Evolution ofE. coliin a mouse model of inflammatory bowel disease leads to a disease-specific bacterial genotype and trade-offs with clinical relevance

Abstract

Objective: Inflammatory bowel disease (IBD) is a persistent inflammatory condition affecting the gastrointestinal tract, presenting significant challenges in its management and treatment. Despite the knowledge that within-host bacterial evolution occurs in the intestine, the disease has so far rarely been studied from an evolutionary perspective. In this study, we aimed to investigate resident bacterial evolution during intestinal inflammation, and whether- and how disease-related bacterial genetic changes may present trade-offs with potential therapeutic importance. Design: Here, we perform an in vivo evolution experiment of E. coli in a gnotobiotic mouse model of IBD, followed by multiomic analyses to identify disease-specific genetic and phenotypic changes in bacteria evolved in an inflamed versus non-inflamed control environment. Results: Our results demonstrate distinct evolutionary changes in E. coli specific to inflammation, including a single nucleotide variant that independently reached high frequency in all inflamed mice. Using ex vivo fitness assays, we find that these changes are associated with a higher fitness in an inflamed environment compared to isolates derived from non-inflamed mice. Further, using large-scale phenotypic assays, we show that bacterial adaptation to inflammation results in clinically relevant phenotypes, which intriguingly include collateral sensitivity towards antibiotics. Conclusions: Bacterial evolution in an inflamed gut yields specific genetic and phenotypic signatures. These results may serve as a basis for developing novel, evolution-informed treatment approaches for patients with intestinal inflammation.