Paneth cell TNF receptor 1 controls zinc deficiency-induced diarrhea
Abstract
IntroductionZinc 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.MethodsWe 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 (P55PanethKO mice) and wild-type controls (P55PanethWT).ResultsEight 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. P55PanethKO mice on ZDD displayed severe diarrhea. Compared with P55PanethWT 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.DiscussionPC-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.
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BibTeX
@article{beul2026paneth,
title = {{Paneth cell TNF receptor 1 controls zinc deficiency-induced diarrhea}},
author = {Somara De Beul and Natalia Garcia-Gonzalez and Tineke Vanderhaeghen and Charlotte Wallaeys and Jolien Vandewalle and Riet De Rycke and Fabien Thery and Francis Impens and Serge Verbanck and Filip Van Immerseel and Filip Boyen and Takao Iwawaki and Richard S. Blumberg and Steven Timmermans and Claude Libert},
journal = {Frontiers in Immunology},
year = {2026},
month = nov,
doi = {10.3389/fimmu.2026.1918555},
url = {https://www.frontiersin.org/articles/10.3389/fimmu.2026.1918555},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Paneth cell TNF receptor 1 controls zinc deficiency-induced diarrhea
AU - Somara De Beul
AU - Natalia Garcia-Gonzalez
AU - Tineke Vanderhaeghen
AU - Charlotte Wallaeys
AU - Jolien Vandewalle
AU - Riet De Rycke
AU - Fabien Thery
AU - Francis Impens
AU - Serge Verbanck
AU - Filip Van Immerseel
AU - Filip Boyen
AU - Takao Iwawaki
AU - Richard S. Blumberg
AU - Steven Timmermans
AU - Claude Libert
PY - 2026
DA - 2026/11/05
JO - Frontiers in Immunology
DO - 10.3389/fimmu.2026.1918555
UR - https://www.frontiersin.org/articles/10.3389/fimmu.2026.1918555
AB - IntroductionZinc 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.MethodsWe 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 (P55PanethKO mice) and wild-type controls (P55PanethWT).ResultsEight 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. P55PanethKO mice on ZDD displayed severe diarrhea. Compared with P55PanethWT 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.DiscussionPC-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.
SN - 1664-3224
ER -