FMO5 Plays a Sex-specific Role in Goblet Cell Maturation and Mucus Barrier Formation
Abstract
Background & aims: The intestine plays a key role in metabolism and nutrient and water absorption and provides both physical and immunological defense against dietary and luminal antigens. The protective mucosal lining in the intestine is a critical component of the intestinal barrier that, when compromised, can lead to increased permeability, a defining characteristic of inflammatory bowel disease, among other intestinal diseases. Here, we define a new role for the flavin-containing monooxygenase (FMO) family of enzymes in maintaining a healthy intestinal epithelium.
Methods: Using Caenorhabditis elegans, we measure intestinal barrier function, actin expression, and intestinal damage response. In mice, we utilize an intestine-specific, tamoxifen-inducible knockout model of the mammalian homolog of Cefmo-2, Fmo5, and assess histology, mucus barrier thickness, and goblet cell physiology. We also treat mice with the endoplasmic reticulum (ER) chaperone tauroursodeoxycholic acid.
Results: In nematodes, we find Cefmo-2 is necessary and sufficient for intestinal barrier function and intestinal actin expression and is induced by intestinal damage. In mice, we find striking changes to the intestine within 2 weeks following FMO5 disruption. Alterations include sex-dependent changes in colon epithelial histology, goblet cell localization, and mucus barrier formation. These changes are significantly more severe in female mice, mirroring differences observed in patients with…
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