State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro-products and School of Marine Science, Ningbo University, Ningbo 315211, China.
The Affiliated People's Hospital of Ningbo University, Ningbo 315040, China.
J Agric Food Chem. 2024 Oct 23;72(42):23211-23223. doi: 10.1021/acs.jafc.4c03278. Epub 2024 Oct 11.
Gut microbiota provides an important insight into clarifying the mechanism of active substances with low bioavailability, but its specific action mechanism varied case by case and remained unclear. Dihydroquercetin (DHQ) is a bioactive flavonoid with low bioavailability, which showed beneficial effects on colitis alleviation and gut microbiota modulation. Herein, we aimed to explore the microbiota-dependent anticolitis mechanism of DHQ in sight of gut microbiota metabolites and their interactions with microRNAs (miRNAs). Dietary supplementation of DHQ alleviated dextran sulfate sodium-induced colitis phenotypes and improved gut microbiota dysbiosis. Fecal microbiota transplantation further revealed that the anticolitis activity of DHQ was mediated by gut microbiota. To clarify how the modulated gut microbiota alleviated colitis in mice, the tandem analyses of the microbiome and targeted metabolome were performed, and altered profiles of metabolite short-chain fatty acids (SCFAs) and bile acids and their producers were observed in DHQ-treated mice. In addition, SCFA treatment showed anticolitis activity compared to that of bile acids, along with the specific inhibition on the phosphoinositide-3-kinase (PI3K)-protein kinase B (Akt) pathway. Subsequently, the colonic miRNA profile of mice receiving SCFA treatment was sequenced, and a differentially expressed miR-10a-5p was identified. Both prediction analysis and dual-luciferase reporter assay indicated that miR-10a-5p directly bind to the 3'-untranslated regions of gene 3, inhibit the PI3K-Akt pathway activation, and lead to colitis alleviation. Together, we proposed that gut microbiota mediated the anticolitis activity of DHQ through the SCFAs/miR-10a-5p/PI3K-Akt axis, and it provided a novel insight into clarifying the microbiota-dependent mechanism via the interaction between metabolites and miRNAs.
肠道微生物群为阐明低生物利用度活性物质的作用机制提供了重要的见解，但具体作用机制因情况而异，尚不清楚。二氢槲皮素（DHQ）是一种生物活性黄酮类化合物，其生物利用度较低，对缓解结肠炎和调节肠道微生物群有有益作用。在此，我们旨在从肠道微生物群代谢物及其与 microRNAs（miRNAs）的相互作用的角度探索 DHQ 的抗结肠炎的菌群依赖性机制。DHQ 的饮食补充缓解了葡聚糖硫酸钠诱导的结肠炎表型，并改善了肠道微生物群失调。粪便微生物群移植进一步表明 DHQ 的抗结肠炎活性是由肠道微生物群介导的。为了阐明调节肠道微生物群如何在小鼠中缓解结肠炎，对微生物组和靶向代谢组进行了串联分析，观察到 DHQ 处理小鼠的代谢物短链脂肪酸（SCFAs）和胆汁酸及其产生菌的图谱发生变化。此外，与胆汁酸相比，SCFA 处理显示出抗结肠炎活性，同时特异性抑制了磷酸肌醇 3-激酶（PI3K）-蛋白激酶 B（Akt）途径。随后，对接受 SCFA 处理的小鼠的结肠 miRNA 图谱进行测序，鉴定出一个差异表达的 miR-10a-5p。预测分析和双荧光素酶报告基因检测均表明，miR-10a-5p 直接结合基因 3 的 3'-非翻译区，抑制 PI3K-Akt 途径的激活，从而缓解结肠炎。综上所述，我们提出肠道微生物群通过 SCFAs/miR-10a-5p/PI3K-Akt 轴介导 DHQ 的抗结肠炎活性，通过代谢物和 miRNAs 之间的相互作用为阐明菌群依赖性机制提供了新的见解。
