Hassan, Mohsin; Juanola, Oriol; Huber, Stefania; Kellmann, Philipp; Zimmermann, Jakob; Lazzarini, Edoardo; Ganal-Vonarburg, Stephanie C; Gomez de Agüero, Mercedes; Moghadamrad, Sheida (2023). Absence of gut microbiota impairs depletion of Paneth cells but not goblet cells in germ-free Atoh1lox/lox VilCreERT2 mice. American journal of physiology. Gastrointestinal and liver physiology, 324(6), G426-G437. American Physiological Society 10.1152/ajpgi.00123.2022
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Mouse atonal homolog 1 (Math1/Atoh1) is a basic helix-loop-helix transcription factor important for the differentiation of secretory cells within the intestinal epithelium. The analysis of Paneth depletion efficiency upon Math1lox/loxVilCreERT2 (Math1∆IEC) mice treatment with Tamoxifen in the presence or absence of intestinal microbiota, showed a failure on Paneth cell depletion in germ-free mice as compared to SPF mice. However, goblet cells were efficiently depleted in Math1∆IEC germ-free mice. The gene expression of Math1 was significantly reduced in the ileum of germ-free Math1∆IEC mice 5 days post tamoxifen injection as compared to germ-free control, but its protein expression was still detectable in the nuclei of epithelial cells in the crypts. Germ-free mice showed low proliferative ileal crypts as well as apoptotic cells that were mainly detected in the tip of the villus, consistent with a slow turnover rate of epithelial cells. Although Paneth cells were not depleted in germ-free Math1∆IEC mice for the first 7 weeks after the last tamoxifen injection - far already from the 5 days timelaps observed in SPF conditions- but an incomplete depletion of Paneth cells was observed 14 weeks after last tamoxifen injection. Colonization of germ-free mice restored the phenotype observed in SPF mice, highlighting the regulatory role of gut microbes in our model. We conclude that absence of intestinal microbiota in Math1∆IEC mice is associated with reduced epithelial cell renewal and delays the depletion of preexisting Paneth cells.
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