The Homeostatic Protein Fam3D Orchestrates Colon Mucosal Protection Against Infection, Inflammation, and Carcinogenesis

Abstract

Fam3D (FAM3D in human) is a homeostatic protein expressed mainly in gastrointestinal tract that plays an essential role in promoting colon mucosal development and homeostasis. However, the mechanistic basis for the action of Fam3D, particularly its relationship to colon mucosal development and microbiome balance, is less clear. In this study, Fam3D expression was increased in colon epithelial cells of germ-free (GF) <i>Fam3D^+/+</i> mice following <i>E. coli</i> infection and GF <i>Fam3D^-/-</i> mice were more susceptible to <i>E. coli</i> colonization in the colon. In chemically induced colitis and colon cancer, GF <i>Fam3D^-/-</i> mice showed more severe inflammatory responses, colon mucosal damage, and tumorigenesis. Unlike SPF mice, GF <i>Fam3D^-/-</i> mice exhibited decreased production of the gut barrier protein Muc2. Mechanism study revealed that in colon epithelial cells, LPS upregulated Fam3D expression through TLR4, while Fam3D promoted Muc2 production through Fpr1 and Fpr2. In addition, Fam3D also upregulated the expression of MAP kinase phosphatase 1 (MKP-1) which is crucial for restraining inflammatory responses. Fam3D deficiency reduced MKP-1 expression, thereby increasing IL-1β and TNF-α production in colon mucosa of GF mice. Thus, Fam3D is critical in colon homeostasis and constitutes a therapeutic target for inflammatory colon diseases.