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
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Gegen-Qinlian decoction alleviates metabolic dysfunction-associated steatohepatitis by modulating the microbiota-bile acid axis in mice.
Metabolic dysfunction-associated steatohepatitis (MASH) is the progressive form of metabolic dysfunction-associated steatotic liver disease (MASLD), and is currently the most prevalent chronic liver disease worldwide. Gegen-Qinlian decoction (GQD), a classical Traditional Chinese Medicine (TCM) formula from Treatise on Febrile Diseases, has been historically used to treat heat-dampness syndromes. Recent studies revealed that GQD is effective in treating MASH, but the underlying mechanisms remain unknown.
This study aims to evaluate the therapeutic effect of GQD on MASH and explore the potential mechanisms targeting the gut microbiota-bile acid (BA) axis.
Phytochemical profiling of GQD was performed using UPLC-Q-TOF-MS. MASH was induced in mice via a fructose-, palmitate-, and cholesterol-enriched (FPC) diet, followed by treatment with low-, medium-, or high-dose GQD. H&E and oil red O staining were utilized to examine the histological change, and serum lipids and enzymes were biochemically analyzed. 16SrDNA sequencing was applied to analyze the alteration of the gut microbiota, and the gas chromatography-mass spectrometry technique was introduced to investigate the fecal bile acid (BA) profile. Serum lipopolysaccharide (LPS) concentrations were analyzed by enzyme-linked immunosorbent assay. Intestinal tight junction proteins (ZO1, Occludin) and BA receptors (FXR, TGR5, and VDR) were detected by Western blot and immunofluorescence staining.
The quality of GQD was confirmed, and GQD treatment improved hepatic steatosis, reduced the content of liver triglyceride (20-40 % reduction, p < 0.01) and cholesterol (20-25 % reduction, p < 0.01) in FPC-induced MASH mice. High-dose GQD further decreased serum TC (3.97 ± 1.00 vs 5.51 ± 1.11, p < 0.05), LDL-c (0.53 ± 0.18 vs 1.07 ± 0.28, p < 0.01), ALT (31.90 ± 6.20 vs 47.90 ± 12.78, p < 0.05) and ALP (90.83 ± 13.46 vs 132.90 ± 23.67, p < 0.05) levels, suggesting the effects of GQD in counteracting metabolic inflammation. GQD treatment restored gut microbiota diversity and reversed gut dysbiosis by decreasing the abundance of pathogenic bacteria, resulting in reduced serum LPS while enhancing intestinal tight junction proteins (ZO1, Occludin). Concurrently, GQD treatment reshaped fecal BA profiles, increased intestinal TGR5/VDR expression, with BA shifts strongly correlating to microbiota changes.
GQD alleviated hepatic and metabolic disorders in MASH mice, possibly through reversing gut dysbiosis and modulating BA profile. Targeting the microbiota-BA axis represents a promising pattern for TCM prescriptions in treating MASH.
Shu X
，Cao Y
，Wu Y
，Chen M
，Zhao W
，Ji G
，Zhang L
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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
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