Phocaeicola dorei YGMCC0564 attenuates HFD-induced glycolipid metabolic disorders in association with remodeling of the gut microbiota and bile acid profiles

Abstract

Background Glycolipid Metabolic Disorders (GLMD) are characterized by imbalances in glucose and lipid homeostasis, often presenting with severe clinical symptoms. Current pharmacotherapies such as orlistat and metformin show clear efficacy but are associated with long-term tolerability concerns. This study aimed to evaluate whether the next-generation probiotic candidate Phocaeicola dorei YGMCC0564 attenuates HFD-induced glycolipid metabolic disturbances in mice. We hypothesized that the protective effect of YGMCC0564 would be associated with modulation of bile acid metabolism and may be partly mediated by it. Methods A high-fat diet (HFD)-induced mouse model of glycolipid metabolic disturbance was used, with YGMCC0564 supplementation initiated concurrently with HFD feeding in a prevention design. Lactobacillus rhamnosus GG and orlistat served as reference controls. Efficacy was assessed by body composition, histopathology, biochemical assays, and quantitative PCR, combined with 16S rRNA gene sequencing, non-targeted metabolomics, targeted quantification of fecal short-chain fatty acids, and cell-based functional assays. Safety was evaluated in acute and 4-week subchronic tests in immunodeficient and normal mice. Results YGMCC0564 attenuated HFD-induced body weight gain, dyslipidemia, and hyperglycemia, reduced hepatic steatosis and gluconeogenic gene expression, and improved insulin resistance. Multi-omics analysis showed that YGMCC0564 reshaped the gut microbiota and restored fecal short-chain fatty acid concentrations that had been reduced by HFD feeding. The fecal bile acid profile was remodeled, with elevated lithocholic acid (LCA) and 3β,7α-dihydroxy-5-cholestenoate and reduced α-muricholic acid (α-MCA), chenodeoxycholic acid (CDCA), taurodeoxycholic acid (TDCA), and isoLCA. Intestinal expression of Fxr, Fgf15, Gpbar1/Tgr5, and Glp-1 was upregulated, consistent with enhanced bile acid receptor signaling. In vitro, a 1:1 mixture of LCA and 3β,7α-dihydroxy-5-cholestenoate, the two bile acids elevated by YGMCC0564 in vivo, activated FXR-FGF19 signaling in HT-29 intestinal cells and suppressed gluconeogenic gene expression and glucose output in HepG2 cells. Oral YGMCC0564 produced no obvious adverse effects in acute and subchronic tests in immunodeficient and normal mice. Conclusion These findings indicate that YGMCC0564 may modulate FXR-FGF15/19 and GPBAR1/TGR5 signaling via the gut environment, thereby potentially contributing to its hypoglycemic and hypolipidemic effects.