Salvia-Nelumbinis naturalis extract protects mice against MCD diet-induced steatohepatitis via activation of colonic FXR-FGF15 pathway

• Published in: Biomedicine & pharmacotherapy 2021-07, Vol.139, p.111587-111587, Article 111587
• Main Authors: Li, Chunlin, Zhou, Wenjun, Li, Meng, Shu, Xiangbing, Zhang, Li, Ji, Guang
• Format: Article
• Language: English
• Subjects: Animals; Choline Deficiency - complications; Choline Deficiency - genetics; Choline Deficiency - metabolism; Choline Deficiency - pathology; Colon - drug effects; Colon - metabolism; Diet; Drugs, Chinese Herbal - pharmacology; Drugs, Chinese Herbal - therapeutic use; Dysbiosis - drug therapy; Dysbiosis - genetics; Dysbiosis - metabolism; Farnesoid X receptor; Fibroblast growth factor 15; Fibroblast Growth Factors - genetics; Fibroblast Growth Factors - metabolism; Gastrointestinal Microbiome - drug effects; Gut microbiota; Liver - drug effects; Liver - metabolism; Liver - pathology; Male; Methionine - deficiency; Mice; Mice, Inbred C57BL; Non-alcoholic Fatty Liver Disease - drug therapy; Non-alcoholic Fatty Liver Disease - genetics; Non-alcoholic Fatty Liver Disease - metabolism; Non-alcoholic Fatty Liver Disease - pathology; NorDeoxycholic acid; Protective Agents - pharmacology; Protective Agents - therapeutic use; Receptors, Cytoplasmic and Nuclear - genetics; Receptors, Cytoplasmic and Nuclear - metabolism; Salvia-Nelumbinis naturalis; Signal Transduction - drug effects; Steatohepatitis
• ISSN: 0753-3322; 1950-6007
• DOI: 10.1016/j.biopha.2021.111587

Salvia-Nelumbinis naturalis (SNN) formula is a traditional Chinese medicine prescription, and has been confirmed to be effective in treating non-alcoholic steatohepatitis (NASH), but the underlying mechanisms are still unknown. Here we showed that 4-week SNN administration alleviated methionine-choline-deficiency (MCD) diet-induced hepatic steatosis and inflammation as well as serum levels of alanine transaminase (ALT) increase in C57BL/6 mice. Fecal 16S rDNA sequencing indicated that SNN altered the structure of gut microbiota and partially reversed the gut dysbiosis. Simultaneously, we analyzed the fecal BA profile using liquid chromatography coupled with triple quadrupole mass spectrometry (UPLC-TQMS) -based metabolomics, and found that SNN modulated fecal BA profile, predominantly increased the microbiomes related BA species (e.g. nordeoxycholic acid) which in turn, activated farnesoid X receptor (FXR)-fibroblast growth factor 15 (FGF15) signaling pathway in the colon but not the ileum. The activation of intestinal FXR-FGF15 signaling was accompanied by increase of liver protein kinase B (PKB/Akt) phosphorylation, and decrease of p-65 subunit of NF-κB phosphorylation, resulting in less liver CD68 positive macrophages, and inflammatory cytokine IL-1β and TNF-α expression. Our results established the link between SNN treatment, gut microbiota, BA profile and NASH, which might shed light into the mechanisms behind the beneficial effects of SNN on NASH, thus provide evidence for the clinical application of SNN. [Display omitted] •SNN improves hepatic steatosis and inflammation in MCD-diet-induced NASH mice.•SNN modulates gut microbiota and BA components (e.g. norDCA), and the responded microbiomes and BAs are correlated.•Activation of the colonic FXR-FGF15 pathway upon gut microbiome and BA interaction may contribute to the effects of SNN on NASH.