Alteri, C. J. | bioRxiv Science

bioRxiv2025

Immune phenotype-guided identification of disease-associated pathobionts in Crohn's disease

Aberrant immune activation within the gut mucosa and gut dysbiosis have been implicated in the pathogenesis of Crohns disease (CD). However, the specific immune responses triggered by dysbiotic microbiota, as well as the bacteria responsible for this activation, remain incompletely understood. Here, using the human microbiota-associated (HMA) mouse system, we demonstrated that colonization with dysbiotic gut microbiota from CD patients specifically induces the accumulation of mononuclear phagocytes, which may drive an interleukin-1 (IL-1)-driven inflammatory signature. Moreover, we identified pathobiont strains with a potent IL-1{beta}-inducing capacity, termed IL-1{beta}-inducing pathobionts (IBIP). Isolated IBIP strains exhibit genetic and functional similarities to adherent-invasive Escherichia coli but harbor unique virulence-associated genes. Colonization with the IBIP E. coli strain exacerbated experimental colitis in an IL-1 signal-dependent manner. Notably, the colonization of IBIP E. coli can be detected by measuring the levels of specific immunoglobulin A (IgA) in their stool samples. Moreover, the level of IBIP-reactive IgA in stool may serve as a predictive biomarker for treatment response to anti-TNF therapies in treatment-naive pediatric CD patients. Altogether, IBIP colonization could help identify CD patients with inflammatory dysbiosis who are likely to be refractory to anti-TNF therapies.

immunology↗

bioRxiv2022

Site-specific adaptation mechanisms of an oral pathobiont in the oral and gut mucosae

Periodontal inflammation leads to oral dysbiosis with the expansion of oral pathobionts. Besides the pathogenic role of oral pathobionts during periodontal inflammation, studies have revealed that oral pathobionts contribute to diseases in distant organs beyond the oral mucosa. For example, the oral pathobiont Klebsiella aerogenes, which accumulates in the oral mucosa during periodontitis in mice, can exacerbate colitis when it ectopically colonizes the gastrointestinal tract. However, the precise mechanisms by which oral pathobionts establish their colonization in extra-oral mucosal sites remains incompletely understood. We performed high-throughput in vivo genetic screening to identify fitness genes required for the adaptation of the oral pathobiont K. aerogenes to different mucosal sites - the oral and gut mucosae - at the steady state and during inflammation. In addition, the global transcriptome of K. aerogenes in different environments was analyzed. We determined that K. aerogenes employs genes related to iron acquisition and chaperone usher pili, which are encoded on a newly identified genomic locus named "locus of colonization in the inflamed gut" (LIG), for adaptation in the gut mucosa, particularly during inflammation. In contrast, the LIG virulence factors are not required for K. aerogenes to adapt to the oral mucosa. Thus, oral pathobionts likely exploit distinct adaptation mechanisms in their ectopically colonized intestinal niche compared to their original niche. Author SummaryThe symbiotic bacterial community evolves uniquely at each body site. However, under certain circumstances, symbionts may disseminate far from their original niche and colonize a site ectopically. It has been reported that oral resident bacteria associated with periodontal disease, namely oral pathobionts, contribute to gastrointestinal diseases, such as inflammatory bowel disease and colorectal cancer, through ectopic colonization of the gut. However, the molecular mechanisms by which oral pathobionts adapt to the gut environment remain largely unexplored. In this study, using a model oral pathobiont Klebsiella aerogenes, we screened genes essential for the colonization of the pathobiont at different mucosal sites. We discovered that the oral pathobiont uses distinct virulence mechanisms at two different mucosal sites - the oral and gut mucosae. Understanding the strategies of bacteria localized in ectopic organs may lead to the development of strategies to prevent disease caused by the dissemination of pathogenic oral bacteria.

microbiology↗