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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“[ 85 ] Furthermore, when intestinal microflora composition is altered, conjugated BAs and their metabolites can be increased, which inhibits intestinal FXR signaling leading to reduced BA secretion from the liver and promotion of NAFLD.”
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“It has been noticed that obesity and obesity-related diseases such as type 2 diabetes (T2D), non-alcoholic fatty liver disease (NAFLD) and cardiovascular diseases (CVD) are associated with altered BAs metabolism (Li et al., 2021); meanwhile BAs intervention could effectively control and prevent obesity and NAFLD (Jiao…”
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“prausnitzii displayed among individuals suffering from such disorders [35,36].”
BackgroundWang, R., Ren, Y., Bao, T., Wang, T., Li, Y., Liu, Y., Zhang, X., Yang, S., & Wang, H. (2022) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2022.02.033 · Cited by 30
Ju, J., Zhang, C., Yang, J., Yang, Q., Yin, P., & Sun, X. (2023) · PeerJ · doi:10.7717/peerj.14842 · Cited by 30
“BAs mainly function by activating receptors to regulate glucose, lipid, and energy metabolism ( Jiao et al., 2018 ; Xie et al., 2021 ).”
Jin, C., Zhou, T., Duan, Z., Deng, Y., Zhang, X., Changyi, X., He, G., He, G., Zhou, Y. H., & Li, S. (2023) · Journal of Ethnopharmacology · doi:10.1016/j.jep.2023.116950 · Cited by 29
Zhu, Z., Xu, Y., Xia, Y., Jia, X., Chen, Y., Liu, Y., Zhang, L., Chai, H., & Sun, L. (2023) · Life Sciences · doi:10.1016/j.lfs.2023.122304 · Cited by 34
Mao, Q., Lin, B., Zhang, W., Zhang, Y., Zhang, Y., Cao, Q., & Xu, M. (2024) · Frontiers in Pharmacology · doi:10.3389/fphar.2024.1371574 · Cited by 29
Wang, X., Jin, Y., Di, C., Zeng, Y., Zhou, Y., Chen, Y., Pan, Z., Li, Z., & Ling, W. (2024) · Nutrients · doi:10.3390/nu16081169 · Cited by 29
Nuclear receptors and non-alcoholic fatty liver disease: An update
Xiao, Y., Gonzalez, F. J., Huang, M., & Bi, H. (2020) · Liver Research · doi:10.1016/j.livres.2020.03.001 · Cited by 29
Plaza‐Díaz, J., Solis‐Urra, P., Aragón‐Vela, J., Rodríguez‐Rodríguez, F., Arancibia, J. E. O., & Álvarez‐Mercado, A. I. (2021) · Biomedicines · doi:10.3390/biomedicines9020145 · Cited by 31
“In addition, important variables are related to the gut microbiota in the characterization of NASH, such as the serum bile acid profile and the hepatic gene expression pattern that support an increased bile acid production in NASH patients [53].”
BackgroundZhao, S., Fu, H., Zhou, T., Cai, M., Huang, Y., Gan, Q., Zhang, C., Qian, C., Wang, J., Zhang, Z., et al. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.772368 · Cited by 26
“Age 54 (49–57) 58 (44–66) 59 (43-66) 58 (51-71) 58 (46-66) 61 (41-68) 0.”
Chen, Q., Zhao, L., Mei, L., Zhao, X., Han, P., Liu, J., Meng, C., Li, R., Zhong, R., Wang, K., et al. (2023) · Frontiers in Pharmacology · doi:10.3389/fphar.2023.1163694 · Cited by 29
“Disorder of the bile acid pool is related to multiple diseases, including obesity and MAFLD (Devkota et al., 2012; Jiao et al., 2018).”
BackgroundIntestinal FGF15 regulates bile acid and cholesterol metabolism but not glucose and energy balance
Bozadjieva-Kramer, N., Shin, J. H., Li, Z., Rupp, A. C., Miller, N., Kernodle, S., Lanthier, N., Henry, P., Seshadri, N., Myronovych, A., et al. (2024) · JCI Insight · doi:10.1172/jci.insight.174164 · Cited by 28
“Several reports have shown that circulating FGF19 levels are lower in individuals with obesity (28–31) and MASLD (32, 33) supporting the role of FGF19 as a hormone in metabolism.”
BackgroundWang, Y., Chen, X., Huws, S., Xu, G., Li, J., Ren, J., Xu, J., Guan, L. L., Yao, J., & Wu, S. (2024) · Microbiome · doi:10.1186/s40168-024-01964-0 · Cited by 31
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Miao, R., Zhan, S., Cui, S., & Qu, X. (2022) · The FASEB Journal · doi:10.1096/fj.202200148rr · Cited by 29
Role of gut microbial metabolites in nonalcoholic fatty liver disease
Zhao, Z. H., Lai, J. K., Qiao, L., & Fan, J. (2019) · Journal of Digestive Diseases · doi:10.1111/1751-2980.12709 · Cited by 28
“NAFLD, and the percentage of DCA is increased while CDCA is decreased.(47) Furthermore, total serum bile acid is positively correlated”
BackgroundThe Species of Gut Bacteria Associated with Antitumor Immunity in Cancer Therapy
Qi, X., Liu, Y., Hussein, S., Choi, G., Kimchi, E. T., Staveley-O’Carroll, K. F., & Li, G. (2022) · Cells · doi:10.3390/cells11223684 · Cited by 29
Gut–Liver Axis Dysregulation in Portal Hypertension: Emerging Frontiers
Lombardi, M., Troisi, J., Motta, B. M., Torre, P., Masarone, M., & Persico, M. (2024) · Nutrients · doi:10.3390/nu16071025 · Cited by 27
“In these contexts, the GM seems to be characterized by an excess of bacteria that generate secondary bile acids, such as deoxycholic acid, which serves as an FXR antagonistic bile acid, suppressing FXR-and FGFR4-mediated signaling [36].”
BackgroundSun, K., Zhu, N.-L., Huang, S., Qu, H. Y., Gu, Y., Li, Q., Liu, J., & Leng, Y. (2024) · Acta Pharmacologica Sinica · doi:10.1038/s41401-024-01303-x · Cited by 29
Trauner, M., Karpen, S. J., & Dawson, P. A. (2025) · Hepatology · doi:10.1097/hep.0000000000001438 · Cited by 27
“[73,74] Impaired FXR activation in MASLD could be explained in part by increased free fatty acids interfering with FXR-mediated activation of SHP, thus promoting BA synthesis and uptake through upregulated CYP7A1 and NTCP. [75] Moreover, insulin resistance may also contribute to dysregulated BA…”
l-Fucose ameliorates high-fat diet-induced obesity and hepatic steatosis in mice
Wu, G., Niu, M., Tang, W., Hu, J., Wei, G., He, Z., Chen, Y., Jiang, Y., & Chen, P. (2018) · Journal of Translational Medicine · doi:10.1186/s12967-018-1718-x · Cited by 27
Fuchs, C. D., Krivanec, S., Steinacher, D., Mlitz, V., Wahlstrom, A. M., Ståhlman, M., Claudel, T., Scharnagl, H., Stojaković, T., Marschall, H., et al. (2020) · Liver International · doi:10.1111/liv.14423 · Cited by 26
Tian, M., Yan, J., Zhang, H., Wei, Y., Zhang, M., Rao, Z., Zhang, M., Wang, H., Wang, Y., & Li, X. (2021) · Environmental Pollution · doi:10.1016/j.envpol.2022.118837 · Cited by 27
Gillard, J., & Leclercq, I. A. (2023) · Clinical Science · doi:10.1042/cs20220697 · Cited by 29
Li, M., Cheng, D., Peng, C., Huang, Y., Geng, J., Huang, G., Wang, T., & Xu, A. (2023) · Chinese Medicine · doi:10.1186/s13020-023-00752-6 · Cited by 28
“Primary bile acids can be metabolized into secondary bile acids (DCA and LCA) by secondary BA-producing gut microbiota [65, 66].”
BackgroundBioactive metabolites: A clue to the link between MASLD and CKD?
Chen, W., Zhang, J.-H., Chen, L., Byrne, C. D., Targher, G., Luo, L., Ni, Y., Zheng, M., & Sun, D. (2024) · Clinical and Molecular Hepatology · doi:10.3350/cmh.2024.0782 · Cited by 27
Nuclear receptors: a bridge linking the gut microbiome and the host
Wang, Z., Chen, W., & Wang, Y. (2021) · Molecular Medicine · doi:10.1186/s10020-021-00407-y · Cited by 29
“ADRP: Adipose differentiation‑related protein; AFLD: Alcoholic fatty liver disease; AHR: Aryl hydrocarbon receptor; ALA: α‑Linolenic acid; ALD: Alcoholic liver disease; AMPK: Adenosine monophosphate‑activated protein kinase; ANGPTL4: Angiopoietin‑like 4; ATG16L1: Autophagy related 16 like 1; BAs: Bile acids; BSH: Bile…”
BackgroundInfluentialYang, L., Dai, Y., He, H., Liu, Z., Liao, S., Zhang, Y., Liao, G., & An, Z. (2022) · Frontiers in Microbiology · doi:10.3389/fmicb.2022.969757 · Cited by 26
Riehl, L., Fürst, J., Kress, M., & Rykalo, N. A. (2024) · Frontiers in Neuroscience · doi:10.3389/fnins.2023.1302957 · Cited by 30
Farnesoid X receptor: From Structure to Function and Its Pharmacology in Liver Fibrosis
Ding, C., Wang, Z., Dou, X., Yang, Q., Ning, Y., Kao, S., Sang, X., Hao, M., Wang, K., Peng, M., et al. (2023) · Aging and Disease · doi:10.14336/ad.2023.0830 · Cited by 29
“In the context of metabolic diseases, there is an upregulation of FXR antagonistic DCA in serum, coupled with a downregulation of CDCA (an FXR agonist) [38].”
BackgroundLuo, Y., Peng, S.-J., Cheng, J., Yang, H., Lin, L., Yang, G., Jin, Y., Wang, Q., & Wen, Z. (2024) · Journal of Functional Biomaterials · doi:10.3390/jfb15080236 · Cited by 28
“Bile acids and their receptors are considered latent therapeutic targets for intervening in NAFLD [68].”
Background
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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