Nigakinone alleviates DSS‐induced experimental colitis via regulating bile acid profile and FXR/NLRP3 signaling pathways

Abstract

The correlation of bile acid (BA) metabolism disorder with the pathogenesis of ulcerative colitis (UC) is realized nowadays. Farnesoid X receptor (FXR), a controller for BA homeostasis and inflammation, is a promising target for UC therapy. Nigakinone has potential therapeutic effects on colitis. Herein, we investigated the anti‐UC effects and mechanism of nigakinone in colitic animals induced by dextran sulfate sodium (DSS). The related targets involved in the nucleotide‐binding oligomerization domain, leucine‐rich repeat, and pyrin domain‐containing 3 (NLRP3) signaling pathway were measured. BA‐targeted metabolomics was employed to reveal the regulatory effects of nigakinone on BA profile in colitis, while expressions of FXR and its mediated targets referring to BA enterohepatic circulation were determined. The critical role of FXR in the treatment of nigakinone for colitis was studied via molecule‐docking, dual‐luciferase reporter® (DLR™) assays, FXR silencing cells, and FXR knockout mice. Results showed nigakinone attenuated DSS‐induced colitis symptoms, including excessive inflammatory response by NLRP3 activation, and injury of the intestinal mucosal barrier. Nigakinone regulated BA disorders by controlling cholesterol hydroxylase and transporters mediated by FXR, then decreased BA accumulation in colon. Molecular‐docking and DLR™ assays indicated FXR might be a target of nigakinone. In vitro, nigakinone restrained BA‐induced inflammation and cell damage via FXR activation and inhibition of inflammatory cytokines. However, ameliorating effects of nigakinone on colitis were suppressed by FXR knockout or silencing in vivo or in vitro. Taken together, nigakinone ameliorated experimental colitis via regulating BA profile and FXR/NLRP3 signaling pathway.

Serum fibroblast growth factor 19 level correlates inversely with clinical and endoscopic activity of inflammatory bowel disease

“…The results of preliminary studies with 2 FGF19 analogs, aldafermin and M52, are encouraging. 25,[27][28][29][30][31]…”

“…The control group consisted of 17 healthy volunteers, including 9 men and 8 women, with a median age of 28 (27)(28)(29)(30) years and without any gastroenterological symptoms.…”

“…There were no significant differences between the subgroups with respect to sex, age, BMI, and disease duration. The whole group consisted of 68 men (65%) and 37 women (35%) with a median age of 33 (27)(28)(29)(30)(31)(32)(33)(34)(35)(36)(37)(38)(39)(40)(41) years and disease duration of 63 (13-132) months.…”

Ji-Ni-De-Xie ameliorates type 2 diabetes mellitus by modulating the bile acids metabolism and FXR/FGF15 signaling pathway

“…Activation of intestinal FXR can induce the release of FGF15, which reaches liver cells via the portal vein. Then, FGF15 is bound with the liver FGF4/βKlotho receptor, inhibiting the expression of CYP7A1, thereby suppressing the synthesis of BAs in the liver ( Liu et al, 2023 ). The specific mechanism of anti-diabetes is shown in Figure 7 .…”

Farnesoid X receptor: From Structure to Function and Its Pharmacology in Liver Fibrosis

“…These cytokines not only influence macrophage recruitment within the liver but also directly affect brain function, thereby participating in the emergence of neurological disorders [ 121 ]. Of paramount importance is the role of BAs in transmitting signals to the central nervous system through two distinct pathways: a direct central FXR-TGR5 signal and an indirect pathway involving the activation of intestinal FXR and TGR5, leading to the induction of FGF19 and GLP-1 [ 122 - 124 ]. FXR is not confined to the gut and liver; it is also expressed in the brain, indicating its potential circulatory effect.…”