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

Area of Science:

• Gastroenterology
• Microbiome Research
• Immunology

Background:

• The gut microbiome is linked to Crohn's disease (CD) pathogenesis.
• Experimental evidence is needed to confirm if specific microbial alterations drive CD development.

Purpose of the Study:

• To determine if the gut microbiome from individuals who later developed CD promotes colitis in germ-free mice.
• To investigate the functional impact of the pre-CD microbiome on gut inflammation.

Main Methods:

• Germ-free mice were colonized with fecal samples from siblings discordant for CD (pre-CD vs. healthy matched control).
• Colitis was induced via T-cell transfer post-colonization.
• Comparative analysis of mouse colitis severity and human donor metadata was performed.

Main Results:

• Mice receiving pre-CD stool showed increased weight loss, fecal lipocalin-2, and intestinal damage.
• Metabolomic analysis revealed distinct metabolite profiles and shared metabolic pathways (including sphingolipids) between pre-CD humans and mice.
• Sphingolipid alterations correlated with increased colitis severity in mice.

Conclusions:

• The gut microbiome of individuals susceptible to CD is functionally altered years before diagnosis.
• This altered microbiome possesses greater inflammatory potential, contributing to colitis development when transferred to susceptible hosts.