Targeting the microbiota-gut-brain axis: prebiotics have anxiolytic and antidepressant-like effects and reverse the impact of chronic stress in mice
Open accessAbstract
BACKGROUND: The realization that the microbiota-gut-brain axis plays a critical role in health and disease, including neuropsychiatric disorders, is rapidly advancing. Nurturing a beneficial gut microbiome with prebiotics, such as fructo-oligosaccharides (FOS) and galacto-oligosaccharides (GOS), is an appealing but underinvestigated microbiota manipulation. Here we tested whether chronic prebiotic treatment modifies behavior across domains relevant to anxiety, depression, cognition, stress response, and social behavior. METHODS: C57BL/6J male mice were administered FOS, GOS, or a combination of FOS+GOS for 3 weeks prior to testing. Plasma corticosterone, microbiota composition, and cecal short-chain fatty acids were measured. In addition, FOS+GOS- or water-treated mice were also exposed to chronic psychosocial stress, and behavior, immune, and microbiota parameters were assessed. RESULTS: Chronic prebiotic FOS+GOS treatment exhibited both antidepressant and anxiolytic effects. Moreover, the administration of GOS and the FOS+GOS combination reduced stress-induced corticosterone release. Prebiotics modified specific gene expression in the hippocampus and hypothalamus. Regarding short-chain fatty acid concentrations, prebiotic administration increased cecal acetate and propionate and reduced isobutyrate concentrations, changes that correlated significantly with the positive effects seen on behavior. Moreover, FOS+GOS reduced chronic stress-induced elevations in corticosterone and proinflammatory cytokine levels and depression-like and anxiety-like behavior in addition to normalizing the effects of stress on the microbiota. CONCLUSIONS: Taken together, these data strongly suggest a beneficial role of prebiotic treatment for stress-related behaviors. These findings strengthen the evidence base supporting therapeutic targeting of the gut microbiota for brain-gut axis disorders, opening new avenues in the field of nutritional neuropsychopharmacology.
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Butyrate possesses an antidepressant-like effect that reverses behavioral alterations in mouse models, such as low energy, anhedonia, and cognitive and sociability impairments.
“Moreover, current knowledge shows that butyrate possesses an antidepressant-like effect that reverses behavioral alterations in mouse models, such as low energy (126, 152), anhedonia (153), and cognitive and sociability impairments (154).”
From The Role of Short-Chain Fatty Acids From Gut Microbiota in Gut-Brain Communication (2020) · cites this paper as [154]
Citation 154 is attached to the cognitive and sociability impairments. The Behavior section reports that stress impaired memory and social interaction, but prebiotics only tended to improve memory; the Social Behavior section reports increased prosocial behavior on one test, not a reversal of social impairment. These were findings about prebiotic treatment, not evidence that butyrate itself reversed either impairment. (LLM, conf=0.86)
Experimental — accuracy not yet measuredMice fed FOS+GOS spent more time in center of open-field test and had increased entries into open area, indicating reduced anxiety phenotype.
“Moreover, mice fed FOS+GOS spent more time in the center of an open-field test, with an increase in the percentage of entries into the open area (Burokas et al., 2017), indicating a reduced anxiety phenotype.”
From The Microbiota-Gut-Brain Axis (2019) · cites this paper as Burokas et al., 2017
The Anxiety-like Behavior section reports that FOS+GOS significantly increased time in the center of the open-field test, but the increase in center entries was only a tendency (p=0.060). Its significant increase in the percentage of entries into an open area refers to the open arms of a different test, the elevated plus maze. The open-field finding is consistent with reduced anxiety-like behavior, but the sentence conflates the two tests. (LLM, conf=0.91)
Experimental — accuracy not yet measuredFOS+GOS and GOS administration reduced stress-induced corticosterone release, increased cecal acetate and propionate, and reduced iso-butyrate.
“Administration of FOS-+GOS and GOS has been shown to reduce stress-induced corticosterone release, combined with a significant increase in cecal acetate and propionate concentrations, with a reduction in iso-butyrate levels.”
From The Microbiota-Gut-Brain Axis (2019) · cites this paper as Burokas et al., 2017
The Endocrine response section reports reduced stress-induced corticosterone in prebiotic-treated mice. The Short Chain Fatty Acids (SCFAs) section reports increased propionate and decreased iso-butyrate with prebiotic administration, but increased cecal acetate only with FOS and FOS+GOS—not GOS alone. (LLM, conf=0.92)
Experimental — accuracy not yet measuredSCFAs play an important role in human neurological illnesses because of anti-inflammatory properties and capacity to strengthen the BBB.
“SCFAs play an important role in human neurological illnesses because of their anti-inflammatory properties and their capacity to strengthen the BBB [78,79].”
From Neuroprotective Effects of Bifidobacterium breve CCFM1067 in MPTP-Induced Mouse Models of Parkinson’s Disease (2022) · cites this paper as [79]
Preclinical behavioral screening platforms are most frequently used to identify candidate psychobiotics for further evaluation in clinical platforms.
“Currently, preclinical behavioral screening platforms are most frequently used to identify candidate psychobiotics for further evaluation in clinical platforms (Bravo et al., 2011;Savignac et al., 2014Savignac et al., , 2015;;Burokas et al., 2017).”
From Gut reactions: Breaking down xenobiotic–microbiome interactions (2019) · cites this paper as Burokas et al., 2017
Administration of prebiotics increased the relative abundance of Akkermansia during exposure to stressors.
“However, the administration of prebiotics increased the relative abundance of Akkermansia during exposure to stressors [65,66].”
From Flavonoid-rich orange juice intake and altered gut microbiome in young adults with depressive symptom: a randomized controlled study (2020) · cites this paper as [66]
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“304 Restoration of the gut eubiosis can prevent the occurrence of MDD, and probiotics can normalize the gut ecosystem.”
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Self-citationGut Microbiota’s Effect on Mental Health: The Gut-Brain Axis
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“In addition, the prebiotic combination was able to normalise the effects of chronic psychological stress on the microbiota (Burokas et al., 2017).”
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Current perspectives on gut microbiome dysbiosis and depression
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Focus on the essentials: tryptophan metabolism and the microbiome-gut-brain axis
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You’ve got male: Sex and the microbiota-gut-brain axis across the lifespan
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Gutted! Unraveling the Role of the Microbiome in Major Depressive Disorder
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- Authors
- Burokas, A., Arboleya, S., Moloney, R. D., Peterson, V. L., Murphy, K., Clarke, G., Stanton, C., Dinan, T. G., & Cryan, J. F.
- Affiliations
- University College Cork (IE)
- Teagasc - The Irish Agriculture and Food Development Authority (IE)
- Corresponding author
- Cryan, John F.
- ORCID
- Venue
- Biological Psychiatry
- Publisher
- Elsevier BV
- Published
- 2017-10
- Volume
- 82
- Issue
- 7
- Pages
- 472-487
- ISSN
- 0006-3223 (ISSN-L)
- OpenAlex
- W2590245531
- Semantic Scholar
- 042e18725c5f9501c07020319ec2813d81f57816
- Cited by
- 952
- References
- 65
- Citations by year
- 2026: 63 · 2025: 100 · 2024: 114 · 2023: 137 · 2022: 113 · 2021: 104 · 2020: 120 · 2019: 110 · 2018: 61 · 2017: 29
- FWCI
- 73.89
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Biological Psychiatry (publishedVersion)
- PubMed (publishedVersion)
- Cork Open Research Archive (University College Cork, Ireland) (acceptedVersion, cc-by-nc-nd)
- Arrow@dit (Dublin Institute of Technology) (submittedVersion, cc-by-nc-nd)
- DIGITAL.CSIC (Spanish National Research Council (CSIC)) (submittedVersion, cc-by-nc-nd)
- Funders
- Mead Johnson Nutrition
- Science Foundation Ireland (SFI/12/RC/, 12/RC/2273, 02/CE/B124, 12/RC/, SFI/12/RC/2273., 07/CE/B1368)
- APC Microbiome Institute (SFI/12/RC/2273)
- Topics
- Health Sciences › Nursing › Nutrition and Dietetics › Microbial Metabolites in Food Biotechnology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
- Life Sciences › Agricultural and Biological Sciences › Food Science › Probiotics and Fermented Foods
- Keywords
- microbiota-gut-brain axis, prebiotics, fructooligosaccharides, galactooligosaccharides, chronic psychosocial stress, anxiety-like behavior, depression-like behavior, corticosterone, short-chain fatty acids, hippocampus, hypothalamus, inflammatory cytokines, gut microbiota
- MeSH terms
- Gastrointestinal Microbiome, Animals, Antidepressive Agents, Anxiety, Brain, Corticosterone, Depression, Disease Models, Animal, Locomotion, Male, Mice, Inbred C57BL, Oligosaccharides, Stress, Psychological, Anti-Anxiety Agents, Tryptophan, Gene Expression, Neurotransmitter Agents, Gastrointestinal Tract, Mice, Prebiotics, Nociception
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