Abstract
Goblet cells secrete mucin to create a protective mucus layer against invasive bacterial infection and are therefore essential for maintaining intestinal health. However, the molecular pathways that regulate goblet cell function remain largely unknown. Although GPR35 is highly expressed in colonic epithelial cells, its importance in promoting the epithelial barrier is unclear. In this study, we show that epithelial Gpr35 plays a critical role in goblet cell function. In mice, cell-type-specific deletion of Gpr35 in epithelial cells but not in macrophages results in goblet cell depletion and dysbiosis, rendering these animals more susceptible to Citrobacter rodentium infection. Mechanistically, scRNA-seq analysis indicates that signaling of epithelial Gpr35 is essential to maintain normal pyroptosis levels in goblet cells. Our work shows that the epithelial presence of Gpr35 is a critical element for the function of goblet cell-mediated symbiosis between host and microbiota.
Highlights
Goblet cells are the most abundant secretory epithelial cells (ECs) in the colon
Gpr35wt larvae treated with the GPR35 agonists lysophosphatidic acid (LPA) and Zaprinast displayed increased goblet cell numbers indicated by Alcian blue staining, the LPA treatment did not reach statistical significance (Fig. 1c, d)
To investigate whether loss of epithelial Gpr[35] leads to further changes in colonic goblet cells that may not be detected in histological analysis, we measured the level of transcription factors involved in goblet cell differentiation
Summary
Goblet cells are the most abundant secretory epithelial cells (ECs) in the colon. Their principal functions involve the production and secretion of mucins, thereby providing a thick mucus layer covering the apical surface of the intestinal epithelium. This mucus layer acts as the first line of defense by fending off luminal bacteria, reducing bacterial exposure of epithelial and immune cells. Mucus layer impairment leads to infection and inflammation, as described for inflammatory bowel disease[2,3]. Ulcerative colitis (UC) has been associated with a reduced number of goblet cells, defective production and secretion of mucins, and increased bacterial penetration[4]. The precise mechanisms that alter the mucus layer leading to defective barrier integrity remain largely unknown
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