Human Intestinal AIEC Strains Alter the Mucosal Microbiome and Establish a Niche for AIEC and Non‐AIEC Strains in Il10−/− Mice

Abstract

Inflammatory bowel disease (IBD) affects over one million people in the United States and costs billions of dollars in direct medical expenses annually. This chronic inflammatory condition, which includes Crohn’s disease, currently has no medical cure. Additionally, patients with IBD are at a greater risk of developing inflammation‐associated colorectal cancer (I‐CRC). IBD and I‐CRC are associated with an increase of mucosally‐adhered bacteria, particularly Adherent‐Invasive Escherichia coli (AIEC). This proximity to the host can promote host‐directed pro‐inflammatory and pro‐carcinogenic activities by AIEC and co‐colonizing microbes. The overall aim of the project is to assess how colonization with Crohn’s‐associated clinicalE. coli strains alters the mucosal microbial community in the inflamed and non‐inflamed intestine.To this end, we have developed a polymicrobial colonization strategy that uses a novel barcoding technology to easily distinguish genetically similar, but functionally distinct sub‐strains of E. coli in a complex community. We have developed this strategy using a collection of well‐characterized clinical AIEC and non‐AIEC strains isolated from the intestinal mucosa of IBD and healthy patients. These strains are administered to formerly germ‐free mice (either inflammation susceptible Il10−/− or resistant WT) also with a murine fecal microbial transplant (FMT) to simulate physiologically‐relevant conditions. Our in vivo modeling has revealed that colonization with a pool of clinical isolates in the presence of the FMT enhances inflammation and promotes higher levels of E. coli colonizing the mucosa in inflammation‐susceptible mice. Importantly, colonization with these strains very significantly alters the composition of the mucosal microbiome, assessed by 16S rRNA sequencing, in inflamed but not uninflamed mice, including expansion of a co‐occuring pro‐inflammatory taxon and contraction of multiple protective species. These data suggest that colonization of the chronically inflamed with high levels of E. coli influence host health through both host‐microbe and microbe‐microbe interactions.Support or Funding InformationSupported by K01 award to JCA and the SPIRE NIH IRACDA program.