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》

Beneficial effects of silibinin on serum lipids, bile acids, and gut microbiota in methionine-choline-deficient diet-induced mice.

Silibinin (SIL) is a flavonoid lignin isolated from the fruit and seeds of silybum marianum that exhibits good therapeutic potential for NASH. However, the effects of SIL on serum lipids, bile acids (BAs), and gut microbiota (GM) in NASH mice remain unknown. The present work aimed to explore the beneficial effects of SIL supplementation on serum lipids, bile acids, and gut microbiota in MCD mice. After male C57BL/6 mice were fed with a methionine-choline deficient (MCD) diet and simultaneously gavaged with SIL (20 mg/kg. d) for 8 weeks, the pathological changes of liver tissue were observed by oil red O, haematoxylin-eosin, and Masson tricolor staining; the levels of serum AST and ALT, and liver TG and MDA were detected by assay kits; metabonomics and 16S rDNA sequencing were used to analyze the composition of serum lipids and BAs and the abundance of GM; and the mRNA expression levels of hepatic genes related to BAs homeostasis were detected by RT-qPCR. The results indicated that SIL treatment decreased the levels of 26 lipids (including four arachidonic acids, seven FFAs, 12 acyl carnitines, and three GPs) and two BAs (23-DCA, GLCA), while Dubosiella increased the levels of 10 lipids (including TxB3, PG16:0_18:1, Cer t18:0/24:0 and 7 TGs), five BAs (β-MCA, α-MCA, UDCA, 3-oxo-DCA and HCA), and two GMs (Verrucomicrobiota and Akkermansiaceae) of MCD mice, but had no significant effect on the mRNA expression of CYP7A1, CYP27A1, Bsep, Mrp2, Ntcp, or Oatp1b2. Therefore, influencing GM composition and then regulating the levels of serum lipids and BAs through enterohepatic axis should be an important mechanism of SIL-induced alleviative effect on MCD mice. More importantly, we found that SIL had a good coordination in regulating the abundance of GM and the contents of serum lipids and BAs in MCD mice, that is, when the abundance of probiotics was up-regulated, the content of beneficial unsaturated fatty acids in serum was up-regulated, while the serum levels of harmful lipids and BAs were down-regulated. The alleviating effect of SIL on NASH may be closely related to the correction of intestinal bacteria disorder, serum bile acid, and lipid metabolic disturbance in mice.

Wang W ，Zhai T ，Luo P ，Miao X ，Wang J ，Chen Y ... -  《-》

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 ... -  《-》

Honokiol affects the composition of gut microbiota and the metabolism of lipid and bile acid in methionine-choline deficiency diet-induced NASH mice.

Honokiol (HNK), one of the main active components of Magnolia officinalis, has a positive effect on non-alcoholic steatohepatitis (NASH). However, the effects of HNK on the composition of serum lipids and bile acids (BAs) and gut microbiota (GM) of NASH mice are still unknown.C57BL/6 mice were fed with methionine-choline deficiency (MCD) diet and gavaged with HNK (20 mg/kg/d) for 8 weeks, then the serum lipids and BAs were detected by LC-MS, the composition of ileum microflora and the mRNA expression of hepatic BAs homeostasis related genes were analyzed by 16S rDNA sequencing and RT-qPCR, respectively. HNK treatment decreased the degree of hepatic lipid drops, inflammatory cell infiltration and fibrosis. Meantime, the serum levels of 34 lipids and 4 BAs in MCD mice were significantly altered by HNK treatment, as well as the increased abundance of Ruminococcaceae, Caulobacteraceae and Brevundimonas, and the decreased abundance of Firmicutes and Dubosiella. Besides, HNK treatment increased the hepatic mRNA expression of Oatp1b2 in MCD mice. The ameliorating effect of HNK on NASH may be partly related to its correction on the disorders of GM, serum lipids and BAs of MCD mice.

Zhai T ，Wang J ，Chen Y 《-》

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 ... -  《-》