Sex-Dimorphic Gut Microbiota Modulation by Icariin in Older Mice

TL;DR

This study shows that icariin, a plant compound, can reshape gut microbes in older mice differently in males and females, potentially offering sex-specific ways to combat aging-related gut changes.

Contribution

The study reveals sex-specific effects of icariin on gut microbiota aging and identifies distinct microbial and metabolic responses in male and female mice.

Findings

Icariin treatment improved microbial diversity more in aged female mice compared to males.

Females showed Lactobacillus enrichment linked to estrogen metabolism, while males showed Akkermansia amplification.

Icariin upregulated steroid biosynthesis pathways more in females than in males.

Abstract

This study investigates the sexually dimorphic effects of icariin—a bioactive flavonoid from Epimedium—on gut microbiota remodeling in older C57BL/6J mice, evaluate its impact on microbial diversity, structure, and metabolic functions, and analyzes the role of sex differences in its intervention effects. Through 16S rRNA sequencing (V3-V4, Illumina NovaSeq) and PICRUSt2-based metabolic prediction, we demonstrate that 15 days icariin treatment (100 mg/kg/day) preferentially restores youthful microbial profiles in older mice (24-month-old), with females exhibiting 25% greater α-diversity improvement (Shannon index, p < 0.05) and 40% closer β-diversity proximity to young controls (Bray-Curtis, p = 0.008) compared to males. Sex-stratified analysis revealed distinct taxonomic shifts: aged females showed Lactobacillus enrichment (4.1-fold) linked to estrogen metabolism, while males displayed Akkermansia amplification (3.9-fold, p = 0.012) associated with mucin degradation. Functionally, icariin upregulated steroid biosynthesis pathways 3.2-fold in females versus 1.8-fold in males (q < 0.05), correlating with phytoestrogen-mediated microbial regulation. These findings not only establish icariin as a sex-specific modulator of gut microbiota aging but also provide mechanistic insights into sexual dimorphism in host-microbiome interactions, advocating for gender-precise nutraceutical strategies to counteract age-related dysbiosis.