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

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: from fiction to function.Am J Physiol - Gastrointest Liver Physiol. 2019; 317: G602-G608Crossref PubMed Scopus (0) Google Scholar Although these characteristics are often found in the microbiota of patients with IBD, the bidirectional nature of intestinal inflammation and concurrent microbial dysbiosis has only recently been investigated. Historically, many studies have recruited patients for cohort analysis and identified alterations in their gut microbiome relative to healthy controls, displaying reduced microbial diversity and increased temporal and compositional variability.11Matsuoka K. Kanai T. The gut microbiota and inflammatory bowel disease.Semin Immunopathol. 2015; 37: 47-55Crossref PubMed Scopus (532) Google Scholar, 12Kostic A.D. Xavier R.J. Gevers D. 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Most of these studies identified significant differences in microbial taxa between inflamed and noninflamed sites (eg, increased Enterobacteriaceae and Bacteroides or decreased Firmicutes), however, the specific taxa identified varied between studies and between patients within the same study.13Ryan F.J. Ahern A.M. Fitzgerald R.S. et al.Colonic microbiota is associated with inflammation and host epigenomic alterations in inflammatory bowel disease.Nat Commun. 2020; 11: 1-12Crossref PubMed Scopus (147) Google Scholar,15Hirano A. Umeno J. Okamoto Y. et al.Comparison of the microbial community structure between inflamed and non-inflamed sites in patients with ulcerative colitis.J Gastroenterol Hepatol. 2018; 33: 1590-1597Crossref Scopus (77) Google Scholar, 16Moen A.E.F. Lindstrøm J.C. Tannæs T.M. et al.The prevalence and transcriptional activity of the mucosal microbiota of ulcerative colitis patients.Sci Rep. 2018; 8: 1-12Google Scholar, 17Walker A.W. Sanderson J.D. Churcher C. et al.High-throughput clone library analysis of the mucosa-associated microbiota reveals dysbiosis and differences between inflamed and non-inflamed regions of the intestine in inflammatory bowel disease.BMC Microbiol. 2011; 11: 1-12Crossref PubMed Scopus (561) Google Scholar The limitations of these past IBD microbiome studies include relatively shallow sequencing depth that rarely surpasses the genus level, as well as small cohort sizes, notwithstanding the inherent complexity associated with studying the microbiota,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 including consideration of composition, functionality, microbial member interactions, and host factors. Despite these limitations, these noted findings indicate that microbiota composition differences are patient specific, with no single bacterial suspect identified for CD or UC, supporting the notion that diverse microbiota members can promote disease progression. Although it is evident that inflammation and microbial dysbiosis co-occur in patients with IBD, whether microbial dysbiosis plays a causal role in IBD or is merely a byproduct of inflammation has been difficult to investigate. Prospective cohort studies are notoriously challenging to conduct. However, a recent study used samples from currently healthy first-degree relatives of patients with CD collected by the Crohn's and Colitis Canada's Genetic Environmental Microbial project to identify key microbial taxa associated with the future development of CD.18Raygoza Garay J.A. Turpin W. Lee S.-H. et al.Gut microbiome composition is associated with future onset of Crohn's Disease in healthy first-degree relatives.Gastroenterology. 2023; 165: 670-681Abstract Full Text Full Text PDF PubMed Scopus (12) Google Scholar Using machine learning, a Microbiome Risk Score was generated for 70 patients who developed CD (of 3483 total participants), which identified Ruminococcus torques and Blautia (both mucin-degraders), Colidextribacter, Oscillospiraceae, and Roseburia as predictors of CD onset.18Raygoza Garay J.A. Turpin W. Lee S.-H. et al.Gut microbiome composition is associated with future onset of Crohn's Disease in healthy first-degree relatives.Gastroenterology. 2023; 165: 670-681Abstract Full Text Full Text PDF PubMed Scopus (12) Google Scholar In addition, functional microbiota changes, including increased bacterial proteolytic activity, were previously identified in healthy individuals who later developed UC.19Galipeau H.J. Caminero A. Turpin W. et al.Novel fecal biomarkers that precede clinical diagnosis of ulcerative colitis.Gastroenterology. 2021; 160: 1532-1545Abstract Full Text Full Text PDF PubMed Scopus (86) Google Scholar These pioneering studies provide a stepping stone for future longitudinal studies to trace microbiota changes before disease onset in at-risk groups and throughout the natural progression of disease. Such information could help define key transition stages and microbiota members that may contribute to IBD development. Many animal studies have demonstrated that intestinal inflammation can drive dysbiosis, and that gut microbial dysbiosis can also exacerbate inflammation.20Singh V.P. Proctor S.D. Willing B.P. Koch's postulates, microbial dysbiosis and inflammatory bowel disease.Clin Microbiol Infect. 2016; 22: 594-599Abstract Full Text Full Text PDF PubMed Scopus (33) Google Scholar, 21Glymenaki M. Singh G. 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Even so, microbial dysbiosis likely reflects an array of intertwined bacterial-host interactions, which likely differs between patients, based on their disease status, and their baseline microbiota. One popular hypothesis suggests that IBD progression, including dysbiosis and inflammation, is facilitated by the concomitant loss of beneficial commensals24Cococcioni L. Panelli S. Varotto-boccazzi I. et al.IBDs and the pediatric age: their peculiarities and the involvement of the microbiota.Dig Liver Dis. 2021; 53: 17-25Scopus (7) Google Scholar and their metabolites, including the short-chain fatty acid butyrate.25Byndloss M.X. Olsan E.E. Rivera-Chávez F. et al.Microbiota-activated PPAR-g signaling inhibits dysbiotic Enterobacteriaceae expansion.Science. 2017; 575: 570-575Google Scholar Reduced butyrate levels shift colonocyte metabolism from oxidative phosphorylation to glycolysis, elevating luminal oxygen levels and accelerating the loss of strict anaerobes.25Byndloss M.X. Olsan E.E. Rivera-Chávez F. et al.Microbiota-activated PPAR-g signaling inhibits dysbiotic Enterobacteriaceae expansion.Science. 2017; 575: 570-575Google Scholar Correspondingly, we know that facultative anaerobic commensals, including Escherichia coli, can survive this oxygen-rich environment, assume vacated niches, acquire nutrients, and expand in numbers.25Byndloss M.X. Olsan E.E. Rivera-Chávez F. et al.Microbiota-activated PPAR-g signaling inhibits dysbiotic Enterobacteriaceae expansion.Science. 2017; 575: 570-575Google Scholar,26Baldelli V. Scaldaferri F. Putignani L. et al.The role of enterobacteriaceae in gut microbiota dysbiosis in inflammatory bowel diseases.Microorganisms. 2021; 9: 1-15Google Scholar Along with commensal E coli, there are other microbes, many possessing pathogenic qualities, that expand within or potentially contribute to the inflammation seen in the intestines of patients with IBD. These microbes are known as "pathobionts" and are hypothesized to play a role in either the initiation, or the aggravation of IBD.27Chow J. Tang H. Mazmanian S.K. Pathobionts of the gastrointestinal microbiota and inflammatory disease.Curr Opin Immunol. 2011; 23: 473-480Crossref PubMed Scopus (309) Google Scholar The term "pathobiont" was first introduced in 2008 in a study on Helicobacter hepaticus, where it was defined as a gut commensal bacterium with pathogenic potential.28Mazmanian S.K. Round J.L. Kasper D.L. A microbial symbiosis factor prevents intestinal inflammatory disease.Nature. 2008; 453: 620-625Crossref PubMed Scopus (1814) Google Scholar To expand this initial definition and describe the mechanisms by which diverse pathobionts function,29Stecher B. Maier L. Hardt W.D. "Blooming" in the gut: how dysbiosis might contribute to pathogen evolution.Nat Rev Microbiol. 2013; 11: 277-284Crossref PubMed Scopus (262) Google Scholar, 30Ha C.W.Y. Martin A. 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Barnich N. et al.Presence of adherent Escherichia coli strains in ileal mucosa of patients with Crohn's disease.Gastroenterology. 1998; 115: 1405-1413Abstract Full Text Full Text PDF PubMed Scopus (687) Google Scholar from the inflamed ileal mucosa of patients with CD, these bacteria are genetically diverse and characterized based on their functions (such as invasion) rather than genetic markers, meaning they express a varied array of toxins and other virulence factors. The AIEC strain LF82 uses its adhesin FimH to adhere to intestinal epithelial cells (IEC) expressing the carcinoembryonic antigen-related cell adhesion molecule 6 receptor.34Dreux N. Denizot J. Martinez-Medina M. et al.Point mutations in FimH adhesin of Crohn's disease-associated adherent-invasive Escherichia coli enhance intestinal inflammatory response.PLoS Pathog. 2013; 9: e1003141Crossref PubMed Scopus (123) Google Scholar,35Barnich N. Carvalho F.A. 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Barnich N. et al.Adherent invasive Escherichia coli strains from patients with Crohn's disease survive and replicate within macrophages without inducing host cell death.Infect Immun. 2001; 69: 5529-5537Crossref PubMed Scopus (346) Google Scholar Recently AIEC invasion, relative to other E coli strains, was found to correlate with levels of inflammation and colitis potentiation in mice, suggesting AIEC strains may indeed play a causal role in gut inflammation.37Kittana H. Gomes-neto J.C. Heck K. et al.Evidence for a causal role for Escherichia coli strains identified as adherent-invasive (AIEC) in intestinal inflammation.mSphere. 2023; 8 (e00478-22)Google Scholar Recent success in blocking AIEC's FimH adhesin suggests that identifying and targeting pathobionts may prove effective in treating IBD symptoms in the future.38Chevalier G. Laveissière A. Desachy G. et al.Blockage of bacterial FimH prevents mucosal inflammation associated with Crohn's disease.Microbiome. 2021; 9: 1-16Google Scholar Although studying AIEC has been instrumental to advancing our current understanding of IBD pathobionts, these microbes have already been well described in previous review articles.39Darfeuille-Michaud A. Adherent-invasive Escherichia coli: s putative new E. coli pathotype associated with Crohn's disease.Int J Med Microbiol. 2002; 292: 185-193Crossref PubMed Scopus (123) Google Scholar, 40Rolhion N. Darfeuille-Michaud A. Adherent-invasive Escherichia coli in inflammatory bowel disease.Inflamm Bowel Dis. 2007; 13: 1277-1283Crossref PubMed Scopus (210) Google Scholar, 41Martinez-Medina M. Garcia-Gil L.J. Escherichia coli in chronic inflammatory bowel diseases: an update on adherent invasive Escherichia coli pathogenicity.World J Gastrointest Pathophysiol. 2014; 5: 213Crossref PubMed Google Scholar, 42Palmela C. Chevarin C. 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By addressing the origins of pathobionts, their mechanisms associated with disease pathologies, potential pathobiont interactions, as well as putative therapies, we underscore the concept that several pathobionts could be playing an active role in the development, severity, and chronicity of IBD and their actions may underlie cases of failed treatment response and frequent relapse. The human gut microbiota is the most prominent source of IBD pathobionts. They have been found within the microbiota of healthy individuals44Bücker R. Schulz E. Günzel D. et al.α-Haemolysin of Escherichia coli in IBD: a potentiator of inflammatory activity in the colon.Gut. 2014; 63: 1893-1901Crossref PubMed Scopus (52) Google Scholar, 45Bhattacharjee D. Flores C. Woelfel-Monsivais C. et al.Diversity and prevalence of Clostridium innocuum in the human gut microbiota.mSphere. 2023; 8: 1-16Google Scholar, 46Nadalian B. Yadegar A. Houri H. et al.Prevalence of the pathobiont adherent-invasive Escherichia coli and inflammatory bowel disease: a systematic review and meta-analysis.J Gastroenterol Hepatol. 2021; 36: 852-863Crossref PubMed Scopus (35) Google Scholar where they reside without causing detectable disease, suggesting the gut environment plays the largest role in determining the pathogenic potential of pathobionts. When the gut environment becomes perturbed,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 the disrupted balance between commensals and the environment can support the expansion of pathobionts, production of harmful metabolic byproducts, or expression of virulence factors. Inflammation is likely a prominent source of the environmental perturbation that underlies pathobiont emergence and expansion, similar to its role in the development of E coli blooms.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,26Baldelli V. Scaldaferri F. Putignani L. et al.The role of enterobacteriaceae in gut microbiota dysbiosis in inflammatory bowel diseases.Microorganisms. 2021; 9: 1-15Google Scholar However, in cases where microbial dysbiosis precedes inflammation during IBD onset,18Raygoza Garay J.A. Turpin W. Lee S.-H. et al.Gut microbiome composition is associated with future onset of Crohn's Disease in healthy first-degree relatives.Gastroenterology. 2023; 165: 670-681Abstract Full Text Full Text PDF PubMed Scopus (12) Google Scholar the actions or expansion of pathobionts could be hypothesized to underlie the proinflammatory effects of microbial dysbiosis, however, this requires investigation. With the gut microbiota being arguably the most important environmental factor contributing to IBD, it must be noted that gut microbes are also heritable,47Turpin W. Goethel A. Bedrani L. et al.Determinants of IBD heritability: genes, bugs, and more.Inflamm Bowel Dis. 2018; 24: 1133-1148Crossref PubMed Scopus (103) Google Scholar either based on genetic factors48Turpin W. Espin-Garcia O. Xu W. et al.Association of host genome with intestinal microbial composition in a large healthy cohort.Nat Genet. 2016; 48: 1413-1417Crossref PubMed Scopus (311) Google Scholar or through vertical transmission.49Torres J. Hu J. Seki A. et al.Infants born to mothers with IBD present with altered gut microbiome that transfers abnormalities of the adaptive immune system to germ-free mice.Gut. 2020; 69: 42-51Crossref PubMed Scopus (111) Google Scholar,50Kim E.S. Tarassishin L. Eisele C. et al.Longitudinal changes in fecal calprotectin levels among pregnant women with and without inflammatory bowel disease and their babies.Gastroenterology. 2021; 160: 1118-1130.e3Abstract Full Text Full Text PDF PubMed Scopus (38) Google Scholar The infant microbiome is known to be strongly influenced by the maternal microbiome49Torres J. Hu J. Seki A. et al.Infants born to mothers with IBD present with altered gut microbiome that transfers abnormalities of the adaptive immune system to germ-free mice.Gut. 2020; 69: 42-51Crossref PubMed Scopus (111) Google Scholar,51Wang S. Ryan C.A. Boyaval P. et al.Maternal vertical transmission affecting early-life microbiota development.Trends Microbiol. 2020; 28: 28-45Abstract Full Text Full Text PDF PubMed Scopus (97) Google Scholar and with children being diagnosed with IBD at younger ages, while suffering more severe symptoms than ever before,24Cococcioni L. Panelli S. Varotto-boccazzi I. et al.IBDs and the pediatric age: their peculiarities and the involvement of the microbiota.Dig Liver Dis. 2021; 53: 17-25Scopus (7) Google Scholar,52Day A.S. Lemberg D.A. Identification and diagnosis of Crohn disease and ulcerative colitisin children.J Paediatr Child Health. 2020; 56: 1731-1734Google Scholar this may reflect the acquisition of pathobionts via familial or peri-natal transmission of the microbiota. A 2019 study found mothers with IBD had lower bacterial diversity and altered composition, which was also detected in their infant's stool.49Torres J. Hu J. Seki A. et al.Infants born to mothers with IBD present with altered gut microbiome that transfers abnormalities of the adaptive immune system to germ-free mice.Gut. 2020; 69: 42-51Crossref PubMed Scopus (111) Google Scholar When assessing functional consequences, the microbiota sourced from mothers with IBD, and their infant's stool, caused an imbalance within the adaptive immune systems in recipient germ-free mice. Cells in their colonic lamina propria showed a reduction in class-switched memory B cells, immunoglobulin (Ig) A+ B cells, and regulatory T cells (mother's stool only).49Torres J. Hu J. Seki A. et al.Infants born to mothers with IBD present with altered gut microbiome that transfers abnormalities of the adaptive immune system to germ-free mice.Gut. 2020; 69: 42-51Crossref PubMed Scopus (111) Google Scholar Also in support of vertical transmission, fecal calprotectin levels were found to be elevated in infants born to mothers with IBD, suggesting low levels of inflammation are experienced in early life in correlation with altered microbiome composition.50Kim E.S. Tarassishin L. Eisele C. et al.Longitudinal changes in fecal calprotectin levels among pregnant women with and without inflammatory bowel disease and their babies.Gastroenterology. 2021; 160: 1118-1130.e3Abstract Full Text Full Text PDF PubMed Scopus (38) Google Scholar Extending these concepts to IBD pathobiont transmission, a mouse study showed vertical transmission of AIEC from dam to neonate resulted in increased colitis susceptibility as compared with adult mice colonized with AIEC.53Brand M.W. Proctor A.L. Hostetter J.M. et al.Vertical transmission of attaching and invasive E . coli from the dam to neonatal mice predisposes to more severe colitis following exposure to a colitic insult later in life.PLoS One. 2022; 17e0266005Google Scholar Currently, an ongoing clinical trial is investigating bacterial transmission in utero between mother and newborn to determine subsequent IBD risk (ClinicalTrials.gov Identifier: NCT03116568). Although we know that microbes, and potentially pathobionts, are heritable, large, carefully controlled studies in humans are required to determine if pathobionts are acquired by vertical transmission in infants, potentially promoting the development of IBD. Parental transfer of disease is a challenging concept for families; therefore, discussions should be approached with caution until validated interventions are available. Another source of pathobionts is the oral microbiome, which is increasingly recognized as a contributor to IBD pathogenesis, particularly in pediatric patients.54Schirmer M. Denson L. Vlamakis H. et al.Compositional and temporal changes in the gut microbiome of pediatric ulcerative colitis patients are linked to disease course.Cell Host Microbe. 2018; 2