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The HPA axis dysregulation in severe mental illness: Can we shift the blame to gut microbiota?
Open accessAbstract
Accumulating evidence indicates that patients with severe mental disorders, including major depression, bipolar disorder and schizophrenia present with various alterations of the gut microbiota and increased intestinal permeability. In addition, the hypothalamic-pituitary-adrenal (HPA) axis dysregulation and subclinical inflammation have been reported in this group of patients. Although it has been found that the HPA axis dysregulation appears as a consequence of psychosocial stress, especially traumatic life events, the exact mechanisms of this observation remain unclear. Animal model studies have unraveled several mechanisms linking the gut microbiota with the HPA axis dysfunction. Indeed, the gut microbiota can activate the HPA axis through several mediators that cross the blood-brain barrier and include microbial antigens, cytokines and prostaglandins. There is also evidence that various microbial species can affect ileal corticosterone production that may impact the activity of the HPA axis. However, some metabolites released by various microbes, e.g., short-chain fatty acids, can attenuate the HPA axis response. Moreover, several bacteria release neurotransmitters that can directly interact with vagal afferents. It has been postulated that the HPA axis activation can impact the gut microbiota and intestinal permeability. In this article, we discuss various mechanisms linking the gut microbiota with the HPA axis activity and summarize current evidence for a cross-talk between the gut-brain axis and the HPA axis from studies of patients with mood and psychotic disorders. Finally, we show potential clinical implications that can arise from future studies investigating the HPA axis activity with respect to the gut microbiota in severe mental disorders.
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“Chronic systemic inflammation linked to LGS also disrupts the hypothalamus–pituitary–adrenal (HPA) axis, a key system for providing high-energy fuels such as glucose, amino acids, and free fatty acids to support immune activity. This disruption results in the increased production of glucocorticoids and catecholamines, causing hypercortisolemia and HPA axis overactivation, often accompanied by”
From The Gut–Brain–Microbiota Connection and Its Role in Autism Spectrum Disorders (2025) · cites this paper as [86]
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“Dysbiosis leads to heightened stress responses with elevated cortisol and adrenocorticotropic hormone (ACTH) levels [141,142].”
From Unraveling the Connections: Eating Issues, Microbiome, and Gastrointestinal Symptoms in Autism Spectrum Disorder (2025) · cites this paper as [141]
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“HPA axis dysfunction is also associated with many major psychopathologies, including autism, anxiety disorders, depression, and schizophrenia, as well as other cognitive disorders (145).”
From Signalling cognition: The gut microbiota and hypothalamic-pituitary-adrenal axis (2023) · cites this paper as [145]
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Metadata
- Authors
- Misiak, B., Łoniewski, I., Marlicz, W., Frydecka, D., Szulc, A., Rudzki, L., & Samochowiec, J.
- Affiliations
- Wroclaw Medical University (PL)
- Pomeranian Medical University (PL)
- Medical University of Warsaw (PL)
- Corresponding author
- Misiak, Błażej
- ORCID
- Venue
- Progress in Neuro-Psychopharmacology and Biological Psychiatry
- Publisher
- Elsevier BV
- Published
- 2020-08
- Volume
- 102
- Pages
- 109951
- ISSN
- 0278-5846 (ISSN-L)
- OpenAlex
- W3018120946
- Cited by
- 343
- References
- 147
- Citations by year
- 2026: 47 · 2025: 73 · 2024: 77 · 2023: 64 · 2022: 47 · 2021: 26 · 2020: 9
- FWCI
- 3.49
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Progress in Neuro-Psychopharmacology and Biological Psychiatry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- Narodowe Centrum Nauki
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Health Sciences › Medicine › Gastroenterology › Gastrointestinal motility and disorders
- Keywords
- HPA axis dysregulation, gut microbiota, gut-brain axis, severe mental illness, major depressive disorder, bipolar disorder, schizophrenia, intestinal permeability, subclinical inflammation, psychosocial stress, traumatic life events, short-chain fatty acids, vagal afferents, blood-brain barrier, corticosterone, microbial metabolites
- MeSH terms
- Gastrointestinal Microbiome, Mental Disorders, Humans, Hypothalamo-Hypophyseal System, Pituitary-Adrenal System
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