TL1A overexpression in Crohn’s Disease patients and mice alters Paneth cell biology and intestinal microbiota in promoting ileal inflammation

Small intestinal Paneth cells regulate host-microbial homeostasis and defects in autophagy and host defense pathways have been associated with inflammatory bowel diseases (IBD). Genetic variants in TL1A (TNFSF15) have been associated with susceptibility to and severity of IBD. TL1A expression is increased in IBD patients, particularly in TL1A risk allele carriers. However, the effects of TL1A on the function of ileal Paneth cells and downstream effect on commensal microbiota and development of ileitis has not been investigated. Here, we demonstrate that TL1A overexpression in mice (Tl1a-tg) induces Paneth cell hyperplasia and morphological abnormalities that precedes the development of spontaneous ileitis. In Crohn’s disease (CD) patients, ileal TL1A expression was associated with abnormal Paneth cell phenotypes. Deficiency of the TL1A receptor DR3 in Paneth cells resulted in Paneth cell abnormalities suggesting a direct effect of TL1A on Paneth cells which we confirmed in human CD patient-derived Paneth cell enriched organoid cultures. Commensal microbiota were required for TL1A-mediated Paneth cell dysfunction, and development of spontaneous ileitis. Overexpression of TL1A results in dysbiosis with an enrichment in short chain fatty acid-producing bacteria Bifidobacterium and Allobaculum and metabolomic analysis revealed an increase of the metabolite acetate. Acetate supplementation in germ-free or SPF housed mice caused ileal inflammation and elevated IFN-g secretion, suggesting that acetate is sufficient to cause ileitis. Our findings provide a mechanistic link between overexpression of TL1A in CD patients with TNFSF15 risk variants, Paneth cell dysfunction, intestinal dysbiosis and enrichment of acetate-producing bacteria that promote ileal inflammation.