Gut microbiome-linked metabolites in the pathobiology of major depression with or without anxiety-a role for bile acids
Open accessAbstract
Background The gut microbiome may play a role in the pathogenesis of neuropsychiatric diseases including major depressive disorder (MDD). Bile acids (BAs) are steroid acids that are synthesized in the liver from cholesterol and further processed by gut-bacterial enzymes, thus requiring both human and gut microbiome enzymatic processes in their metabolism. BAs participate in a range of important host functions such as lipid transport and metabolism, cellular signaling and regulation of energy homeostasis. BAs have recently been implicated in the pathophysiology of Alzheimer's and several other neuropsychiatric diseases, but the biochemical underpinnings of these gut microbiome-linked metabolites in the pathophysiology of depression and anxiety remains largely unknown. Method Using targeted metabolomics, we profiled primary and secondary BAs in the baseline serum samples of 208 untreated outpatients with MDD. We assessed the relationship of BA concentrations and the severity of depressive and anxiety symptoms as defined by the 17-item Hamilton Depression Rating Scale (HRSD 17 ) and the 14-item Hamilton Anxiety Rating Scale (HRSA-Total), respectively. We also evaluated whether the baseline metabolic profile of BA informs about treatment outcomes. Results The concentration of the primary BA chenodeoxycholic acid (CDCA) was significantly lower at baseline in both severely depressed (log 2 fold difference (LFD) = −0.48; p = 0.021) and highly anxious (LFD = −0.43; p = 0.021) participants compared to participants with less severe symptoms. The gut bacteria-derived secondary BAs produced from CDCA such as lithocholic acid (LCA) and several of its metabolites, and their ratios to primary BAs, were significantly higher in the more anxious participants (LFD's range = [0.23, 1.36]; p 's range = [6.85E-6, 1.86E-2]). The interaction analysis of HRSD 17 and HRSA-Total suggested that the BA concentration differences were more strongly correlated to the symptoms of anxiety than depression. Significant differences in baseline CDCA (LFD = −0.87, p = 0.0009), isoLCA (LFD = −1.08, p = 0.016) and several BA ratios (LFD's range [0.46, 1.66], p 's range [0.0003, 0.049]) differentiated treatment failures from remitters. Conclusion In patients with MDD, BA profiles representing changes in gut microbiome compositions are associated with higher levels of anxiety and increased probability of first-line treatment failure. If confirmed, these findings suggest the possibility of developing gut microbiome-directed therapies for MDD characterized by gut dysbiosis.
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In patients with depression and anxiety, bile acid profiles associated with altered gut microbiota composition are significantly different in those with more severe symptoms.
“In a study of patients with depression and anxiety, BA profiles associated with altered GM composition were significantly different in those with more severe symptoms, and specific BA parameters were able to distinguish treatment failures from remitters (330).”
From Signalling cognition: The gut microbiota and hypothalamic-pituitary-adrenal axis (2023) · cites this paper as [330]
Specific bile acid parameters can distinguish treatment failures from remitters in patients with depression and anxiety.
“In a study of patients with depression and anxiety, BA profiles associated with altered GM composition were significantly different in those with more severe symptoms, and specific BA parameters were able to distinguish treatment failures from remitters (330).”
From Signalling cognition: The gut microbiota and hypothalamic-pituitary-adrenal axis (2023) · cites this paper as [330]
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- Authors
- MahmoudianDehkordi, S., Bhattacharyya, S., Brydges, C. R., Jia, W., Fiehn, O., Rush, A. J., Dunlop, B. W., & Kaddurah-Daouk, R.
- Affiliations
- Duke University (US)
- Arkansas State University (US)
- University of California, Davis (US)
- Hong Kong Baptist University (HK)
- Texas Tech University (US)
- Emory University (US)
- Corresponding author
- Dunlop, Boadie W.
- Kaddurah-Daouk, Rima
- ORCID
- Venue
- Frontiers in Neuroscience
- Publisher
- Frontiers Media SA
- Published
- 2022-07-20
- Volume
- 16
- Pages
- 937906-937906
- ISSN
- 1662-453X (ISSN-L)
- PMC
- PMC9350527
- OpenAlex
- W4286208770
- Cited by
- 75
- References
- 85
- Citations by year
- 2026: 19 · 2025: 16 · 2024: 26 · 2023: 13 · 2022: 1
- FWCI
- 4.55
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Frontiers in Neuroscience (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion, cc-by)
- Funders
- National Institutes of Health
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
- Life Sciences › Neuroscience › Biological Psychiatry › Tryptophan and brain disorders
- Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
- Keywords
- major depressive disorder, anxiety, bile acids, gut microbiota, chenodeoxycholic acid, lithocholic acid, secondary bile acids, primary bile acids, serum metabolomics, depression severity, anxiety levels, treatment response, antidepressant response, gut-brain axis, bile acid ratio, comorbid depression and anxiety, energy homeostasis, neuroinflammation
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