Abstract
The mucus layer is the first line of innate host defense in the gut that protects the epithelium by spatially separating commensal bacteria. MUC2 mucin is produced and stored by goblet cells that is constitutively exocytosed or hyper secreted upon sensing a threat. How coordinated mucus exocytosis maintains homeostasis in the intestinal epithelium and modulates the immunological landscape remains elusive. Here we describe how the vesicle SNARE protein VAMP8 coordinates mucin exocytosis from goblet cells. Vamp8−/− exhibit a mild pro-inflammatory state basally due to an altered mucus layer and increased encounters with microbial antigens. Microbial diversity shifts to a detrimental microbiota with an increase abundance of pathogenic and mucolytic bacteria. To alleviate the heavy microbial burden and inflammatory state basally, Vamp8−/− skews towards tolerance. Despite this, Vamp8−/− is highly susceptible to both chemical and infectious colitis demonstrating the fragility of the intestinal mucosa without proper mucus exocytosis mechanisms.
Highlights
The mucus layer is the first line of innate host defense in the gut that protects the epithelium by spatially separating commensal bacteria
We have recently reported that the protozoan parasite Entamoeba histolytica induces the activation of the vesicle R-SNARE VAMP8 upon interaction within goblet cells and lack of Vamp[8] leads to abrogated mucin release, increased parasitic adherence and an aggravated immune response following infection[16,17]
To fully characterize how mucin is released from intestinal goblet cells and the role coordinated mucin exocytosis plays in host physiology, we utilized Vamp8−/− mice and interrogated alterations in the mucosal barrier
Summary
The mucus layer is the first line of innate host defense in the gut that protects the epithelium by spatially separating commensal bacteria. Microbial sensing through these germline encoded receptors appears an attractive mechanism for the host to decipher how imminent a threat is to the epithelial surface, where a thinner mucus layer delivering microbial-associated molecular patterns warrants a secretory response. Perturbation of these pathogenrecognition receptors (PRRs) leads to attenuated mucus release from goblet cells allowing for microbial interaction with the mucosal surface basally and exacerbating animal models of disease, such as chemical or infectious colitis[7,9]. Lack of mucin exocytosis increases susceptibility to chemical and infectious colitis highlighting the critical importance these mechanisms play in maintaining intestinal homeostasis
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