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

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.

Li C ，Zhou W ，Li M ，Shu X ，Zhang L ，Ji G ... -  《-》

Soyasaponin A(2) Alleviates Steatohepatitis Possibly through Regulating Bile Acids and Gut Microbiota in the Methionine and Choline-Deficient (MCD) Diet-induced Nonalcoholic Steatohepatitis (NASH) Mice.

Nonalcoholic steatohepatitis (NASH) is a chronic progressive disease with complex pathogenesis of which the bile acids (BAs) and gut microbiota are involved. Soyasaponins (SS) exhibits many health-promoting effects including hepatoprotection, but its prevention against NASH is unclear. This study aims to investigate the preventive bioactivities of SS monomer (SS-A2 ) against NASH and further clarify its mechanism by targeting the BAs and gut microbiota. The methionine and choline deficient (MCD) diet-fed male C57BL/6 mice were intervened with obeticholic acid or SS-A2 for 16 weeks. Hepatic pathology is assessed by hematoxylin-eosin and Masson's trichrome staining. BAs in serum, liver, and colon are measured by ultra-performance liquid chromatography coupled with triple quadrupole mass spectrometry (UPLC-TQMS). Gut microbiota in caecum are determined by 16S rDNA amplicon sequencing. In the MCD diet-induced NASH mice, SS-A2 significantly reduces hepatic steatosis, lobular inflammation, ballooning, nonalcoholic fatty liver disease activity score (NAS) scores, and fibrosis, decreases Erysipelotrichaceae (Faecalibaculum) and Lactobacillaceae (Lactobacillus) and increases Desulfovibrionaceae (Desulfovibrio). Moreover, SS-A2 reduces serum BAs accumulation and promotes fecal BAs excretion. SS-A2 changes the BAs profiles in both liver and serum and specifically increases the taurohyodeoxycholic acid (THDCA) level. Faecalibaculum is negatively correlated with serum THDCA. SS-A2 alleviates steatohepatitis possibly through regulating BAs and gut microbiota in the MCD diet-induced NASH mice.

Xiong F ，Zheng Z ，Xiao L ，Su C ，Chen J ，Gu X ，Tang J ，Zhao Y ，Luo H ，Zha L ... -  《-》

Qiang-Gan formula extract improves non-alcoholic steatohepatitis via regulating bile acid metabolism and gut microbiota in mice.

Qiang-Gan formula is a traditional Chinese medicine formula, which has been widely used in treating liver diseases in China. To investigate the effect of Qiang-Gan formula extract (QGE) on non-alcoholic steatohepatitis (NASH) and its underlying possible mechanisms. The high-performance liquid chromatography finger-print method was used for the quality control of chemical components in QGE. Methionine- and choline-deficient diet-induced NASH mice were administrated with QGE via gavage for four weeks. Phenotypic parameters including liver histological change as well as serum levels of alanine transaminase (ALT), aspartate transaminase (AST) were detected. Bile acid profile in the serum, liver and fecal samples was analyzed by gas chromatography-mass spectrometer technique, and fecal microbiota was detected by 16S rDNA sequencing. Expression of liver G protein-coupled bile acid receptor 1 (TGR5), farnesiod X receptor (FXR), tumor necrosis factor-α (TNF-α), interleukin 1β (IL-1β) as well as molecules in nuclear factor kappa B (NF-κB) pathway was assayed by immunohistochemistry staining, RT-qPCR, or Western blot, respectively. QGE alleviated liver inflammation, reduced serum ALT and AST levels and liver TNF-α and IL-1β expression in NASH mice. It also decreased liver and serum BA concentration and increased fecal lithocholicacid (LCA) production in this animal model. QGE altered the structure of gut microbiota, predominantly increased LCA-producing bacteria Bacteroides and Clostridium in NASH mice. In addition, the expression of liver TGR5 but not FXR was increased, and the molecules in NF-κB pathway were decreased in QGE-treated NASH mice. QGE was effective in preventing NASH, possibly by regulation of gut microbiota-mediated LCA production, promotion of TGR5 expression and suppression of the NF-κB activation.

Li Q ，Li M ，Li F ，Zhou W ，Dang Y ，Zhang L ，Ji G ... -  《-》

Hepatoprotective and antioxidant activities of extracts from Salvia-Nelumbinis naturalis against nonalcoholic steatohepatitis induced by methionine- and choline-deficient diet in mice.

Liu Y ，Song H ，Wang L ，Xu H ，Shu X ，Zhang L ，Li Y ，Li D ，Ji G ... -  《Journal of Translational Medicine》

Dysregulated FXR-FGF19 signaling and choline metabolism are associated with gut dysbiosis and hyperplasia in a novel pig model of pediatric NASH.

Hernandez GV ，Smith VA ，Melnyk M ，Burd MA ，Sprayberry KA ，Edwards MS ，Peterson DG ，Bennet DC ，Fanter RK ，Columbus DA ，Steibel JP ，Glanz H ，Immoos C ，Rice MS ，Santiago-Rodriguez TM ，Blank J ，VanderKelen JJ ，Kitts CL ，Piccolo BD ，La Frano MR ，Burrin DG ，Maj M ，Manjarin R ... -  《-》