The evolutionarily ancient FOXA transcription factors shape the murine gut microbiome via control of epithelial glycosylation.

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Swisa A, Kieckhaefer J, Daniel SG, El-Mekkoussi H, Kolev HM, Tigue M, Jin C, Assenmacher CA, Dohnalová L, Thaiss CA, Karlsson NG, Bittinger K, Kaestner KH

Dev. Cell 59 (16) 2069-2084.e8 [2024-08-19; online 2024-05-30]

Evolutionary adaptation of multicellular organisms to a closed gut created an internal microbiome differing from that of the environment. Although the composition of the gut microbiome is impacted by diet and disease state, we hypothesized that vertebrates promote colonization by commensal bacteria through shaping of the apical surface of the intestinal epithelium. Here, we determine that the evolutionarily ancient FOXA transcription factors control the composition of the gut microbiome by establishing favorable glycosylation on the colonic epithelial surface. FOXA proteins bind to regulatory elements of a network of glycosylation enzymes, which become deregulated when Foxa1 and Foxa2 are deleted from the intestinal epithelium. As a direct consequence, microbial composition shifts dramatically, and spontaneous inflammatory bowel disease ensues. Microbiome dysbiosis was quickly reversed upon fecal transplant into wild-type mice, establishing a dominant role for the host epithelium, in part mediated by FOXA factors, in controlling symbiosis in the vertebrate holobiont.

Glycoproteomics and MS Proteomics [Collaborative]

PubMed 38821056

DOI 10.1016/j.devcel.2024.05.006

Crossref 10.1016/j.devcel.2024.05.006

mid: NIHMS2001028
pmc: PMC11338728
pii: S1534-5807(24)00323-X