Eucommia alleviates high fat diet-induced MASLD via the F. prausnitzii/butyrate/GPR43/GLP-1 signaling
Zhineng Wang1, Ying Zhu1, Guohua Wang1
1Science and Technology Innovation Center, Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 200071, China.
Ethnopharmacological Relevance:
Metabolic dysfunction-associated steatotic liver disease (MASLD) has become the most prevalent chronic liver disorder worldwide, and remains without truly effective therapies. Eucommia ulmoides Oliver (Eucommia), a traditional Chinese medicinal herb, is widely known for its hepatoprotective actions, but its therapeutic potential in MASLD and underlying mechanisms remain largely unexplored.
Aim Of The Study:
In vitro and in vivo studies, the protective effect of Eucommia bark extract (EBE) on MASLD was elucidated, and investigate its hepatoprotective mechanism.
Materials And Methods:
A high-fat diet (HFD)-induced MASLD mouse model was used to evaluate the therapeutic efficacy of EBE. Mice were orally administered EBE throughout HFD feeding, and metabolic parameters, liver histology, and key signaling pathways were systematically assessed. To investigate the underlying mechanisms, gut microbiota composition was analyzed by 16S rRNA sequencing, and fecal microbiota transplantation from EBE-treated donors was performed to determine the microbiota-mediated effects.
Results:
EBE dramatically attenuated HFD-induced weight gain, oxidative stress, inflammation, lipid accumulation, and fibrosis in MASLD mice. Mechanistically, EBE raised circulating glucagon-like peptide-1 (GLP-1) levels, enhanced adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK) phosphorylation downstream of GLP-1 receptor (GLP-1R), thereby suppressing lipogenesis and promoting lipophagy. Although EBE did not directly trigger GLP-1 release in STC-1 cells, microbiome profiling revealed a selective bloom of Faecalibacterium prausnitzii (F. prausnitzii) - a major butyric acid producer-leading to elevated colonic butyric acid. Butyrate activated G protein-coupled receptor 43 (GPR43) on enteroendocrine cells to drive GLP-1 synthesis, a response abolished by GPR43 knockdown. Crucially, fecal microbiota transplantation from EBE-treated donors recapitulated these metabolic improvements in recipient mice.
Conclusion:
EBE ameliorates MASLD by reshaping the gut microbiota to enrich F. prausnitzii-derived butyrate, which in turn stimulates endogenous GLP-1 secretion and activates the hepatic GLP-1R/AMPK axis to preserves lipid metabolism disorders.
