Colon-delivered short-chain fatty acids attenuate the cortisol response to psychosocial stress in healthy men: a randomized, placebo-controlled trial
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Short-chain fatty acids (SCFAs) are products of microbial fermentation of dietary fiber in the colon and may mediate microbiota-gut-brain communication. However, their role in modulating psychobiological processes that underlie the development of stress- and anxiety-related disorders is not mechanistically studied in humans. In this triple-blind, randomized, placebo-controlled intervention trial, we examine in a parallel group design the effects of 1-week colonic SCFA-mixture delivery in doses equivalent to fermentation of 10 g or 20 g of arabinoxylan oligosaccharides on responses to psychosocial stress and fear tasks in 66 healthy men. We demonstrate that low and high doses of SCFAs significantly attenuate the cortisol response to psychosocial stress compared to placebo. Both doses of SCFAs increase serum SCFA levels and this increase in circulating SCFAs co-varies significantly with the attenuation of the cortisol response to psychosocial stress. Colonic SCFA delivery does not modulate fecal SCFA concentrations, serum brain-derived neurotrophic factor, cortisol awakening response, fear learning and extinction, or subjective mood ratings. These results demonstrate that colon-delivered SCFAs modulate hypothalamic-pituitary-adrenal axis reactivity to psychosocial stress, thereby supporting their hypothesized role in microbiota-gut-brain communication.
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In humans, SCFA supplementation downregulates the HPA axis by attenuating the cortisol response.
“SCFA supplementation was shown to downregulate the HPA axis by significantly attenuating the cortisol response.”
From Signalling cognition: The gut microbiota and hypothalamic-pituitary-adrenal axis (2023) · cites this paper as [292]
Altered SCFA production is demonstrated in a variety of neuropathologies.
“Altered SCFA production has also been demonstrated in a variety of neuropathologies (42, 116, 127, 130, 132, 292–295).”
From Signalling cognition: The gut microbiota and hypothalamic-pituitary-adrenal axis (2023) · cites this paper as [292]
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Vasovagal reactions following venepuncture result in aberrant stress-induced cortisol levels
Dalile, B., Verbeke, K., & Oudenhove, L. V. (2021) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2021.105220 · Cited by 13 · see citing works
Self-citationThe gut-derived metabolites as mediators of the effect of healthy nutrition on the brain
Leyrolle, Q., Prado-Perez, L., & Layé, S. (2023) · Frontiers in Nutrition · doi:10.3389/fnut.2023.1155533 · Cited by 12 · see citing works
Acute stress enhances synaptic plasticity in male mice via a microbiota-dependent mechanism
Rosell‐Cardona, C., Collins, M., O’Riordan, K. J., Goodson, M. S., Kelley‐Loughnane, N., Cryan, J. F., & Clarke, G. A. (2025) · Neuropharmacology · doi:10.1016/j.neuropharm.2025.110434 · Cited by 12 · see citing works
Wang, H., Wang, B., Pan, M.-B., Jiang, S.-T., Wang, Y.-C., Zhu, Y., Zhang, Q., & Dong, Y. (2022) · Behavioural Brain Research · doi:10.1016/j.bbr.2022.114246 · Cited by 12 · see citing works
Császár-Nagy, N., Bob, P., & Bókkon, I. (2024) · Current Neuropharmacology · doi:10.2174/1570159x22666240507095700 · Cited by 13 · see citing works
Characterization of luminal contents from the fasted human proximal colon
Steigert, S., Brouwers, J., Verbeke, K., Vanuytsel, T., & Augustijns, P. (2024) · European Journal of Pharmaceutical Sciences · doi:10.1016/j.ejps.2024.106821 · Cited by 11 · see citing works
Self-citation
- Authors
- Dalile, B., Vervliet, B., Bergonzelli, G., Verbeke, K., & Van Oudenhove, L.
- Affiliations
- KU Leuven (BE)
- Nestlé (Switzerland) (CH)
- Venue
- Neuropsychopharmacology
- Published
- 2020-06-10
- Volume
- 45
- Issue
- 13
- Pages
- 2257-2266
- ISSN
- 0893-133X (ISSN-L)
- 1740-634X
- PMC
- PMC7784980
- OpenAlex
- W3033823110
- Cited by
- 201
- References
- 87
- Citations by year
- 2026: 36 · 2025: 46 · 2024: 38 · 2023: 27 · 2022: 28 · 2021: 21 · 2020: 5
- FWCI
- 6.57
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Neuropsychopharmacology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Lirias (KU Leuven) (submittedVersion, other-oa)
- Funders
- Fondation Nestlé
- 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
- short-chain fatty acids, arabinoxylan oligosaccharides, psychosocial stress, cortisol response, hypothalamic-pituitary-adrenal axis, dietary fiber fermentation, fear extinction, brain-derived neurotrophic factor, cortisol awakening response, anxiety
- MeSH terms
- Gastrointestinal Microbiome, Colon, Fatty Acids, Volatile, Humans, Hydrocortisone, Hypothalamo-Hypophyseal System, Male, Pituitary-Adrenal System, Stress, Psychological
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