The presence and severity of nonalcoholic steatohepatitis is associated with specific changes in circulating bile acids

Puri, Puneet; Daita, Kalyani; Joyce, Andrew; Mirshahi, Faridoddin; Santhekadur, Prasanna K.; Cazanave, Sophie C.; Luketic, Velimir A.; Siddiqui, Mohammad Shadab; Boyett, Sherry; Min, Hae‐Ki; Kumar, Divya P.; Kohli, Rohit; Zhou, Huiping; Hylemon, Phillip B.; Contos, Melissa J.; Idowu, Michael O.; Sanyal, Arun J.

doi:10.1002/hep.29359

Cited by 325 publications

(370 citation statements)

References 39 publications

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“…Regarding circulating BAs, the main difference between the two phenotypes was the reduction of the primary BAs and the increase of the secondary BAs in the protected group. This is in agreement with a recent study which described increased primary and reduced secondary BAs in serum of NAFLD and NASH patients . Previous studies have also reported an increase in serum and fecal primary BAs in NAFLD patients.…”

Section: Discussionsupporting

confidence: 93%

“…Furthermore, supplementation of a HFD with soybean protein increased the secondary/primary BA ratio in mice, conferring metabolic benefits . This increase in primary BAs in NAFLD could be attributed to an enhanced synthesis through CYP7A1, the rate‐limiting enzyme in this process, that has been reported to be overexpressed in NAFLD patients and HFD‐fed rats . In the present study, CYP7A1 downregulation has been shown in protected mice, justifying the reduction in primary αMCA and βMCA.…”

Section: Discussionsupporting

confidence: 56%

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A Network Involving Gut Microbiota, Circulating Bile Acids, and Hepatic Metabolism Genes That Protects Against Non‐Alcoholic Fatty Liver Disease

Petrov

García‐Mediavilla

Guzmán

et al. 2019

Molecular Nutrition Food Res

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Scope Gut microbiota contributes to non‐alcoholic fatty liver disease (NAFLD) pathogenesis by multiple mechanisms not yet completely understood. Novel differential features between germ‐free mice (GFm) transplanted with protective or non‐protective cecal microbiota against NAFLD are investigated. Methods and results Gut microbiota composition, plasma, and fecal bile acids (BAs) and liver mRNAs are quantified in GFm recipients from four donor mice differing in NAFLD severity (control diet, high‐fat diet [HFD]‐responder, HFD‐non‐responder, and quercetin‐supplemented HFD). Transplanted GFm are on control or HFD for 16‐weeks. Multivariate analysis shows that GFm colonized with microbiota from HFD‐non‐responder and quercetin supplemented‐HFD donors (protected against NAFLD) clusters together, whereas GFm colonized with microbiota from control and HFD‐responder mice (non‐protected against NAFLD) establishes another cluster. Protected phenotype is associated with increased gut Desulfovibrio and Oscillospira, reduced gut Bacteroides and Oribacterium, lower primary and higher secondary BAs in plasma and feces, induction of hepatic BA transporters, and repression of hepatic lipogenic and BA synthesis genes. Conclusion Protective gut microbiota associates with increased specific secondary BAs, which likely inhibit lipogenic pathways and enhance bile flow in the liver. This novel cross‐talk between gut and liver, via plasma BAs, that promotes protection against NAFLD may have clinical and nutritional relevance.

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Section: Discussionsupporting

confidence: 93%

Section: Discussionsupporting

confidence: 56%

A Network Involving Gut Microbiota, Circulating Bile Acids, and Hepatic Metabolism Genes That Protects Against Non‐Alcoholic Fatty Liver Disease

Petrov

García‐Mediavilla

Guzmán

et al. 2019

Molecular Nutrition Food Res

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“…In addition, plasma level of glycocholate, taurocholate, glycochenodeoxycholate, taurochenodeoxycholate and ursodeoxycholic acid were increased in patients with NASH compared with patients with NAFL 87. Levels of taurolithocholic acid, glycocholate and taurocholate correlated with severity of portal inflammation, lobular inflammation, steatosis and hepatocyte ballooning, respectively 87. The ratio of DCA to CDCA was significantly increased in patients with NASH,70 84 85 and levels of FXR were lower in liver tissues from paediatric patients with NAFLD compared with healthy children 88.…”

Section: Microbiota-derived Metabolites In Nafldmentioning

confidence: 92%

“…Interestingly, another research group found that liver levels of cholic acid and DCA were significantly decreased in patients with NASH 86. In addition, plasma level of glycocholate, taurocholate, glycochenodeoxycholate, taurochenodeoxycholate and ursodeoxycholic acid were increased in patients with NASH compared with patients with NAFL 87. Levels of taurolithocholic acid, glycocholate and taurocholate correlated with severity of portal inflammation, lobular inflammation, steatosis and hepatocyte ballooning, respectively 87.…”

Section: Microbiota-derived Metabolites In Nafldmentioning

confidence: 99%

Small metabolites, possible big changes: a microbiota-centered view of non-alcoholic fatty liver disease

Chu

Duan

Yang

et al. 2018

Gut

271

209

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The spectrum of non-alcoholic fatty liver disease (NAFLD) ranges from simple hepatic steatosis, commonly associated with obesity, to non-alcoholic steatohepatitis, which can progress to fibrosis, cirrhosis and hepatocellular carcinoma. NAFLD pathophysiology involves environmental, genetic and metabolic factors, as well as changes in the intestinal microbiota and their products. Dysfunction of the intestinal barrier can contribute to NAFLD development and progression. Although there are technical limitations in assessing intestinal permeability in humans and the number of patients in these studies is rather small, fewer than half of the patients have increased intestinal permeability and translocation of bacterial products. Microbe-derived metabolites and the signalling pathways they affect might play more important roles in development of NAFLD. We review the microbial metabolites that contribute to the development of NAFLD, such as trimethylamine, bile acids, short-chain fatty acids and ethanol. We discuss the mechanisms by which metabolites produced by microbes might affect disease progression and/or serve as therapeutic targets or biomarkers for NAFLD.

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“…In line with this hypothesis, the investigators show that the expression of SHP (positive FXR target) is markedly down‐regulated in livers of patients with NAFL or NASH, whereas cholesterol 7 alpha‐hydroxylase (CYP7A1; negatively regulated by FXR through small heterodimer partner [SHP]) is strongly induced. Consistently, serum 7‐alpha‐hydroxy‐4‐cholesten‐3‐one levels are increased in NASH . Whether CDCA‐mediated induction of FXR transcriptional activity is, in fact, modulated by CA has, however, not been formally tested on the molecular level.…”

mentioning

confidence: 99%

Bile acids in nonalcoholic steatohepatitis: Pathophysiological driving force or innocent bystanders?

Jahn

Geier

2017

Hepatology

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The presence and severity of nonalcoholic steatohepatitis is associated with specific changes in circulating bile acids

Cited by 325 publications

References 39 publications

A Network Involving Gut Microbiota, Circulating Bile Acids, and Hepatic Metabolism Genes That Protects Against Non‐Alcoholic Fatty Liver Disease

A Network Involving Gut Microbiota, Circulating Bile Acids, and Hepatic Metabolism Genes That Protects Against Non‐Alcoholic Fatty Liver Disease

Small metabolites, possible big changes: a microbiota-centered view of non-alcoholic fatty liver disease

Bile acids in nonalcoholic steatohepatitis: Pathophysiological driving force or innocent bystanders?

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