Paneth cell TNF-receptor 1 controls zinc deficiency induced hiarrha

In humans, mild to severe Zn2+ deficiency is manifested by intestinal health issues such as diarrhea, and Zn2+-based therapies are beneficial in such diseases. We established a mouse model, based on a Zn2+ deficient diet (ZDD), and focused on Paneth cells, the most critical cells controlling intestinal microbiota. Eight weeks of ZDD, compared to standard diet (StD), has mild effects on fecal consistency, Paneth cell morphology and Paneth cell transcriptome, but 16S reveals important changes in ileal microbiome composition. The latter renders mice significantly more sensitive to challenges, involving critical functions of intestinal bacteria, such as peritoneal sepsis and TNF-induced systemic inflammatory response syndrome (SIRS). While studying the role of TNF receptor P55 of Paneth cells in this latter finding, we observed that P55PanethKO mice, on a ZDD, display severe diarrhea. The transcriptome in Paneth cells in such mice, compared to P55PanethWT controls on ZDD, suggests the induction of a strong IFN response in these cells and complete absence of Unfolded Protein Response (UPR) and a further skewing of microbes, towards diarrhea-causing Enterococcus gallinarum. We suggest that in wild type mammals, biological activity of TNF on Paneth cells is essential to protect these cells against excessive IFN responses and to prevent diarrhea. Potential underlying mechanisms are discussed.