Bile acids as key modulators of the brain-Gut-Microbiota axis in alzheimer’s disease

Mulak, Agata

doi:10.3233/jad-210608

Cited by 114Gut microbiota and healthAlzheimer's disease research and treatmentsDrug Transport and Resistance Mechanisms

Bile acids as key modulators of the brain-Gut-Microbiota axis in alzheimer’s disease

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Mulak, Agata·2021·Journal of Alzheimer s Disease

DOI 10.3233/jad-210608PMC PMC8673511

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Abstract

Recently, the concept of the brain-gut-microbiota (BGM) axis disturbances in the pathogenesis of Alzheimer's disease (AD) has been receiving growing attention. At the same time, accumulating data revealing complex interplay between bile acids (BAs), gut microbiota, and host metabolism have shed new light on a potential impact of BAs on the BGM axis. The crosstalk between BAs and gut microbiota is based on reciprocal interactions since microbiota determines BA metabolism, while BAs affect gut microbiota composition. Secondary BAs as microbe-derived neuroactive molecules may affect each of three main routes through which interactions within the BGM axis occur including neural, immune, and neuroendocrine pathways. BAs participate in the regulation of multiple gut-derived molecule release since their receptors are expressed on various cells. The presence of BAs and their receptors in the brain implies a direct effect of BAs on the regulation of neurological functions. Experimental and clinical data confirm that disturbances in BA signaling are present in the course of AD. Disturbed ratio of primary to secondary BAs as well as alterations in BA concertation in serum and brain samples have been reported. An age-related shift in the gut microbiota composition associated with its decreased diversity and stability observed in AD patients may significantly affect BA metabolism and signaling. Given recent evidence on BA neuroprotective and anti-inflammatory effects, new therapeutic targets have been explored including gut microbiota modulation by probiotics and dietary interventions, ursodeoxycholic acid supplementation, and use of BA receptor agonists.

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The BA-microbiota axis modulates the immunoregulatory environment along the gut.
“The BA-microbiota axis modulates the immunoregulatory environment along the gut (303).”
From Signalling cognition: The gut microbiota and hypothalamic-pituitary-adrenal axis (2023) · cites this paper as [303]
Circulating BA levels significantly influence the CNS's BA profile.
“circulating BA levels significantly influence the CNS’s BA profile (303).”
From Signalling cognition: The gut microbiota and hypothalamic-pituitary-adrenal axis (2023) · cites this paper as [303]

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Signalling cognition: The gut microbiota and hypothalamic-pituitary-adrenal axis
Rusch, J. A., Layden, B. T., & Dugas, L. R. (2023) · Frontiers in Endocrinology · doi:10.3389/fendo.2023.1130689 · Cited by 415 · see citing works
Tauroursodeoxycholic acid: a potential therapeutic tool in neurodegenerative diseases
Khalaf, K., Tornese, P., Cocco, A., & Albanese, A. (2022) · Translational Neurodegeneration · doi:10.1186/s40035-022-00307-z · Cited by 150 · see citing works
Gut Microbiota Metabolites in Major Depressive Disorder—Deep Insights into Their Pathophysiological Role and Potential Translational Applications
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Gut Microbiota, an Additional Hallmark of Human Aging and Neurodegeneration
Molinero, N., Antón‐Fernández, A., Hernández, F., Ávila, J., Bartolomé, B., & Moreno-Arribas, M. V. (2023) · Neuroscience · doi:10.1016/j.neuroscience.2023.02.014 · Cited by 96 · see citing works
Bile salt hydrolase: The complexity behind its mechanism in relation to lowering-cholesterol lactobacilli probiotics
Agolino, G., Pino, A., Vaccalluzzo, A., Cristofolini, M., Solieri, L., Caggia, C., & Randazzo, C. L. (2024) · Journal of Functional Foods · doi:10.1016/j.jff.2024.106357 · Cited by 87 · see citing works
Therapeutics for neurodegenerative diseases by targeting the gut microbiome: from bench to bedside
Ma, Y., Li, X., Yu, J., & Wang, Y. (2024) · Translational Neurodegeneration · doi:10.1186/s40035-024-00404-1 · Cited by 87 · see citing works
Gut microbiota-driven metabolic alterations reveal gut–brain communication in Alzheimer’s disease model mice
Chen, Y., Li, Y., Fan, Y., Chen, S., Chen, L., Chen, Y., & Chen, Y. (2024) · Gut Microbes · doi:10.1080/19490976.2024.2302310 · Cited by 90 · see citing works
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Gut microbiota-driven neuroinflammation in Alzheimer's disease: from mechanisms to therapeutic opportunities
Lei, W., Cheng, Y., Liu, X., Gao, J., Zhu, Z., Ding, W., Xu, X., Li, Y., Ling, Z., Jiang, R., et al. (2025) · Frontiers in Immunology · doi:10.3389/fimmu.2025.1582119 · Cited by 68 · see citing works
The potential role of mitochondria in the microbiota-gut-brain axis: Implications for brain health
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The microbiota–gut–brain axis in Huntington's disease: pathogenic mechanisms and therapeutic targets
Ekwudo, M. N., Gubert, C., & Hannan, A. J. (2024) · FEBS Journal · doi:10.1111/febs.17102 · Cited by 59 · see citing works
The microbiota-gut-brain-immune interface in the pathogenesis of neuroinflammatory diseases: a narrative review of the emerging literature
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Inflammatory Bowel Disease and Neurodegenerative Diseases
Kim, J. S., Chen, M., Wang, H. E., Lu, C., Wang, Y., & Zhang, B. (2023) · Gut and Liver · doi:10.5009/gnl220523 · Cited by 53 · see citing works
Circulating Bile Acids as Biomarkers for Disease Diagnosis and Prevention
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Connecting the Gut Microbiota and Neurodegenerative Diseases: the Role of Bile Acids
Wang, S., Xu, C., Liu, H., Wei, W., Zhou, X., Qian, H., Zhou, L., Zhang, H., Wu, L. M., Chen, Z., et al. (2023) · Molecular Neurobiology · doi:10.1007/s12035-023-03340-9 · Cited by 50 · see citing works
Review of Metabolomics-Based Biomarker Research for Parkinson’s Disease
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The clinical and mechanistic roles of bile acids in depression, Alzheimer's disease, and stroke
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TGR5 deficiency in excitatory neurons ameliorates Alzheimer’s pathology by regulating APP processing
Li, C., Wang, L., Xie, W., Chen, E., Chen, Y., Li, H., Can, D., Lei, A., Wang, Y., & Zhang, J. (2024) · Science Advances · doi:10.1126/sciadv.ado1855 · Cited by 43 · see citing works
The potential role of gut microbiota-derived metabolites as regulators of metabolic syndrome-associated mitochondrial and endolysosomal dysfunction in Alzheimer’s disease
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Influence of human gut microbiome on the healthy and the neurodegenerative aging
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The microbiota–gut–brain axis in mental and neurodegenerative disorders: opportunities for prevention and intervention
Yassin, L. K., Skrabulyte-Barbulescu, J., Alshamsi, S. H., Saeed, S., Alkuwaiti, S. H., Almazrouei, S., Alnuaimi, A., BaniYas, S., Aldhaheri, D., Alderei, M., et al. (2025) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2025.1667448 · Cited by 46 · see citing works
Molecular mechanism and therapeutic strategy of bile acids in Alzheimer’s disease from the emerging perspective of the microbiota–gut–brain axis
Wu, M., Cheng, Y., Zhang, R., Han, W., Jiang, H., Bi, C., Zhang, Z., Ye, M., Lin, X., & Liu, Z. (2024) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2024.117228 · Cited by 38 · see citing works
Bile acid profile associated with CSF and PET biomarkers in Alzheimer’s disease
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Advances in dietary polyphenols: Regulation of inflammatory bowel disease (IBD) via bile acid metabolism and the gut-brain axis
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Does the Gut Microbial Metabolome Really Matter? The Connection between GUT Metabolome and Neurological Disorders
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The gut-immune-brain axis in neurodevelopment and neurological disorders
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Liver Steatosis and Steatohepatitis Alter Bile Acid Receptors in Brain and Induce Neuroinflammation: A Contribution of Circulating Bile Acids and Blood-Brain Barrier
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Tauroursodeoxycholic acid: a bile acid that may be used for the prevention and treatment of Alzheimer’s disease
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Mechanisms by which microbiome-derived metabolites exert their impacts on neurodegeneration
Kern, L., Mastandrea, I., Melekhova, A., & Elinav, E. (2024) · Cell chemical biology · doi:10.1016/j.chembiol.2024.08.014 · Cited by 26 · see citing works
Role of Microbiota-Modified Bile Acids in the Regulation of Intracellular Organelles and Neurodegenerative Diseases
Kiriyama, Y., & Nochi, H. (2023) · Genes · doi:10.3390/genes14040825 · Cited by 22 · see citing works
Beyond metabolic messengers: Bile acids and TGR5 as pharmacotherapeutic intervention for psychiatric disorders
Darmanto, A. G., Yen, T., Jan, J., Linh, T. T. D., Taliyan, R., Yang, C. H., & Sheu, J. (2024) · Pharmacological Research · doi:10.1016/j.phrs.2024.107564 · Cited by 21 · see citing works
Microbiome influences on neuro-immune interactions in neurodegenerative disease
Menees, K. B., Otero, B. A., & Tansey, M. G. (2022) · International review of neurobiology · doi:10.1016/bs.irn.2022.07.006 · Cited by 23 · see citing works
Relationship Between Plasma Lipopolysaccharides, Gut Microbiota, and Dementia: A Cross-Sectional Study
Saji, N., Saito, Y., Yamashita, T., Murotani, K., Tsuduki, T., Hisada, T., Sugimoto, T., Niida, S., Toba, K., & Sakurai, T. (2022) · Journal of Alzheimer s Disease · doi:10.3233/jad-215653 · Cited by 20 · see citing works
Water extract of goji berries improves neuroinflammation induced by a high-fat and high-fructose diet based on the bile acid-mediated gut–brain axis pathway
Dong, W., Huang, Y., Shu, Y., Fan, X., Tian, X., Yan, Y., Mi, J., Lu, L., Zeng, X., & Cao, Y. (2023) · Food & Function · doi:10.1039/d3fo02651e · Cited by 20 · see citing works
Neuroprotective effects of mesenchymal stromal cells in mouse models of Alzheimer’s Disease: The Mediating role of gut microbes and their metabolites via the Microbiome-Gut-Brain axis
Xing, C., Zhang, X., Wang, D., Chen, H., Gao, X., Sun, C., Guo, W., Roshan, S., Li, Y., Hang, Z., et al. (2024) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2024.08.047 · Cited by 20 · see citing works
Microbial Metabolomes in Alzheimer’s Disease: From Pathogenesis to Therapeutic Potential
Borrego-Ruiz, A., & Borrego, J. J. (2025) · Current Issues in Molecular Biology · doi:10.3390/cimb47090724 · Cited by 20 · see citing works
Current View on PPAR-α and Its Relation to Neurosteroids in Alzheimer’s Disease and Other Neuropsychiatric Disorders: Promising Targets in a Therapeutic Strategy
Żulińska, S., Strosznajder, A. K., & Strosznajder, J. B. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms25137106 · Cited by 17 · see citing works
Integrated untargeted and targeted metabolomics to reveal therapeutic effect and mechanism of Alpiniae oxyphyllae fructus on Alzheimer’s disease in APP/PS1 mice
Zhou, S., Liu, L., Zhang, Y., Zhang, Z., Li, H., Fan, F., He, J., Kang, J., & Zuo, L. (2023) · Frontiers in Pharmacology · doi:10.3389/fphar.2022.1104954 · Cited by 15 · see citing works
The role of gut microbiota metabolites in the regeneration and protection of nervous tissue: a narrative review
Kostiuchenko, O., Lushnikova, I., & Skibo, G. G. (2024) · Regenerative medicine reports . · doi:10.4103/regenmed.regenmed-d-24-00004 · Cited by 14 · see citing works
Microbiota-gut-brain axis dysregulation in Alzheimer’s disease and its modulation through probiotic supplementation
Marizzoni, M., Mombelli, E., Alboni, S., Rosa, M., Moretti, D. V., Mirabelli, P., Coppola, L., Luongo, D., Salamone, D., Saleri, S., et al. (2025) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2025.106138 · Cited by 14 · see citing works
Comprehensive summary of steroid metabolism in Comamonas testosteroni TA441: entire degradation process of basic four rings and removal of C12 hydroxyl group
Horinouchi, M., & Hayashi, T. (2023) · Applied and Environmental Microbiology · doi:10.1128/aem.00143-23 · Cited by 14 · see citing works
Can Small Molecules Provide Clues on Disease Progression in Cerebrospinal Fluid from Mild Cognitive Impairment and Alzheimer’s Disease Patients?
Andújar, B. T., Mary, A., Venegas, C., Cheng, T., Zaslavsky, L. Y., Bolton, E., Heneka, M. T., & Schymanski, E. (2024) · Environmental Science & Technology · doi:10.1021/acs.est.3c10490 · Cited by 14 · see citing works
The two-directional prospective association between inflammatory bowel disease and neurodegenerative disorders: a systematic review and meta-analysis based on longitudinal studies
Zong, J., Yang, Y. X., Wang, H., Zhang, H., Yang, X., & Yang, X. (2024) · Frontiers in Immunology · doi:10.3389/fimmu.2024.1325908 · Cited by 14 · see citing works
The Role of Livestock Antibiotic Use in Microbiota Dysbiosis and Neuroinflammation
Silvestro, S., Biondo, C., Midiri, A., Lucia, B. P. A., & Mancuso, G. (2025) · Antibiotics · doi:10.3390/antibiotics14060608 · Cited by 13 · see citing works
Gut microbiome‐derived metabolites in Alzheimer's disease: Regulation of immunity and potential for therapeutics
Chandra, S., & Vassar, R. J. (2024) · Immunological Reviews · doi:10.1111/imr.13412 · Cited by 14 · see citing works
Microbiota from Preterm Infants Who Develop Necrotizing Enterocolitis Drives the Neurodevelopment Impairment in a Humanized Mouse Model
Lu, J. N., Drobyshevsky, A., Lu, L., Yu, Y., Caplan, M. S., & Claud, E. C. (2023) · Microorganisms · doi:10.3390/microorganisms11051131 · Cited by 13 · see citing works
The role of bile acid-activated receptor TGR5 in inflammation and liver diseases
Xiang, H., Xiang, H., Wang, S., Wu, P., Luo, Z., & Zhang, J. (2026) · Frontiers in Physiology · doi:10.3389/fphys.2026.1747341 · Cited by 12 · see citing works
Small intestine-residing probiotics suppress neurotoxic bile acid production via extracellular vesicle-mediated inhibition of Clostridium scindens
Chin, W.-L., Lee, B., Hsu, Q.-Y., Hou, C., Pai, M.-C., Lin, C., & Hsu, W.-H. (2025) · Food Research International · doi:10.1016/j.foodres.2025.116049 · Cited by 12 · see citing works
Machine learning approaches for neurological disease prediction: A systematic review
Fatima, A., & Masood, S. (2024) · Expert Systems · doi:10.1111/exsy.13569 · Cited by 10 · see citing works
Decoding TGR5: A comprehensive review of its impact on cerebral diseases
Zhang, Z., Zhang, Y., Peng, H., Yu, Q., Kang, X., Liu, Y., Zheng, Y., Cheng, F., Wang, X., & Li, F. (2025) · Pharmacological Research · doi:10.1016/j.phrs.2025.107671 · Cited by 10 · see citing works
Gut bacteria-derived metabolites and their implications in mental health and neurological diseases
Srivastava, R., & Gupta, M. K. (2025) · World Journal of Microbiology and Biotechnology · doi:10.1007/s11274-025-04656-5 · Cited by 10 · see citing works
Effects of saponins Rb1 and Re in American ginseng intervention on intestinal microbiota of aging model
Shi, M., Fan, H., Liu, H., & Zhang, Y. (2024) · Frontiers in Nutrition · doi:10.3389/fnut.2024.1435778 · Cited by 9 · see citing works
Gut microbiota-bile acid metabolic disorder involved in the cognitive impairments in epilepsy through HO-1 dependent ferroptosis
Li, X., Ji, J., Li, J., Li, S., Luo, Q., Gu, M., Yin, X., Zhang, M., Fan, H., & Yao, R. (2025) · Journal of Pharmaceutical Analysis · doi:10.1016/j.jpha.2025.101291 · Cited by 9 · see citing works
Unveiling Role of Gut Microbiota in Alzheimer’s Disease: Mechanisms, Challenges and Future Perspectives
Radhakrishnan, P., Viswanathan, K., Sonali, L., Suneetha, C., & Muthusamy, S. (2025) · Current Alzheimer Research · doi:10.2174/0115672050403066250904112611 · Cited by 12 · see citing works
Interactions of bile acids and gut microbiota modulate neurological health: a comprehensive review on mechanisms and therapeutic potential of dietary phytochemicals
Wang, J., Zhang, Y., Wu, Q., Zhong, Y., Xu, Z., & Yang, J. (2026) · Frontiers in Microbiology · doi:10.3389/fmicb.2026.1757551 · Cited by 9 · see citing works
Genome-scale metabolic models in translational medicine: the current status and potential of machine learning in improving the effectiveness of the models
Turanlı, B., Gülfidan, G., Aydogan, O. O., Kula, C., Selvaraj, G., & Arğa, K. Y. (2024) · Molecular Omics · doi:10.1039/d3mo00152k · Cited by 9 · see citing works
Research progress on immunometabolism and gut microbiota in cryptococcal meningitis: mechanisms and therapeutic implications
Wen, S., Liu, M., Pan, C., Zhang, L., Yan, R., & Xu, Z. (2025) · Frontiers in Neuroscience · doi:10.3389/fnins.2025.1622349 · Cited by 8 · see citing works
Special Issue: “New Trends in Alzheimer’s Disease Research: From Molecular Mechanisms to Therapeutics: 2nd Edition”
Cacabelos, R. (2025) · International Journal of Molecular Sciences · doi:10.3390/ijms26157175 · Cited by 8 · see citing works
Cholesterol metabolism regulates macrophage function and inflammation-related diseases
Xiao, J., Wang, S., Jin, M., Wei, B., & Wang, H. (2025) · Trends in Cell Biology · doi:10.1016/j.tcb.2025.10.003 · Cited by 7 · see citing works
UHPLC‐Orbitrap‐Fusion‐TMS‐Based Metabolomics Study of Phenylpropionamides in the Seed of Cannabis sativa L. against Alzheimer's Disease
Wu, D., Liu, Y., Guan, W., Pan, J., Kuang, H., & Yang, B. (2023) · Chemistry & Biodiversity · doi:10.1002/cbdv.202201047 · Cited by 6 · see citing works
Microbiota–gut–brain axis and related therapeutics in Alzheimer’s disease: prospects for multitherapy and inflammation control
Li, J., Zhang, F., Zhao, L., & Dong, C. (2023) · Reviews in the Neurosciences · doi:10.1515/revneuro-2023-0006 · Cited by 6 · see citing works
Enterohepatocentrism as the basis of human psychosomatic pathology
Lazebnik, L. B., & Туркина, С. В. (2023) · Экспериментальная и клиническая гастроэнтерология · doi:10.31146/1682-8658-ecg-216-8-9-23 · Cited by 6 · see citing works
Bile acid signaling, metabolism, and aging
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Authors: Mulak, A.
Affiliations: Wroclaw Medical University (PL)
Corresponding author: Mulak, Agata
ORCID: Mulak, Agata
Venue: Journal of Alzheimer s Disease
Publisher: SAGE Publications
Published: 2021-11-09
Volume: 84
Issue: 2
Pages: 461-477
ISSN: 1387-2877 (ISSN-L)
1875-8908
DOI: 10.3233/jad-210608
PMC: PMC8673511
OpenAlex: W3203807665
Cited by: 114
References: 185
Citations by year: 2026: 29 · 2025: 26 · 2024: 29 · 2023: 17 · 2022: 12 · 2021: 1
FWCI: 1.55
Type: journal article
Language: en
Open access: hybrid
doi.org
Licence: cc-by-nc
creativecommons.org/licenses/by-nc/4.0/ (unspecified)
Locations: Journal of Alzheimer s Disease (publishedVersion, cc-by-nc)
PubMed Central (publishedVersion, cc-by-nc)
PubMed (publishedVersion)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
Keywords: bile acids, brain-gut-microbiota axis
MeSH terms: Neuroprotection, Brain-Gut Axis, Alzheimer Disease, Bile Acids and Salts, Humans, Signal Transduction

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Bile acids as key modulators of the brain-Gut-Microbiota axis in alzheimer’s disease

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