Hesperetin Alleviated Experimental Colitis via Regulating Ferroptosis and Gut Microbiota

TL;DR

Hesperetin, a citrus flavonoid, reduces experimental colitis by controlling ferroptosis and improving gut microbiota balance.

Contribution

This study reveals hesperetin's novel role in alleviating colitis through ferroptosis regulation and gut microbiota modulation.

Findings

Hesperetin improved weight loss, colon length, and reduced inflammation markers in DSS-induced colitis in mice.

Hesperetin regulated ferroptosis markers like PTGS2, ACSL4, and Gpx4 in vivo and in vitro.

Hesperetin increased gut microbiota diversity and restored beneficial bacteria while reducing harmful ones.

Abstract

Hesperetin (HT) is a type of citrus flavonoid with various pharmacological activities, including anti-tumor, anti-inflammation, antioxidant, and neuroprotective properties. However, the role and mechanism of HT in ulcerative colitis (UC) have been rarely studied. Our study aimed to uncover the beneficial effects of HT and its detailed mechanism in UC. Experimental colitis was induced by 2.5% dextran sodium sulfate (DSS) for seven days. HT ameliorated DSS-induced colitis in mice, showing marked improvement in weight loss, colon length, colonic pathological severity, and the levels of TNFα and IL6 in serum. A combination of informatics, network pharmacology, and molecular docking identified eight key targets and multi-pathways influenced by HT in UC. As a highlight, the experimental validation demonstrated that PTGS2, a marker of ferroptosis, along with other indicators of ferroptosis (such as ACSL4, Gpx4, and lipid peroxidation), were regulated by HT in vivo and in vitro. Additionally, the supplement of HT increased the diversity of gut microbiota, decreased the relative abundance of Proteobacteria and Gammaproteobacteria, and restored beneficial bacteria (Lachnospiraceae_NK4A136_group and Prevotellaceae_UCG-001). In conclusion, HT is an effective nutritional supplement against experimental colitis by suppressing ferroptosis and modulating gut microbiota.

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