Colonization with the commensal fungus candida albicans perturbs the gut-brain axis through dysregulation of endocannabinoid signaling
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Abstract
Anxiety disorders are the most prevalent mental health disorder worldwide, with a lifetime prevalence of 5-7 % of the human population. Although the etiology of anxiety disorders is incompletely understood, one aspect of host health that affects anxiety disorders is the gut-brain axis. Adolescence is a key developmental window in which stress and anxiety disorders are a major health concern. We used adolescent female mice in a gastrointestinal (GI) colonization model to demonstrate that the commensal fungus Candida albicans affects host health via the gut-brain axis. In mice, bacterial members of the gut microbiota can influence the host gut-brain axis, affecting anxiety-like behavior and the hypothalamus-pituitary-adrenal (HPA) axis which produces the stress hormone corticosterone (CORT). Here we showed that mice colonized with C. albicans demonstrated increased anxiety-like behavior and increased basal production of CORT as well as dysregulation of CORT production following acute stress. The HPA axis and anxiety-like behavior are negatively regulated by the endocannabinoid N-arachidonoylethanolamide (AEA). We demonstrated that C. albicans-colonized mice exhibited changes in the endocannabinoidome. Further, increasing AEA levels using the well-characterized fatty acid amide hydrolase (FAAH) inhibitor URB597 was sufficient to reverse both neuroendocrine phenotypes in C. albicans-colonized mice. Thus, a commensal fungus that is a common colonizer of humans had widespread effects on the physiology of its host. To our knowledge, this is the first report of microbial manipulation of the endocannabinoid (eCB) system that resulted in neuroendocrine changes contributing to anxiety-like behavior.
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Mice colonized with Candida albicans show anxiety-like behavior and increased corticosterone inversely correlated with forebrain AEA, demonstrating HPA axis disruption via ECS dysregulation.
“Healthy mice colonized with Candida albicans showed marked anxiety-like behavior and increased corticosterone concentrations that were inversely correlated with forebrain AEA, demonstrating disruption of the HPA axis through dysregulation of the ECS (253).”
From Signalling cognition: The gut microbiota and hypothalamic-pituitary-adrenal axis (2023) · cites this paper as [253]
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- Authors
- Markey, L., Hooper, A., Melon, L. C., Baglot, S., Hill, M. N., Maguire, J., & Kumamoto, C. A.
- Affiliations
- Tufts University (US)
- University of Calgary (CA)
- Corresponding author
- Kumamoto, Carol A.
- ORCID
- Venue
- Psychoneuroendocrinology
- Publisher
- Elsevier BV
- Published
- 2020-11
- Volume
- 121
- Pages
- 104808
- ISSN
- 0306-4530 (ISSN-L)
- PMC
- PMC7572798
- OpenAlex
- W3044510287
- Cited by
- 45
- References
- 67
- Citations by year
- 2026: 6 · 2025: 7 · 2024: 9 · 2023: 6 · 2022: 10 · 2021: 6 · 2020: 1
- FWCI
- 1.86
- Type
- journal article
- Language
- en
- Open access
- green
- doi.org
- Locations
- Psychoneuroendocrinology (publishedVersion)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute on Alcohol Abuse and Alcoholism
- National Institute of Neurological Disorders and Stroke
- National Institute of Allergy and Infectious Diseases
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
- Health Sciences › Medicine › Pharmacology › Cannabis and Cannabinoid Research
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Keywords
- Candida albicans, gut-brain axis, endocannabinoid system, anxiety-like behavior, hypothalamic-pituitary-adrenal axis, corticosterone, acute stress, fatty acid amide hydrolase, URB597, endocannabinoidome, commensal fungi, gut microbiota
- MeSH terms
- Gastrointestinal Microbiome, Animals, Anxiety, Anxiety Disorders, Arachidonic Acids, Brain, Candida albicans, Corticosterone, Female, Hypothalamo-Hypophyseal System, Mice, Inbred C57BL, Neurosecretory Systems, Pituitary-Adrenal System, Stress, Psychological, Signal Transduction, Models, Animal, Mice, Polyunsaturated Alkamides, Endocannabinoids
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