Microbial-Derived Butyrate Promotes Epithelial Barrier Function through IL-10 Receptor–Dependent Repression of Claudin-2

Abstract

Commensal interactions between the enteric microbiota and distal intestine play important roles in regulating human health. Short-chain fatty acids (SCFAs), such as butyrate, produced through anaerobic microbial metabolism represent a major energy source for the host colonic epithelium and enhance epithelial barrier function through unclear mechanisms. Separate studies revealed that the epithelial anti-inflammatory interleukin-10 receptor α-subunit (IL-10RA) is also important for barrier formation. Based on these findings, we examined if SCFAs promote epithelial barrier through IL-10RA-dependent mechanisms. Using human intestinal epithelial cells (IECs), we discovered that SCFAs, particularly butyrate, enhanced IEC barrier formation, induced IL10RA mRNA, IL-10RA protein, and transactivation through activated Stat3 and HDAC inhibition. Loss and gain of IL10RA expression directly correlates with IEC barrier formation and butyrate represses permeability-promoting claudin-2 (Cldn2) tight-junction protein expression through an IL-10RA-dependent mechanism. Our findings provide a novel mechanism by which microbial-derived butyrate promotes barrier through IL-10RA-dependent repression of Cldn2.

Dietary Supplementation of Black Rice Anthocyanin Extract Regulates Cholesterol Metabolism and Improves Gut Microbiota Dysbiosis in C57BL/6J Mice Fed a High‐Fat and Cholesterol Diet

“…[ 41 ] In addition, the decreased ratio of acetic acid/propanoic acid may relate to inhibiting cholesterol synthesis in HCD‐induced mice fed with BRAE, while butyric acid represents a major energy source for the host colonic epithelium, and enhances mucosal barrier function, which was enhanced by BRAE ( p < 0.05, Table 4). [ 42 ] As shown in Figure 2, BRAE has an ameliorative effect on gut barrier function in pathology of ileum, caecum, and colon, and restore the mRNA expression of mucin2, JAM‐A, Occludin related to intestinal epithelium integrity.…”

Faecal microbiota from patients with cirrhosis has a low capacity to ferment non‐digestible carbohydrates into short‐chain fatty acids

“…Our findings that SCFAs production of the gut microbiota is reduced in cirrhosis do therefore provide a potential mechanism that might play a contributory role in the development of hepatic encephalopathy, or in non‐response to lactulose. In addition, butyrate plays an essential role in maintaining the integrity of the gut barrier . Butyrate is the main source of energy for the colonocytes, it maintains the expression of tight junction proteins in colon epithelia and exhibits anti‐inflammatory effects .…”

Higher prevalence ofBacteroides fragilisin Crohn’s disease exacerbations and strain-dependent increase of epithelial resistance

“…However, short chain fatty acids, including acetate, and lactate are reported to rather strengthen the epithelial barrier. 13,41 The lower acetate and lactate concentrations found in the supernatant of TEER-enhancing strains are therefore unlikely to explain the TEER-enhancing effect.…”

“…10,12 On the other hand, bacterial metabolites, such as the short chain fatty acid butyrate, have been reported to promote mucus production and the sealing capacity of the intercellular junctional complex. 13,14 In CD, an impaired intestinal epithelial barrier function has increasingly been recognized as a hallmark of exacerbations. 1 The impaired barrier function has been associated with alterations in the epithelial junctional complex.…”