UCSF

The gastrointestinal tract relies on the production, maturation, and transit of mucin to protect against pathogens and to lubricate the epithelial lining. However, the molecular and cellular mechanisms that regulate mucin production and movement are unclear. Here, we report that the inflammatory cytokine tumor necrosis factor (TNF), which is generated by the epithelium, contributes to mucin homeostasis by regulating both cell differentiation and cystic fibrosis transmembrane conductance regulator (CFTR) activity. Using genetic mouse models, we found that loss of epithelial TNF promoted differentiation of secretory progenitor cells into mucus-producing goblet cells. Furthermore, co-treatment of intestinal organoids with recombinant TNF and a CFTR inhibitor demonstrated that TNF promotes ion transport and luminal flow via CFTR. The absence of TNF led to slower gut transit times, which we propose results from increased mucus accumulation coupled with decreased luminal fluid pumping. These findings point to a TNF-CFTR signaling axis in the adult intestine and identify epithelial-derived TNF as an upstream regulator of mucin homeostasis.