Within-host evolution of a gut pathobiont facilitates liver translocation

Yi Yang, Mytien Nguyen, Varnica Khetrapal, Nicole D. Sonnert, Anjelica L. Martin, Haiwei Chen, Martin A. Kriegel and Noah W. Palm ()
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Yi Yang: Yale University School of Medicine
Mytien Nguyen: Yale University School of Medicine
Varnica Khetrapal: Yale University School of Medicine
Nicole D. Sonnert: Yale University School of Medicine
Anjelica L. Martin: Yale University School of Medicine
Haiwei Chen: Yale University School of Medicine
Martin A. Kriegel: Yale University School of Medicine
Noah W. Palm: Yale University School of Medicine

Nature, 2022, vol. 607, issue 7919, 563-570

Abstract: Abstract 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 of the 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.

Date: 2022
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DOI: 10.1038/s41586-022-04949-x

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