Paneth cell TNF receptor 1 controls zinc deficiency-induced diarrhea

Introduction Zinc deficiency impairs intestinal homeostasis and alters the gut microbiota composition, ultimately leading to diarrhea. Paneth cells (PCs) are key regulators of intestinal microbial homeostasis by producing antimicrobial peptides, but their role in zinc deficiency-induced diarrhea remains poorly understood. In addition, TNF signaling can regulate PC biology and intestinal barrier function, however, its role during zinc deficiency has not been investigated. This study examined how chronic dietary zinc deficiency affects PCs and the intestinal microbiota, and whether TNF receptor 1 signaling in PCs influences the zinc deficiency-associated intestinal pathology. Methods We established a mouse model based on a zinc-deficient diet (ZDD) and compared it with a standard diet (StD) over 8 weeks. We assessed fecal consistency, PC morphology, the PC transcriptome via bulk RNA sequencing, and ileal microbiome composition via 16S rRNA sequencing. Mice were challenged with peritoneal sepsis or TNF-induced systemic inflammatory response syndrome (SIRS). To study the role of the TNF receptor P55 in PCs, we used mice with a PC-specific P55 deletion (P55 PanethKO mice) and wild-type controls (P55 PanethWT ). Results Eight weeks of ZDD had mild effects on fecal consistency, PC morphology, and the PC transcriptome. However, 16S sequencing revealed important changes in ileal microbiome composition. These changes made mice significantly more sensitive to challenges that depend on the intestinal bacterial composition, such as peritoneal sepsis and TNF-induced SIRS. P55 PanethKO mice on ZDD displayed severe diarrhea. Compared with P55 PanethWT controls on ZDD, their PC transcriptome showed a strong STAT/ISRE/IRF signature and a complete absence of the otherwise abundant XBP1s part of the unfolded protein response (UPR). Ileal bacterial isolates were further skewed towards the diarrhea-causing Enterococcus gallinarum. Discussion PC-specific P55 is essential for suppressing this STAT/ISRE/IRF response specifically under ZDD conditions. We suggest that in wild-type mammals, the biological activity of TNF on PCs is essential to protect them and to prevent diarrhea. Potential underlying mechanisms are discussed.