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 ... -  《-》

Gut Microbiota Plays Essential Roles in Soyasaponin's Preventive Bioactivities against Steatohepatitis in the Methionine and Choline Deficient (MCD) Diet-Induced Non-Alcoholic Steatohepatitis (NASH) Mice.

Su C ，Wang J ，Luo H ，Chen J ，Lin F ，Mo J ，Xiong F ，Zha L ... -  《-》

Intermittent Fasting Alleviates Non-Alcoholic Steatohepatitis by Regulating Bile Acid Metabolism and Promoting Fecal Bile Acid Excretion in High-Fat and High-Cholesterol Diet Fed Mice.

Intermittent fasting (IF) has a protective role across a wide range of chronic disorders, including obesity, diabetes, and cardiovascular disease, but its protection against non-alcoholic steatohepatitis (NASH) is still lacking. This study seeks to investigate how IF alleviates NASH by regulating gut microbiota and bile acids (BAs) composition. Male C57BL/6 mice are fed a high-fat and high-cholesterol (HFHC) diet for 16 weeks to establish a NASH model. Mice then continued HFHC feeding and are treated with or without every other day fasting for 10 weeks. Hepatic pathology is assessed using hematoxylin-eosin staining. Gut microbiota of the cecum are profiled using 16S rDNA gene sequencing and the levels of BAs in serum, colon contents, and feces are measured using ultra-performance liquid chromatography-tandem mass spectrometry. Results indicate that IF significantly decreases murine body weight, insulin resistance, hepatic steatosis, ballooning, and lobular inflammation. IF reshapes the gut microbiota, reduces the accumulation of serum BAs, and increases total colonic and fecal BAs. Moreover, IF increases the expression of cholesterol 7α-hydroxylase 1 in liver, but decreases the expressions of both farnesoid-X-receptor and fibroblast growth factor 15 in the ileum. IF alleviates NASH by regulating bile acid metabolism and promoting fecal bile acid excretion.

Lin X ，Zhu X ，Xin Y ，Zhang P ，Xiao Y ，He T ，Guo H ... -  《-》

Dihydromyricetin ameliorated nonalcoholic steatohepatitis in mice by regulating the composition of serous lipids, bile acids and ileal microflora.

Dihydromyricetin (DMY) is a natural flavonoid with anti-nonalcoholic steatohepatitis (NASH) activity. However, the effects of DMY on the composition of lipids and bile acids (BAs) in serum, and gut microbiota (GM) in ileum of mice with NASH are not clear. After male C57BL/6 mice was fed with methionine and choline deficiency (MCD) diet and simultaneously administered with DMY (300 mg/kg/day) by gavage for 8 weeks, the pathological changes of liver tissue were observed by Oil Red O, hematoxylin eosin and Masson staining, the levels of serum alaninea minotransferase, aspartate aminotransferase and liver triglyceride, malonic dialdehyde were detected by the detection kits, the composition and contents of serum lipids and BAs were detected by Liquid Chromatograph-Mass Spectrometry, the mRNA levels of hepatic BAs homeostasis-related genes were detected by RT-qPCR, and microbiological diversity in ileum was analyzed by 16S rDNA sequencing. The results showed that the significant changes including 29 lipids, 4 BAs (23-nor-deoxycholic acid, ursodeoxycholic acid, 7-ketodeoxycholic acid and cholic acid), 2 BA transporters (Mrp2 and Oatp1b2) and 8 GMs between MCD and DMY groups. Among them, DMY treatment significantly down-regulated 21 lipids, 4 BAs mentioned above, the ratio of Firmicutes/Bacteroidota and the abundance of Erysipelotrichaceae, Faecalibacuium, significantly up-regulated 8 lipids and 5 GMs (Verrucomicrobiota, Bacteroidota, Actinobacteria, Akkermansiaceae and Akkermansia). The results suggested that DMY may alleviate MCD diet-induced NASH through decreasing the serum levels of toxic BAs which regulated by liver Oatp1b2 and Mrp2, regulating the metabolism of related lipids, and up-regulating intestinal probiotics (Actinobacteria and Verrucomicrobiota at the phylum level; Akkermansiaceae at the family level; Akkermansiaat at the genus level) and inhibiting intestinal harmful bacteria (Firmicutes at the phylum level; Erysipelotrichaceae at the family level; Faecalibaculum at the genus level).

Miao X ，Luo P ，Liu J ，Wang J ，Chen Y ... -  《Lipids in Health and Disease》

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 ... -  《-》