Novel FXR agonist nelumal A suppresses colitis and inflammation-related colorectal carcinogenesis

Abstract

FXR is a member of the nuclear receptor superfamily and bile acids are endogenous ligands of FXR. FXR activation has recently been reported to inhibit intestinal inflammation and tumour development. This study aimed to investigate whether the novel FXR agonist nelumal A, the active compound of the plant Ligularia nelumbifolia, can prevent colitis and colorectal carcinogenesis. In a mouse colitis model, dextran sodium sulfate-induced colonic mucosal ulcer and the inflammation grade in the colon significantly reduced in mice fed diets containing nelumal A. In an azoxymethane/dextran sodium sulfate-induced mouse inflammation-related colorectal carcinogenesis model, the mice showed decreased incidence of colonic mucosal ulcers and adenocarcinomas in nelumal A-treated group. Administration of nelumal A also induced tight junctions, antioxidant enzymes, and FXR target gene expression in the intestine, while it decreased the gene expression of bile acid synthesis in the liver. These findings suggest that nelumal A effectively attenuates colonic inflammation and suppresses colitis-related carcinogenesis, presumably through reduction of bile acid synthesis and oxidative damage. This agent may be potentially useful for treatment of inflammatory bowel diseases as well as their related colorectal cancer chemoprevention.

Bile Acids Activated Receptors in Inflammatory Bowel Disease

“…On the other hand, the administration of GPBAR1 agonist reverts intestinal inflammation in mouse models of colitis with a strong increase of IL-10 production [ 43 ]. Further on, FXR knockout mice develop a subclinical inflammation with age and are more prone than their congenic counterparts to develop inflammation [ 1 , 16 , 94 , 95 , 96 , 97 , 98 ]. The mechanisms that support these immune-modulatory activities of FXR in cells of innate immunity involve both NF-KB-dependent and -independent pathways as discussed in previous paragraphs [ 39 , 55 , 99 , 100 ].…”

Intestinal FXR Activation via Transgenic Chimera or Chemical Agonism Prevents Colitis-Associated and Genetically-Induced Colon Cancer

“…The nuclear receptor FXR is the master regulator of BA homeostasis. Pharmacological FXR activation and/or therapeutic exploitation of the enterokine FGF19 is known to attenuate not only intestinal inflammation [22,23,[31][32][33], but also hepatocellular carcinoma [41,47], by decreasing circulating BA levels and modulating the BA pool size and composition to a more hydrophilic one. Moreover, FXR expression is reduced in human intestinal cancer samples [36] and FXR deficiency in mice promotes inflammation, cell proliferation and intestinal carcinogenesis [35,36] as well as hepatocellular carcinoma [48,49], due to the lack of the negative feedback loop controlling BA homeostasis.…”

“…Furthermore, FXR activation not only ameliorates intestinal inflammation but also IBD-associated CRC. In fact, FXR activation by Nelumal A in mice subjected to a chemical model of colitis and colorectal carcinogenesis attenuates inflammation and oxidative stress and reduces cell proliferation in the colonic mucosa [33]. Several studies have highlighted the crucial role of FXR in intestinal carcinogenesis and the inverse relationship between Fxr expression levels and CRC development [34][35][36][37].…”

Variation in the Efficacy of Anti-Ulcerative Colitis Treatments Reveals the Conflict Between Precipitating Compatibility of Traditional Chinese Medicine and Modern Technology: A Case of Scutellaria-Coptis

“…In this study, UC was induced in mice by administering dextran sulfate sodium (DSS). To determine the curative effect of Scutellaria-Coptis decocted separately and in combination, Disease Activity Index (DAI) scores, histopathological inflammatory factors, and antioxidant capacity were evaluated, in addition to the combined effects of Scutellaria-Coptis decoction ( Miyazaki et al, 2021 ). Furthermore, 16S rRNA sequencing was used to analyze the structure and diversity of intestinal flora, and the effect of Scutellaria-Coptis decoction on the intestinal flora of DSS-induced UC in mice was investigated ( Li et al, 2015 ; Liu et al, 2020; Singh et al, 2019 ; Zhang et al, 2020 ).…”