TL1A overexpression in Crohn’s Disease and mice alters Paneth cells and microbiota promoting ileal inflammation

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 ) and its receptor DR3 ( TNFRSF25 ) have been associated with IBD. TL1A expression is increased in IBD patients, particularly in TL1A risk allele carriers. However, effects of TL1A on Paneth cells, resident microbiota, and development of ileitis remain unknown. TL1A overexpression in mice induces Paneth cell hyperplasia and morphological abnormalities preceding the development of ileitis. In Crohn’s disease (CD) patients, ileal TL1A expression was associated with abnormal Paneth cell phenotypes. We confirmed direct effects of TL1A on Paneth cells in human iPSC-derived human intestinal organoids and mouse Paneth cell-enriched organoids. Resident microbiota was required for TL1A-mediated Paneth cell dysfunction, and ileitis. Tl1a-tg mice were enriched in short chain fatty acid-producing bacteria and the metabolite acetate. Acetate supplementation in WT or Tl1a-tg mice caused ileal inflammation, suggesting that acetate is sufficient to cause ileitis. DR3-deficiency in Paneth cells resulted in Paneth cell abnormalities and microbiome composition changes. Our findings provide a mechanistic link between overexpression of TL1A in CD patients, Paneth cell dysfunction, and enrichment of acetate-producing bacteria and acetate that promotes ileal inflammation.