MUC2 Mucin and Butyrate Contribute to the Synthesis of the Antimicrobial Peptide Cathelicidin in Response to Entamoeba histolytica- and Dextran Sodium Sulfate-Induced Colitis.
Cobo. Eduardo R ER; Kissoon-Singh. Vanessa V; Moreau. France F; Holani. Ravi R; Chadee. Kris K
Key Findings
- Butyrate and the inflammatory signal IL‑1β increase LL‑37 production, especially in cells that make lots of MUC2 mucin.
- Silencing MUC2 reduces the cell’s ability to raise LL‑37 in response to butyrate or IL‑1β.
- Mice lacking MUC2 have much lower gut cathelicidin levels and fail to up‑regulate it during Entamoeba infection or DSS‑induced colitis.
- Activation of cAMP and MAPK pathways is required for the coordinated expression of MUC2 and LL‑37.
Practical Outcomes
- Support a robust mucus barrier by eating plenty of fermentable fiber (e.g., resistant starch, inulin) or using butyrate supplements to potentially raise LL‑37 levels and gut immunity. Ensure gut health nutrients like glutamine, zinc, and omega‑3s that help maintain mucin production. These steps may improve resistance to gut infections and reduce inflammation.
Summary
The study shows that the gut‑protective mucus protein MUC2 works together with the short‑chain fatty acid butyrate (made by gut bacteria from fiber) to boost the body’s natural antibiotic peptide LL‑37 in the colon. When MUC2 is low or missing, LL‑37 production drops, even during infection or inflammation, indicating a healthy mucus layer is key for this immune defense.
Abstract
Embedded in the colonic mucus are cathelicidins, small cationic peptides secreted by colonic epithelial cells. Humans and mice have one cathelicidin-related antimicrobial peptide (CRAMP) each, LL-37/hCAP-18 and Cramp, respectively, with related structure and functions. Altered production of MUC2 mucin and antimicrobial peptides is characteristic of intestinal amebiasis. The interactions between MUC2 mucin and cathelicidins in conferring innate immunity against <i>Entamoeba histolytica</i> are not well characterized. In this study, we quantified whether MUC2 expression and release could regulate the expression and secretion of cathelicidin LL-37 in colonic epithelial cells and in the colon. The synthesis of LL-37 was enhanced with butyrate (a product of bacterial fermentation) and interleukin-1β (IL-1β) (a proinflammatory cytokine in colitis) in the presence of exogenously added purified MUC2. The LL-37 responses to butyrate and IL-1β were higher in high-MUC2-producing cells than in lentivirus short hairpin RNA (shRNA) MUC2-silenced cells. Activation of cyclic adenylyl cyclase (AMP) and mitogen-activated protein kinase (MAPK) signaling pathways was necessary for the simultaneous expression of MUC2 and cathelicidins. In Muc2 mucin-deficient (<i>Muc2</i><sup>-/-</sup>) mice, murine cathelicidin (<i>Cramp</i>) was significantly reduced compared to that in <i>Muc2</i><sup>+/-</sup> and <i>Muc2</i><sup>+/+</sup> littermates. <i>E. histolytica</i>-induced acute inflammation in colonic loops stimulated high levels of cathelicidin in <i>Muc2</i><sup>+/+</sup> but not in <i>Muc2</i><sup>-/-</sup> littermates. In dextran sodium sulfate (DSS)-induced colitis in <i>Muc2</i><sup>+/+</sup> mice, which depletes the mucus barrier and goblet cell mucin, <i>Cramp</i> expression was significantly enhanced during restitution. These studies demonstrate regulatory mechanisms between MUC2 and cathelicidins in the colonic mucosa where an intact mucus barrier is essential for expression and secretion of cathelicidins in response to <i>E. histolytica-</i> and DSS-induced colitis.
Study Information
pubmed
2017
2017-02-23T00:00:00.000Z
10.1128/iai.00905-16