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Received: 26 September 2021
Accepted: 8 June 2022
Published online: 13 July 2022
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Gut commensal bacteria with the ability to translocate across the intestinal barrier can drive the development of diverse immune-mediated diseases1-4. However, the key factors that dictate bacterial translocation remain unclear. Recent studies have revealed that gut microbiota strains can adapt and evolve throughout the lifetime of the host5-9, raising the possibility that changes in individual commensal bacteria themselves over time may affect their propensity to elicit inflammatory disease. Here we show that within-host evolution ofthe model gut pathobiont Enterococcus gallinarum facilitates bacterial translocation and initiation of inflammation. Using a combination of in vivo experimental evolution and comparative genomics, we found that E.gallinarum diverges into independent lineages adapted to colonize either luminal or mucosal niches in the gut. Compared with ancestral and luminal E. gallinarum, mucosally adapted strains evade detection and clearance by the immune system, exhibit increased translocation to and survival within the mesenteric lymph nodes and liver, and induce increased intestinal and hepatic inflammation. Mechanistically, these changes in bacterial behaviour are associated with non-synonymous mutations or insertion-deletions in defined regulatory genes in E. gallinarum, altered microbial gene expression programs and remodelled cell wall structures. Lactobacillus reuteri also exhibited broadly similar patterns of divergent evolution and enhanced immune evasion in a monocolonization-based model of within-host evolution. Overall, these studies define within-host evolution as a critical regulator of commensal pathogenicity that provides a unique source of stochasticity in the development and progression of microbiota-driven disease.
Gut commensals with pathogenic potential, referred to as pathobionts3, are believed to have causal roles in a diverse array of inflammationassociated diseases4, ranging from inflammatory bowel disease to metabolic syndrome. However, putative disease-driving pathobionts are also detected in ostensibly healthy humans10 and pathobiont colonization often precedes overt disease development by years to decades. Genetic and environmental factors clearly contribute to this stochasticity3,4, as host genetic predisposition, microbiome composition and environmental exposures can all affect disease susceptibility. However, the full concert of factors that contribute to stochasticity in pathobiont-driven inflammatory disease remains to be defined.
Although commensal strains are often conceptualized as static functional units that collectively comprise dynamic host-associated microbial communities, it is now clear that discrete microbial strains can adapt and evolve...