these characteristics are in the microbiota of patients with IBD, the of and microbial dysbiosis has been many studies have patients for cohort and identified alterations in their gut microbiome to microbial and increased and The gut microbiota and inflammatory bowel PubMed Scopus Google D. The microbiome in inflammatory bowel current and the Full Text Full Text PDF PubMed Scopus Google et microbiota is associated with and host alterations in inflammatory bowel disease.Nat PubMed Scopus Google J. et microbiome in inflammatory bowel a study.Gut. PubMed Scopus Google Scholar the role a microbiota may play in IBD, several studies have the microbiota within and in patients with CD or UC. of these studies identified significant in microbial between and (eg, increased and or the specific identified between studies and between patients within the et microbiota is associated with and host alterations in inflammatory bowel disease.Nat PubMed Scopus Google A. J. et of the microbial between and in patients with ulcerative Scopus Google et prevalence and activity of the microbiota of ulcerative colitis et of the microbiota dysbiosis and between and of the in inflammatory bowel Microbiol. PubMed Scopus Google Scholar The of these IBD microbiome studies that the as well as cohort the associated with the M. Kolodziejczyk A.A. Thaiss C.A. et al.Dysbiosis and the immune system.Nat Rev Immunol. 2017; 17: 219-232Crossref PubMed Scopus (947) Google Scholar including of microbial and host Despite these these that microbiota are with bacterial identified for CD or the that microbiota can promote disease Although it is that and microbial dysbiosis in patients with IBD, whether microbial dysbiosis plays a causal role in IBD or is a of has been to cohort studies are to However, a recent currently of patients with CD by the Crohn’s and Genetic to key microbial associated with the development of et microbiome is associated with of Crohn’s in 2023; Full Text Full Text PDF PubMed Scopus Google Scholar a Microbiome for patients CD identified and and as of CD et microbiome is associated with of Crohn’s in 2023; Full Text Full Text PDF PubMed Scopus Google Scholar functional microbiota including increased bacterial proteolytic identified in individuals A. et fecal that precede clinical of ulcerative Full Text Full Text PDF PubMed Scopus Google Scholar studies a for studies to microbiota disease in and the of could define key stages and microbiota that may contribute to IBD development. studies have that can and that gut microbial dysbiosis can exacerbate microbial dysbiosis and inflammatory bowel Full Text Full Text PDF PubMed Scopus Google M. 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Escherichia coli in inflammatory bowel an on adherent invasive Escherichia coli PubMed Google et Escherichia coli in inflammatory bowel PubMed Scopus Google S. The of Escherichia 2023; Scholar we will review on identified bacterial and fungal pathobionts that potentially contribute to CD and UC of such as microbial dysbiosis or inflammation, these pathobionts can potentially their disease by new factors, or or disease severity. the origins of pathobionts, their mechanisms associated with disease potential as well as putative therapies, we the concept that several pathobionts could be an role in the and chronicity of IBD and their may of and The gut microbiota is the most of IBD have been within the microbiota of D. et of Escherichia coli in IBD: a of inflammatory activity in the PubMed Scopus Google D. et and prevalence of in the gut 2023; A. 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