A special multifiber dietary mixture ameliorates Crohn's-like colitis in an IL-10-/- mouse model by promoting treg differentiation through the ETS1/RUNX1/Foxp3 axis.

BACKGROUND

Crohn's disease (CD) is a chronic inflammatory disorder characterized by immune dysregulation. Regulatory T cells (Tregs) play a pivotal role in maintaining mucosal tolerance, and their dysfunction directly contributes to CD pathogenesis.

METHODS

We used interleukin-10-/- mice to evaluate the therapeutic effects of a special multifiber mixture (MF) on colitis. T cell phenotypes, transcriptional profiles, gut microbiota composition, and N6-methyl adenosine (m6A) ribonucleic acid (RNA) methylation were analyzed using flow cytometry, RNA sequencing, metagenomics, and methylated RNA immunoprecipitation-quantitative polymerase chain reaction.

RESULTS

MF significantly reduced intestinal inflammation, restored epithelial barrier function, and promoted Treg differentiation while suppressing Th1/Th17 polarization. Integrated transcriptomic and proteomic analyses identified ETS1 as a negative regulator of Treg differentiation, modulated by gut microbiota-derived S-adenosylmethionine (SAM) through methyltransferase-like protein 3-mediated m6A methylation. MF feeding reduced SAM levels and m6A enrichment on ETS1 messenger RNA, leading to decreased ETS1 expression. Silencing of ETS1 enhanced Foxp3 expression and expanded the Treg population. RUNX1 was identified as a functional interactor of ETS1, with reciprocal expression patterns validated in both mouse models and colonic tissues from patients with CD.

CONCLUSION

MF alleviates colitis by reshaping the gut microbiota and suppressing SAM-dependent m6A methylation, resulting in ETS1 downregulation and the restoration of Treg homeostasis through the ETS1/RUNX1/Foxp3 axis. These findings reveal a mechanistic link between microbiota, epigenetics, and immunity, highlighting MF feeding as a promising nutritional intervention for CD treatment.