Within-host evolution of a gut pathobiont facilitates liver translocation

• Published in: Nature (London) Vol. 607; no. 7919; pp. 563 - 570
• Main Authors: Yang, Yi, Nguyen, Mytien, Khetrapal, Varnica, Sonnert, Nicole D., Martin, Anjelica L., Chen, Haiwei, Kriegel, Martin A., Palm, Noah W.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 21.07.2022; Nature Publishing Group
• Subjects: 13/31; 14/28; 14/32; 38/91; 45/23; 45/41; 631/181/2475; 631/250/256/2515; 631/250/38; 631/326/2565/2134; 631/326/41/2529; 64/60; Adaptation; Bacteria; Bacteria - genetics; Bacteria - immunology; Bacteria - pathogenicity; Bacterial Translocation - genetics; Biological Evolution; Cell Wall - genetics; Cell walls; Digestive system; Divergence; Enterococcus - genetics; Enterococcus - immunology; Enzymes; Evolution; Evolution & development; Gastrointestinal Microbiome - genetics; Gastrointestinal tract; Gene expression; Genomes; Genomics; Host-Pathogen Interactions - immunology; Humanities and Social Sciences; Humans; Immune clearance; Immune system; Inflammation - microbiology; Inflammation - pathology; Inflammatory diseases; Intestinal microflora; Intestinal Mucosa - microbiology; Intestinal Mucosa - pathology; Intestine; Kinases; Lactose; Limosilactobacillus reuteri - genetics; Limosilactobacillus reuteri - immunology; Liver; Liver - microbiology; Liver - pathology; Lymph nodes; Lymph Nodes - microbiology; Lymphatic system; Microbiota; Microorganisms; Mucosa; multidisciplinary; Mutation; Pathogenicity; Pathogens; Science; Science (multidisciplinary); Stochastic Processes; Stochasticity; Strains (organisms); Symbiosis - genetics; Symbiosis - immunology; Translocation
• ISSN: 0028-0836; 1476-4687; 1476-4687
• DOI: 10.1038/s41586-022-04949-x

Gut commensal bacteria with the ability to translocate across the intestinal barrier can drive the development of diverse immune-mediated diseases 1 – 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 host 5 – 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. Within-host evolution is a critical regulator of commensal pathogenicity that provides a unique source of stochasticity in the development and progression of microbiota-driven disease.