Deoxycholic Acid Triggers NLRP3 Inflammasome Activation and Aggravates DSS-Induced Colitis in Mice

Abstract

A westernized high-fat diet (HFD) is associated with the development of inflammatory bowel disease (IBD). High-level fecal deoxycholic acid (DCA) caused by HFD contributes to the colonic inflammatory injury of IBD; however, the mechanism concerning the initiation of inflammatory response by DCA remains unclear. In this study, we sought to investigate the role and mechanism of DCA in the induction of inflammation via promoting NLRP3 inflammasome activation. Here, we, for the first time, showed that DCA dose-dependently induced NLRP3 inflammasome activation and highly pro-inflammatory cytokine-IL-1β production in macrophages. Mechanistically, DCA-triggered NLRP3 inflammasome activation by promoting cathepsin B release at least partially through sphingosine-1-phosphate receptor 2. Colorectal instillation of DCA significantly increased mature IL-1β level in colonic tissue and exacerbated DSS-induced colitis, while in vivo blockage of NLRP3 inflammasome or macrophage depletion dramatically reduced the mature IL-1β production and ameliorated the aggravated inflammatory injury imposed by DCA. Thus, our findings show that high-level fecal DCA may serve as an endogenous danger signal to activate NLRP3 inflammasome and contribute to HFD-related colonic inflammation. NLRP3 inflammasome may represent a new potential therapeutical target for treatment of IBD.

Immune regulation by microbiome metabolites

“…Consistently, instillation of DCA into the colon exacerbated colitis responses . Bile acid metabolites regulate NLRP3 inflammasome activation, but their exact roles in this regard are controversial . While the functions of bile acid metabolites appear to be complex and are probably determined by receptors, cell types, tissue sites and immunological context, these metabolites play important roles in regulating the immune system.…”

Deoxycholic acid disrupts the intestinal mucosal barrier and promotes intestinal tumorigenesis

“…37,38 Recent studies have shown that cholesterol, 39 titanium dioxide 40 and DCA 41 participate in the progression of intestinal diseases by activating the NLRP3 inflammasome. Zhao et al 41 estimated that DCA triggered NLRP3 inflammasome activation and aggravated dextran sulfate sodium induced colitis in mice. In summary, we indicated that DCA activation of the NLRP3 inflammasome to induce intestinal low grade inflammation during intestinal tumorigenesis in Apc min/+ mice.…”

Inflammasomes and intestinal inflammation

“…Colitis attenuation: Hirota et al, 24 Zaki et al, 25 Allen et al, 26 Itani et al, 27 Macia et al 75 Colitis/enteritis exacerbation: Bauer et al, 28 Bauer et al, 29 Liu et al, 37 Higashimori et al, 39 Ruiz et al, 68 Progatzky et al, 69 Bitzer et al, 70 Youm et al, 71 Zhao et al 74 Seo et al Suzuki et al, 52 Engler et al, 53 Ng et al 54 -H. pylori…”

“…73 However, other studies argue that bile acids can potentially serve as an endogenous danger signal and activate the NLRP3 inflammasome. 74 Finally, it has been shown that diet rich in short-chain fatty acids protects mice against colitis by binding to GPR43 located on colonic epithelial cells, which triggers potassium efflux and hyperpolarization, leading to NLRP3 inflammasome activation. 75…”