Eubiotic gut microbiota mitigate colitis via colonic Treg expansion.

Aberrant gut microbiota has been linked to a disrupted immune response, leading to intestinal pathological conditions ^1,2 . However, the causality and mechanisms have remained unclear. Here we used a wild-type mouse substrain resistant to dextran sulfate sodium (DSS)-induced colitis to understand the characteristics of the eubiotic microbiota and the mechanisms underlying colitis resistance. Colitis-resistant mice presented a significantly greater colonic Foxp3 + regulatory T (Treg) population after DSS challenge, while numbers of helper T1 and 17 cells were comparable. Cohousing experiments revealed that Treg expansion was induced by the gut microbiota of colitis-resistant mice, and mice with eubiotic microbiota maintained high concentrations of three microbial metabolites, SCFAs (acetate, butyrate, and propionate). Furthermore, proteomics revealed that iron binding and iron-metabolizing ceruloplasmin silencing were upregulated relating disease-resistance. Of note, iron plays a pivotal role to SCFA-producing bacteria. Taken together, our results reveal that silencing ceruloplasmin expression restricts iron metabolism, thereby increasing SCFA production. The eubiotic gut microbiota and combinations of SCFAs contribute to Treg induction, which helps control colitis progression.