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

BACKGROUND & AIMS: The gut microbiome is implicated in Crohn's disease (CD) development. However, human microbiome studies need experimental evidence to demonstrate whether specific microbial differences promote CD pathogenesis. This study was conducted to determine whether the gut microbiome from individuals who later developed CD promotes colitis in germ-free recipient mice.

METHODS

Germ-free mice were colonized with fecal samples from 12 pairs of discordant siblings, where one sibling later developed CD (pre-CD), and the other remained a healthy matched control (HMC). After colonization, colitis was induced by T-cell transfer to assess the effect of stool on multiple measures of colitis severity. Comparative analysis with human donor metadata explored transferred pathogenic traits.

RESULTS

Mice receiving pre-CD stool exhibited increased weight loss, fecal lipocalin-2, and intestinal histologic damage compared with mice receiving HMC stool. Fecal metabolomic analysis revealed differences in 40 metabolites between pre-CD and HMC colonized mice. Furthermore, 2 metabolic pathways were shared between pre-CD participants and mice. Notably, sphingolipids showed a positive correlation between humans and mice and associated with increased colitis in mice.

CONCLUSIONS

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.