Suppressed hepatic bile acid signalling despite elevated production of primary and secondary bile acids in NAFLD
Abstract
OBJECTIVE: Bile acids are regulators of lipid and glucose metabolism, and modulate inflammation in the liver and other tissues. Primary bile acids such as cholic acid and chenodeoxycholic acid (CDCA) are produced in the liver, and converted into secondary bile acids such as deoxycholic acid (DCA) and lithocholic acid by gut microbiota. Here we investigated the possible roles of bile acids in non-alcoholic fatty liver disease (NAFLD) pathogenesis and the impact of the gut microbiome on bile acid signalling in NAFLD. DESIGN: Serum bile acid levels and fibroblast growth factor 19 (FGF19), liver gene expression profiles and gut microbiome compositions were determined in patients with NAFLD, high-fat diet-fed rats and their controls. RESULTS: -taurocholate cotransporting polypeptide and paraoxonase 1, no change in mRNA expression for small heterodimer partner and bile salt export pump, and reduced serum FGF19 were evidence of impaired FXR and fibroblast growth factor receptor 4 (FGFR4)-mediated signalling in NAFLD. Taurine and glycine metabolising bacteria were increased in the gut of patients with NAFLD, reflecting increased secondary bile acid production. Similar changes in liver gene expression and the gut microbiome were observed in high-fat diet-fed rats. CONCLUSIONS: The serum bile acid profile, the hepatic gene expression pattern and the gut microbiome composition consistently support an elevated bile acid production in NAFLD. The increased proportion of FXR antagonistic bile acid explains, at least in part, the suppression of hepatic FXR-mediated and FGFR4-mediated signalling. Our study suggests that future NAFLD intervention may target the components of FXR signalling, including the bile acid converting gut microbiome.
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Jiao et al. (2018) found that MAFLD patients present elevated primary and secondary bile acids, among which the proportion of DCA is increased and CDCA is decreased.
“Jiao et al. (2018) found that MAFLD patients present elevated primary and secondary bile acids, among which the proportion of DCA is increased and CDCA is decreased.”
From <i>Akkermansia muciniphila</i> alleviates <scp>high‐fat‐diet</scp> ‐related metabolic‐associated fatty liver disease by modulating gut microbiota and bile acids (2023) · cites this paper as Jiao et al. (2018)
MAFLD patients have enhanced hepatic CYP7A1 expression.
“Additionally, hepatic CYP7A1 expression is enhanced.”
From <i>Akkermansia muciniphila</i> alleviates <scp>high‐fat‐diet</scp> ‐related metabolic‐associated fatty liver disease by modulating gut microbiota and bile acids (2023) · cites this paper as Jiao et al. (2018)
In NASH, BA levels tend to increase and BA composition changes with increasing severity, and FXR and FGF19 signalling is impaired, resulting in increased BA synthesis.
“With increasing severity of NASH and fibrosis, BA levels tend to increase and the composition of BAs changes”
From Novel therapeutic targets for cholestatic and fatty liver disease (2022) · cites this paper as [91]
The gut microbiota may affect gastrointestinal transit through its regulation of bile acid synthesis, in which secondary bile acids may suppress FGF19- and FXR-mediated signaling, leading to induction of CYP7A1, elevated de novo bile acid synthesis, and improved colonic transit.
“First, the gut microbiota may affect gastrointestinal transit through its regulation of BA synthesis. The gut microbiota is equipped with enzymes for the production of secondary BAs, which may suppress the FGF19- and FXR-mediated signaling, leading to the induction of CYP7A1 [ 49 , 50 ], and consequently elevated de novo BA synthesis and improved colonic transit.”
From Role of gut microbiota in functional constipation (2021) · cites this paper as [49]
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“[624] demonstrated that NAFLD was associated with increased serum concentrations of primary and secondary BA.”
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“” Escherichia, Bilophila and Rhodobacter involved in BAs-mediating taurine and glycine metabolism were significantly increased in the faeces of NASH patients (Jiao et al., 2018).”
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“In the NAFLD condition, the proportion of BAs antagonizing the FXR activity increased, which may account for, at least in part, the reduction of FGF15/19 and FGFR4-mediated signaling [117].”
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“CYP7A1 [49, 50], and consequently elevated de novo BA synthesis”
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“Disorders of lipid metabolism usually result from abnormal BA metabolisms, and hepatic lipid accumulation is one of important inducers of NAFLD [8,58].”
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“Dysregulation of BA metabolism was linked to steatosis, inflammation, and fibrosis in patients with NAFLD (137).”
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Why Bile Acids Are So Important in Non-Alcoholic Fatty Liver Disease (NAFLD) Progression
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“Additionally, taurine and glycine metabolizing bacteria were increased in the gut of NAFLD patients, which reflects an increased secondary BA production [46].”
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“Likewise, a comprehensive study performed by Jiao et al have shown that circulating bile acid profile, hepatic gene expression pattern and gut microbiome composition in NASH are in favour of an increased proportion of FXR antagonist bile acids which could at least partially explain a reduced FXR signalling in NASH.(23…”
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“In fact, our research group has previously identified an association between Clostridium genus and an altered BA fecal metabolome [24], whereas Streptococcus has been linked with NASH or even cirrhosis and hepatocarcinoma development [40,44].”
BackgroundInfluentialAltered Microbiota Diversity and Bile Acid Signaling in Cirrhotic and Noncirrhotic NASH-HCC
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“Here, an increase in BA levels and an altered composition of the BA pool with an increase in secondary conjugated BA was observed (24).”
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“In NASH, the levels of serum FGF19, fibroblast growth factor receptor 4 (FGFR4), and bile acids are significantly increased, and results in impaired FXR and FGFR4-mediated signaling [317,318].”
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BackgroundInfluentialFibroblast Growth Factor 15/19: From Basic Functions to Therapeutic Perspectives
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“Under physiological concentrations, bile acids, especially hydrophilic secondary bile acids, play a role in the assembly of NLRP3 inflammasomes as negative regulators, and this effect requires functional FXR [36, 37].”
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Nonalcoholic Fatty Liver Disease: An Emerging Driver of Cardiac Arrhythmia
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Bile acids contribute to the development of non-alcoholic steatohepatitis in mice
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“…combination of traditional transcriptomics approaches with emerging technologies, including proteomics (Ordureau et al., 2014), metabolomics (Shah et al., 2012), and metagenomics (Jiao et al., 2017), will offer unprecedented opportunities to precisely elucidating and dissecting fibrosis mechanisms.”
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“In children with NAFLD, serum concentrations of primary and secondary BAs and intestinal secondary BA-producing bacteria are increased, whereas hepatic FXR-mediated and FGF receptor 4-mediated BA signaling is suppressed (108).”
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Microbial Metabolites: Critical Regulators in NAFLD
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“Additionally, patients with NAFLD exhibited higher serum levels of PBAs and SBAs [133].”
Recent advances on FXR-targeting therapeutics
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“Interestingly, serum FXR antagonistic bile acids lithocholic acid and deoxycholic acid were increased (similar to patients with NAFLD[19]), whereas tauro- β- muricholic acid (increased by FXR agonist[20]) was decreased in CSELKO mice (Figure S12A,B).”
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Bile Acids, Their Receptors, and the Gut Microbiota
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Metabolic Reprogramming of HCC: A New Microenvironment for Immune Responses
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Advances in the Involvement of Gut Microbiota in Pathophysiology of NAFLD
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“In addition, secondary BAs were increased in the intestine of patients with NAFLD via enhancing the metabolism of taurine and glycine (83).”
BackgroundChronic lead exposure induces fatty liver disease associated with the variations of gut microbiota
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The ameliorative effect of probiotics on diet-induced lipid metabolism disorders: A review
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“Importantly, recent studies have shown that the concentration of BAs was increased of patients with lipid metabolism disorders induced by HFD (Jiao et al. 2018).”
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“Diet-induced obese mice have higher levels of bile salt hydrolases, a class of bacterial enzymes involved in the conversion of primary to secondary BAs (92).”
Influential
- Authors
- Jiao, N., Baker, S. S., Chapa-Rodriguez, A., Liu, W., Nugent, C. A., Tsompana, M., Mastrandrea, L., Buck, M. J., Baker, R. D., Genco, R. J., Zhu, R., & Zhu, L.
- Affiliations
- Tongji University (CN)
- University at Buffalo, State University of New York (US)
- Department of Pediatrics, Digestive Diseases and Nutrition Center, The State University of New York at Buffalo, Buffalo, New York, USA
- Corresponding author
- Baker, Susan S
- Zhu, Lixin
- ORCID
- Venue
- Gut
- Publisher
- BMJ
- Published
- 2017-08-03
- Volume
- 67
- Issue
- 10
- Pages
- 1881-1891
- ISSN
- 0017-5749 (ISSN-L)
- 1468-3288
- OpenAlex
- W2605955022
- Cited by
- 737
- References
- 50
- Citations by year
- 2026: 81 · 2025: 112 · 2024: 128 · 2023: 105 · 2022: 93 · 2021: 83 · 2020: 68 · 2019: 44 · 2018: 17 · 2017: 4
- FWCI
- 15.93
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Gut (publishedVersion)
- PubMed (publishedVersion)
- HighWire Press Open Archive (submittedVersion)
- Funders
- GEM Community of Excellence, the University at Buffalo
- the University at Buffalo Departmental Start-Up Fund
- Natural Science Foundation of Shanghai
- National Natural Science Foundation of China
- the Peter and Tommy Fund, Inc., Buffalo, NY
- Topics
- Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
- Health Sciences › Medicine › Epidemiology › Liver Disease Diagnosis and Treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
- Keywords
- non-alcoholic fatty liver disease, bile acids, bile acid signaling, farnesoid X receptor, FGFR4, FGF19, gut microbiota, secondary bile acids, deoxycholic acid, lithocholic acid, taurine metabolism, hepatic gene expression, high-fat diet
- MeSH terms
- Gastrointestinal Microbiome, Receptor, Farnesoid X-Activated, Animals, Bile Acids and Salts, Cholesterol 7-alpha-Hydroxylase, Female, Fibroblast Growth Factors, Humans, Male, Middle Aged, Signal Transduction, Receptors, Cytoplasmic and Nuclear, Gene Expression Profiling, Rats, Diet, High-Fat, Non-alcoholic Fatty Liver Disease
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