Cao Ji, Shi Donglin, Cui Yong, Zhu Haiyan, Liang Haiping, Wei Qing, Huang Jianzhen
Jiangxi Provincial Key Laboratory for Animal Health, Institute of Animal Population Health, College of Animal Science and Technology, Jiangxi Agricultural University, Nanchang, 330045, China; State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, 210009, China.
Jiangxi Provincial Key Laboratory for Animal Health, Institute of Animal Population Health, College of Animal Science and Technology, Jiangxi Agricultural University, Nanchang, 330045, China.
J Nutr Biochem. 2025 Nov;145:110036. doi: 10.1016/j.jnutbio.2025.110036. Epub 2025 Jul 18.
Genistein (GEN) is a natural polyphenolic compound widely present in leguminous plants, which has many biological functions such as anti-inflammatory and antioxidant activities, and has attracted attention in the treatment of inflammatory bowel disease (IBD). However, the molecular mechanism underlying the beneficial effects of GEN in IBD remains unclear. Here, we demonstrated that GEN enhanced the relative abundance of beneficial bacteria (e.g., Akkermansia muciniphila) and increased microbiota-derived short-chain fatty acids (SCFAs) levels in colitis mice. Further, the antibiotic cocktails (ABX) and fecal microbiota transplantation (FMT) experiments confirmed that gut microbiota at least partially mediated the anti-colitis effect of GEN. Interestingly, we found that GEN could also activate G protein-coupled receptor 30 (GPR30) and its downstream transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) in intestinal epithelial cells (IECs). The activation of the GPR30-Nrf2 signaling led to reduced reactive oxygen species (ROS) production, which consequently inhibited NLRP3 inflammasome activation and improved intestinal epithelial barrier dysfunction. In addition, studies using GPR30 knockout mice confirmed that GPR30 is crucial for inhibiting NLRP3 inflammasome activation and alleviating colitis. Collectively, our study unveils that GEN is an effective anti-inflammatory agent and suggests that both the gut microbiota and the GPR30-Nrf2 signaling pathway represent potential therapeutic targets for treating IBD.
染料木黄酮（GEN）是一种广泛存在于豆科植物中的天然多酚化合物，具有抗炎和抗氧化等多种生物学功能，在炎症性肠病（IBD）的治疗中受到关注。然而，GEN在IBD中发挥有益作用的分子机制仍不清楚。在此，我们证明GEN提高了结肠炎小鼠体内有益细菌（如嗜黏蛋白阿克曼氏菌）的相对丰度，并增加了微生物群衍生的短链脂肪酸（SCFA）水平。此外，抗生素鸡尾酒（ABX）和粪便微生物群移植（FMT）实验证实，肠道微生物群至少部分介导了GEN的抗结肠炎作用。有趣的是，我们发现GEN还可以激活肠道上皮细胞（IEC）中的G蛋白偶联受体30（GPR30）及其下游转录因子核因子红细胞2相关因子2（Nrf2）。GPR30-Nrf2信号的激活导致活性氧（ROS）产生减少，从而抑制NLRP3炎性小体激活并改善肠道上皮屏障功能障碍。此外，使用GPR30基因敲除小鼠的研究证实，GPR30对于抑制NLRP3炎性小体激活和减轻结肠炎至关重要。总之，我们的研究揭示了GEN是一种有效的抗炎剂，并表明肠道微生物群和GPR30-Nrf2信号通路均代表治疗IBD的潜在治疗靶点。
