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February 5, 2026Open Access

A novel exopolysaccharide from Lactiplantibacillus plantarum H6 improves cholesterol metabolism via Muribaculum- mediated activation of the enterohepatic FXR–FGF15 axis

YLYue LiJilin Agricultural University JWJialin WangInstitute of Food Science & Technology HWHao WangGeneral Cardiology

Key Points

This study aims to investigate the effects of a novel exopolysaccharide from Lactiplantibacillus plantarum H6 on cholesterol metabolism.
Isolated EPS-D1 from Lactiplantibacillus plantarum H6 and characterized its composition.
Administered EPS-D1 to high-cholesterol diet mice and measured cholesterol levels.
Utilized 16S rRNA sequencing and fecal microbiota transplantation to identify enriched bacteria.
Examined the mechanistic role of Muribaculum intestinale in cholesterol lowering and FXR-FGF15 axis activation.
EPS-D1 reduced total cholesterol, triglycerides, and LDL-C by approximately 40%, 37%, and 43% respectively.
Identified Muribaculum intestinale as a key bacterium linked to cholesterol-lowering effects.
Muribaculum intestinale administration replicated cholesterol-lowering effects, decreasing ileal and fecal cholesterol levels by over 74% and 53%.
Activated FXR-FGF15 axis leading to increased CYP7A1 expression and decreased cholesterol absorption.

Abstract

Hypercholesterolemia is a major risk factor for atherosclerotic cardiovascular disease; however, current therapeutic options such as statins are limited by issues including hepatotoxicity and patient intolerance. Probiotics and their metabolites show promise in modulating cholesterol metabolism through the gut‒liver axis, yet the specific commensal bacteria and molecular mechanisms underlying these effects remain poorly understood. In this study, we isolated and characterized EPS-D1, a novel exopolysaccharide (15.003 kDa) derived from Lactiplantibacillus plantarum H6, which is composed primarily of mannose (46.10%) and glucose (33.98%) and features a highly branched structure (branching degree of 29.5%). The administration of EPS-D1 significantly reduced the serum total cholesterol (TC), triglyceride (TG), and low-density lipoprotein cholesterol (LDL-C) by 40.31%, 37.55%, and 43.15%, respectively, in high-cholesterol diet (HCD) mice. Additionally, it improved hepatic steatosis and reduced markers of liver injury. Through 16S rRNA sequencing and fecal microbiota transplantation (FMT), we identified Muribaculum as the key commensal bacterium enriched by EPS-D1. Direct administration of Muribaculum (Muribaculum intestinale) replicated the cholesterol-lowering effects, decreasing ileal and fecal cholesterol levels by 74.79% and 53.16%, respectively. Mechanistically, both EPS-D1 and M. intestinale activated the enterohepatic FXR‒FGF15 axis, which resulted in the upregulation of hepatic cholesterol 7α-hydroxylase (CYP7A1) expression and the downregulation of ileal ASBT and NPC1L1, thereby promoting bile acid synthesis and inhibiting cholesterol absorption. Furthermore, M. intestinale increased intestinal short-chain fatty acids (SCFAs), particularly acetic acid and caproic acid, by 37.88% while also modulating the composition of the bile acid pool. These findings establish M. intestinale as a precise microbial target for cholesterol management and demonstrate that EPS-D1 from L. plantarum H6 enhances cholesterol metabolism through microbiota-mediated activation of the enterohepatic FXR‒FGF15 axis, providing a novel therapeutic strategy for managing hypercholesterolemia.

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