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Rifaximin Ameliorates Non-alcoholic Steatohepatitis in Mice Through Regulating gut Microbiome-Related Bile Acids.

ABSTRACT: Non-alcoholic steatohepatitis (NASH) is the progressive stage of non-alcoholic fatty liver disease (NAFLD). The non-absorbable antibiotic rifaximin has been used for treatment of irritable bowel syndrome, traveling diarrhea, and hepatic encephalopathy, but the efficacy of rifaximin in NASH patients remains controversial. This study investigated the effects and underlying mechanisms of rifaximin treatment in mice with methionine and choline deficient (MCD) diet-induced NASH. We found that rifaximin greatly ameliorated hepatic steatosis, lobular inflammation, and fibrogenesis in MCD-fed mice. Bacterial 16S rRNA sequencing revealed that the gut microbiome was significantly altered in MCD-fed mice. Rifaximin treatment enriched 13 amplicon sequence variants (ASVs) belonging to the groups Muribaculaceae, Parabacteroides, Coriobacteriaceae_UCG-002, uncultured Oscillospiraceae, Dubosiella, Rikenellaceae_RC9_gut_group, Mucispirillum, and uncultured Desulfovibrionaceae. However, rifaximin treatment also reduced seven ASVs in the groups Aerococcus, Oscillospiraceae, uncultured Ruminococcaceae, Bilophila, Muribaculaceae, Helicobacter, and Alistipes in MCD-fed mice. Bile acid-targeted metabolomic analysis indicated that the MCD diet resulted in accumulation of primary bile acids and deoxycholic acid (DCA) in the ileum. Rifaximin delivery reduced DCA levels in MCD-fed mice. Correlation analysis further showed that DCA levels were associated with differentially abundant ASVs modulated by rifaximin. In conclusion, rifaximin may ameliorate NASH by decreasing ileal DCA through alteration of the gut microbiome in MCD-fed mice. Rifaximin treatment may therefore be a promising approach for NASH therapy in humans.

SUBMITTER: Jian J

PROVIDER: S-EPMC9017645 | biostudies-literature | 2022

REPOSITORIES: biostudies-literature

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Rifaximin Ameliorates Non-alcoholic Steatohepatitis in Mice Through Regulating gut Microbiome-Related Bile Acids.

Jian Jie J Nie Mei-Tong MT Xiang Baoyu B Qian Hui H Yin Chuan C Zhang Xin X Zhang Menghui M Zhu Xuan X Xie Wei-Fen WF

Frontiers in pharmacology 20220404

Non-alcoholic steatohepatitis (NASH) is the progressive stage of non-alcoholic fatty liver disease (NAFLD). The non-absorbable antibiotic rifaximin has been used for treatment of irritable bowel syndrome, traveling diarrhea, and hepatic encephalopathy, but the efficacy of rifaximin in NASH patients remains controversial. This study investigated the effects and underlying mechanisms of rifaximin treatment in mice with methionine and choline deficient (MCD) diet-induced NASH. We found that rifaxim ...[more]

PMID: 35450049

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Project description:Background & aimsThrough FXR and TGR5 signaling, bile acids (BAs) modulate lipid and glucose metabolism, inflammation and fibrosis. Hence, BAs returning to the liver after enteric secretion, modification and reabsorption may contribute to the pathogenesis of non-alcoholic steatohepatitis (NASH). Herein, we characterized the enterohepatic profile and signaling of BAs in preclinical models of NASH, and explored the consequences of experimental manipulation of BA composition.MethodsWe used high-fat diet (HFD)-fed foz/foz and high-fructose western diet-fed C57BL/6J mice, and compared them to their respective controls. Mice received a diet supplemented with deoxycholic acid (DCA) to modulate BA composition.ResultsCompared to controls, mice with NASH had lower concentrations of BAs in their portal blood and bile, while systemic BA concentrations were not significantly altered. Notably, the concentrations of secondary BAs, and especially of DCA, and the ratio of secondary to primary BAs were strikingly lower in bile and portal blood of mice with NASH. Hence, portal blood was poor in FXR and TGR5 ligands, and conferred poor anti-inflammatory protection in mice with NASH. Enhanced primary BAs synthesis and conversion of secondary to primary BAs in NASH livers contributed to the depletion in secondary BAs. Dietary DCA supplementation in HFD-fed foz/foz mice restored the BA concentrations in portal blood, increased TGR5 and FXR signaling, improved the dysmetabolic status, protected from steatosis and hepatocellular ballooning, and reduced macrophage infiltration.ConclusionsBA composition in the enterohepatic cycle, but not in systemic circulation, is profoundly altered in preclinical models of NASH, with specific depletion in secondary BAs. Dietary correction of the BA profile protected from NASH, supporting a role for enterohepatic BAs in the pathogenesis of NASH.Lay summaryThis study clearly demonstrates that the alterations of enterohepatic bile acids significantly contribute to the development of non-alcoholic steatohepatitis in relevant preclinical models. Indeed, experimental modulation of bile acid composition restored perturbed FXR and TGR5 signaling and prevented non-alcoholic steatohepatitis and associated metabolic disorders.

Project description:The aim of this study was to investigate the protective effects and potential mechanisms of Tetrahydrocurcumin (THC) on methionine-choline-deficient diet (MCD)-induced MASH in C57BL/6 mice by using multi-omics techniques. The C57BL/6 mice were fed with the MCD for 8 weeks to establish a MASH model, while THC (100 mg·kg-1·d-1) and obeticholic acid (6.5 mg·kg-1·d-1) were administered via gavage to the THC group and the positive control group, respectively. The biochemical indexes of the serum and liver were detected using kits. Liver tissue sections were taken to observe the pathomorphological changes. Serum lipid and bile acid contents were measured via LC-MS, and the changes in ileal intestinal flora were detected by 16S rDNA high-throughput sequencing technology. The results revealed that THC significantly attenuated oxidative stress and lipid accumulation in NCTC-1469 cells and relieved hepatic injury and oxidative stress, reduced hepatic TG content, and improved hepatic steatosis in mice. THC alleviated 34 lipid abnormalities caused by the MCD; increased the abundance and diversity of intestinal flora, the ratio of Firmicutes to Bacteroidota, and the abundance of the probiotic (Verrucomicrobiota, Christensenellaceae, Akkermansiaceae, Lachnospiraceae, Desulfovibrionaceae); and reduced the abundance of obesity-associated pathogenic flora such as Firmicutes. Bile acid analysis showed that THC administration reduced the levels of serum toxic bile acid 7-KDCA and CA. In addition, RT-qPCR studies showed that THC down-regulated the transcript levels of the hepatic lipogenesis-related genes Srebp1c, Acc1, Scd1, and Fas, and up-regulated the transcript levels of the hepatic bile acid secretion-related genes Mrp2 and Bsep. The above results suggest that THC may alleviate MCD-induced MASH by downregulating liver Srebp1c, Acc1, Scd1, and Fas levels to inhibit lipid synthesis, upregulating Mrp2 and Bsep levels to regulate serum toxic BA levels, up-regulating the abundance of intestinal probiotic flora, and down-regulating the abundance of intestinal harmful bacterial flora. The multi-omics findings from the above study identified potential new mechanisms by which THC alleviates MASH, providing new reference targets for the development of anti-MASH drugs. These results also offer a basis for screening clinical diagnostic biomarkers for MASH and provide new directions for personalized diagnosis and treatment.

Project description:Diarrhea is one of the most common infirmities affecting international travelers, occurring in 20 to 50% of persons from industrialized countries visiting developing regions. Enterotoxigenic Escherichia coli (ETEC) is the most common causative agent and is isolated from approximately half of the cases of traveler's diarrhea. Rifaximin, a largely water-insoluble, nonabsorbable (<0.4%) antibiotic that inhibits bacterial RNA synthesis, is approved for use for the treatment of traveler's diarrhea caused by diarrheagenic E. coli. However, the drug has minimal effect on the bacterial flora or the infecting E. coli strain in the aqueous environment of the colon. The purpose of the present study was to evaluate the antimicrobial effect and bioavailability of rifaximin in aqueous solution in the presence and absence of physiologic concentrations of bile acids. The methods used included growth measurement of ETEC (strain H10407), rifaximin solubility measurements, total bacterial protein determination, and assessment of the functional activity of rifaximin by monitoring inhibition of bacterial beta-galactosidase expression. Solubility studies showed rifaximin to be 70- to 120-fold more soluble in bile acids (approximately 30% in 4 mM bile acids) than in aqueous solution. Addition of both purified bile acids and human bile to rifaximin at subinhibitory and inhibitory concentrations significantly improved the drug's anti-ETEC effect by 71% and 73%, respectively, after 4 h. This observation was confirmed by showing a decrease in the overall amount of total bacterial protein expressed during incubation of rifaximin plus bile acids. Rifaximin-treated samples containing bile acids inhibited the expression of ETEC beta-galactosidase at a higher magnitude than samples that did not contain bile acids. The study provides data showing that bile acids solubilize rifaximin on a dose-response basis, increasing the drug's bioavailability and antimicrobial effect. These observations suggest that rifaximin may be more effective in the treatment of infections in the small intestine, due to the higher concentration of bile in this region of the gastrointestinal tract than in the colon. The water insolubility of rifaximin is the likely explanation for the drug's minimal effects on colonic flora and fecal pathogens, despite in vitro susceptibility.

Project description:Prior research has indicated that the gut-lung-axis can be influenced by the intestinal microbiota, thereby impacting lung immunity. Rifaximin is a broad-spectrum antibacterial drug that can maintain the homeostasis of intestinal microflora. In this study, we established an influenza A virus (IAV)-infected mice model with or without rifaximin supplementation to investigate whether rifaximin could ameliorate lung injury induced by IAV and explore the molecular mechanism involved. Our results showed that IAV caused significant weight loss and disrupted the structure of the lung and intestine. The analysis results of 16S rRNA and metabolomics indicated a notable reduction in the levels of probiotics Lachnoclostridium, Ruminococcaceae_UCG-013, and tryptophan metabolites in the fecal samples of mice infected with IAV. In contrast, supplementation with 50 mg/kg rifaximin reversed these changes, including promoting the repair of the lung barrier and increasing the abundance of Muribaculum, Papillibacter and tryptophan-related metabolites content in the feces. Additionally, rifaximin treatment increased ILC3 cell numbers, IL-22 level, and the expression of RORγ and STAT-3 protein in the lung. Furthermore, our findings demonstrated that the administration of rifaximin can mitigate damage to the intestinal barrier while enhancing the expression of AHR, IDO-1, and tight junction proteins in the small intestine. Overall, our results provided that rifaximin alleviated the imbalance in gut microbiota homeostasis induced by IAV infection and promoted the production of tryptophan-related metabolites. Tryptophan functions as a signal to facilitate the activation and movement of ILC3 cells from the intestine to the lung through the AHR/STAT3/IL-22 pathway, thereby aiding in the restoration of the barrier. KEY POINTS: • Rifaximin ameliorated IAV infection-caused lung barrier injury and induced ILC3 cell activation. • Rifaximin alleviated IAV-induced gut dysbiosis and recovered tryptophan metabolism. • Tryptophan mediates rifaximin-induced ILC3 cell activation via the AHR/STAT3/IL-22 pathway.

Project description:BackgroundDihydromyricetin (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.MethodsAfter 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.ResultsThe 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).ConclusionsThe 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).

Dataset Information

Rifaximin Ameliorates Non-alcoholic Steatohepatitis in Mice Through Regulating gut Microbiome-Related Bile Acids.

Publications

Rifaximin Ameliorates Non-alcoholic Steatohepatitis in Mice Through Regulating gut Microbiome-Related Bile Acids.

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