Pre-Crohn's Disease Stool from Discordant Siblings Promotes the Development of Colitis in Germ-Free Mice.

Abstract

The gut microbiome is implicated in Crohn's disease (CD) development. However, human microbiome studies need experimental evidence to demonstrate if specific microbial differences promote CD pathogenesis. This study aims to determine if the gut microbiome from individuals who later developed CD promotes colitis in germ-free recipient mice. Germ-free mice were colonized with fecal samples from 12 pairs of discordant siblings: where one sibling later developed CD (pre-CD), while the other remained a healthy matched control (HMC). After colonization, colitis was induced by T-cell transfer to assess effect of stool on multiple measures of colitis severity. Comparative analysis with human donor metadata explored transferred pathogenic traits. Mice receiving pre-CD stool exhibited increased weight loss, fecal lipocalin-2, and intestinal histological damage compared to mice receiving HMC stool. Fecal metabolomic analysis revealed differences in 40 metabolites between pre-CD and HMC colonized mice. Furthermore, two metabolic pathways were shared between pre-CD participants and mice. Notably, sphingolipids showed a positive correlation between humans and mice, associated with increased colitis in mice. This study functionally demonstrates that the stool microbiome of individuals susceptible to CD is altered years before diagnosis, exhibiting greater inflammatory potential when transferred to susceptible mice.