The DOI matches its Crossref record; 49 of the 50 references it cites were found in a registry or an index.
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.”
From Akkermansia muciniphila alleviates high‐fat‐diet ‐related metabolic‐associated fatty liver disease by modulating gut microbiota and bile acids (2023) · cites this paper as Jiao et al. (2018)
In the citing paper
“Additionally, hepatic CYP7A1 expression is enhanced.”
From Akkermansia muciniphila alleviates high‐fat‐diet ‐related metabolic‐associated fatty liver disease by modulating gut microbiota and bile acids (2023) · cites this paper as Jiao et al. (2018)
In the citing paper
“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]
In the citing paper
“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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“63 – 65 However, the mechanisms driving differences in circulating BA and the gut microbiota metabolism in these studies are not well-established.”
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“A disrupted BA pool composition has been linked to metabolic disorders such as obesity, type 2 diabetes mellitus (T2DM) [4], and metabolic dysfunction-associated steatotic liver disease (MASLD) [5, 6].”
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“In poultry, bile acids (BAs) are classified into primary and secondary BAs (Jiao et al., 2018).”
An Atlas of Inter-Organ Metabolite Trafficking in Health and Atherogenic Conditions
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“Additionally, the report of cholestasis induced by NAFLD [26, 27] indicated that bile acid production was significantly increased during the NAFLD condition and the proportion of FXR antagonistic bile acid was elevated, thereby explaining hepatic FXR and FGFR4 signaling suppression.”
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“Moreover, NAFLD is also associated with a deranged bile acid metabolism (18), in particular their flow on the GI tract is enhanced, producing local inflammation and focal defects on the intestinal mucosa, thus possibly driving the carcinogenic process.”
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BackgroundMetabolic drivers of MASLD and MASH: from hormonal imbalance to fibrosis
Gastaldelli, A., Scoditti, E., & Macedo, M. P. (2026) · Diabetologia · doi:10.1007/s00125-026-06774-7 · Cited by 11
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BackgroundNAFLDkb: A Knowledge Base and Platform for Drug Development against Nonalcoholic Fatty Liver Disease
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“Nevertheless, the expression level of CYP7A1 and BSEP in the DM group was significantly lower than in the NC group (Fig.”
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Maj, M. A., Gehani, T. R., Immoos, C. E., Medrano, M. S., Fanter, R. K., Strand, C. R., Glanz, H., Piccolo, B. D., Abo-Ismail, M. K., Frano, M. R. L., et al. (2022) · Brain Sciences · doi:10.3390/brainsci12091193 · Cited by 9
The gut’s feeling on bile acid signaling in NAFLD
Chiang, J. Y. L. (2018) · HepatoBiliary Surgery and Nutrition · doi:10.21037/hbsn.2018.01.02 · Cited by 9
“reported recently that the serum bile acids concentrations and the percent of deoxycholic acid (DCA) were significantly increased while the percent of chenodeoxycholic acid (CDCA) was decreased, and the ratio of DCA + ursodeoxycholic acid (UDCA) to CDCA + cholic acid (CA) was increased in patients with NAFLD compared…”
Gallstone and Gallbladder Disease: Biliary Tract and Cholangiopathies
Ceci, L., Han, Y., Krutsinger, K., Baiocchi, L., Wu, N., Kundu, D., Kyritsi, K., Zhou, T., Gaudio, E., Francis, H., et al. (2023) · Comprehensive physiology · doi:10.1002/cphy.c220028 · Cited by 17
“Bacteria that metabolize taurine and glycine, two critical components in producing secondary BAs are increased (156).”
Mancera‐Hurtado, Y., López-Contreras, B. E., Flores-López, R., Villamil‐Ramírez, H., Del-Rio-Navarro, B. E., Canizales‐Quinteros, S., & Morán‐Ramos, S. (2023) · Obesity · doi:10.1002/oby.23797 · Cited by 8
“Interestingly, serum levels of FGF19, a main regulator of hepatic BA metabolism whose secretion is regulated by the BA-FXR signaling pathway, were significantly lower in children with MetS (p = 0.016; Figure 3).”
BackgroundResultInfluentialSecondary bile acids are associated with body lipid accumulation in obese pigs
Hu, Y., Wu, A., Yan, H., Pu, J., Luo, J., Zheng, P., Luo, Y., Yu, J., He, J., Yu, B., et al. (2024) · Animal nutrition · doi:10.1016/j.aninu.2024.04.019 · Cited by 8
Dynamic pattern of postprandial bile acids in paediatric non‐alcoholic fatty liver disease
Huang, J., Lin, H., Liu, A., Wu, W., Alisi, A., Loomba, R. S., Xu, C., Xiang, W., Shao, J., Dong, G., et al. (2024) · Liver International · doi:10.1111/liv.16054 · Cited by 8
“19 Our data also revealed that only We also found GHCA and THCA had significantly lower post-prandial concentrations in OWOB-NAFLD and OWOB than in HC (Figure 4H,I).”
InfluentialWang, S., Zhao, C., Huang, X., Gao, Y., Qiu, Y., Jiao, R., Zhu, H., Ding, H., Lin, R., & He, Z. (2024) · Journal of Functional Foods · doi:10.1016/j.jff.2024.106466 · Cited by 9
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Bile acids and gestational diabetes mellitus: exploring the link and implications - a review
Lu, C., Gao, Z., & Lei, X. (2025) · Frontiers in Endocrinology · doi:10.3389/fendo.2025.1574228 · Cited by 11
“…more versatile molecules with diverse functions (17), including promoting intestinal epithelial regeneration (18, 19), regulating gene expression (20, 21), in fl uencing insulin secretion (22, 23), epigenetic mechanisms (24, 25), fi brogenesis (26), lipid metabolism (27)and glucose metabolism (28).”
Chandra, M., Li, T., & Tong, W. (2025) · Toxicological Sciences · doi:10.1093/toxsci/kfaf100 · Cited by 8
“Dysregulation of these pathways has been linked to liver disorders, with impaired bile secretion contributing to cholestasis (Trauner et al. 1998) and non-alcoholic fatty liver disease (NAFLD) (Jiao et al. 2018), whereas hepatitis C virus is a major driver of liver fibrosis, steatosis, hepatocellular carcinoma, and li…”
Genomic medicine in hepatology: mechanisms and liver treatment strategies
Kozlov, D., Rodimova, S. A., Filatov, P. V., Mozherov, A. M., Timashev, P. S., Zyuzin, M. V., & Kuznetsova, D. S. (2025) · Molecular Medicine · doi:10.1186/s10020-025-01358-4 · Cited by 9
“Recently the role of gut–liver axis in progression of NAFLD/NASH garnered significant attention [318–323].”
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“Numerous studies have shown that MASLD patients have increased levels of total BAs, increased hepatic BA synthesis, and intestinal flora disorders leading to an imbalance in secondary BA metabolism, which promotes disease progression [52].”
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MiR-203 is an anti-obese microRNA by targeting apical sodium-dependent bile acid transporter
Liu, X., Cheng, F., Bai, X., Zhao, T., Zhao, L., Wang, L., Li, M., Wu, X., Chen, X., Tang, P., et al. (2022) · iScience · doi:10.1016/j.isci.2022.104708 · Cited by 8
Gao, F., Guan, D., Wang, G., Zhang, L., He, J., Lv, W., Zhang, X., Tao, W., Dai, Y., Xu, S., et al. (2022) · Frontiers in Pharmacology · doi:10.3389/fphar.2022.882764 · Cited by 8
“Free BAs (CA, CDCA, DCA, and LCA) act as key signal molecules in the activation of FXR, inhibit the promotion of 7 α-hydroxylase, downregulate the gene expression of 7 α-hydroxylase and reduce the synthesis of BAs (Kliewer and Mangelsdorf, 2015).”
BackgroundInfluentialChen, L., Chen, L., Li, X., Lin, Q., Zhu, Y., Zhang, Q., Tan, D., He, Y., & Wang, Y. (2023) · Frontiers in Endocrinology · doi:10.3389/fendo.2022.1034494 · Cited by 8
“(8) found that the expression of bile acid synthesis enzymes (CYP7A1, CYP8B1, and CYP27A1) and two transporter proteins (OATP1B1 and OATP1B3) were increased in NASH patients.”
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Danger-associated metabolites trigger metaflammation: A crowbar in cardiometabolic diseases
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The role of gut microbiota associated metabolites in digestive disorders
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“Some studies revealed that BAs are involved in the pathology of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis that can progress to HCC [88,89].”
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“Clinical studies have demonstrated that during the progression of metabolic dysfunction-associated fatty liver disease (MAFLD), bile acid levels increase (21), and this phenomenon is closely linked to the bile acid dysregulation induced by obesity-and type 2 diabetes (T2D) (22, 23).”
Peng, Q., Hao, L., Li, S., Yu, F., Li, N., & Hu, X. (2025) · Frontiers in Pharmacology · doi:10.3389/fphar.2025.1640873 · Cited by 7
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Exploring the roles of non-coding RNAs in liver regeneration
Li, P., Ma, X., Huang, D., & Gu, X. (2024) · Non-coding RNA Research · doi:10.1016/j.ncrna.2024.04.003 · Cited by 8
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Metadata
- 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 › Hepatology › 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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