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The Gut-Brain-Health Connection

The health of the gut and the brain are so closely linked that people sometimes now refer to the gut as the 'second brain'. In this article, Cliff summarises the research on the gut and mental health.

Key points

  • The gut and both its barrier and inflammation-regulating functions affect the brain and mental health
  • ‘States’ of mental health also affect the gut (esp. motility) and the microbiota
  • Comorbidities exist between mental health challenges like depression and bipolar disorder and IBS, IBDs, and other gut disorders
  • Many psychiatric illnesses are characterised by differing microbiome signatures
  • Probiotics, prebiotics and other gut interventions may be of use in psychiatric treatment

The gut and brain are linked, and this has led some to call the gut ‘the second brain’ as it helps to play a role in the regulation of the central nervous system. While once, mental health challenges were considered to be restricted to structural or functional (i.e. neurotransmitter imbalances) problems within the brain, it is now known that systemic health, inflammation, and gut-health play a role in the health of the brain, nervous system, and the psyche of an individual.1

The gut-brain axis (more importantly, the effect of the microbiome on the entire body) has been implicated in mental health and it is now clear that there is an intimate connection between psychiatry and gastrointestinal health.

It is now clear that there is an intimate connection between psychiatry and gastointestinal health

The gut and depression

Recent research provides a strong indication that depression is both an inflammatory disease and that there is communication between the gut and the brain and nervous system, and that this is related to depression and other mental health challenges. Reviews of the research shows associations between disturbed gut microbiota and psychiatric illness in humans, and animal research has shown that when the faecal microbiome from animals showing depressive signs is transplanted into non-depressed subjects, they develop depressive symptoms. Animal research also suggests a role for probiotics as antidepressants and a negative effect from antibiotics.

Several probiotics in particular have shown promise:

  • L. rhamnosus – reduced stress response
  • Combination B. bifidum W23, B. lactis W52, L. acidophilus W37, L. brevis W63, L. casei W56, L. salivarius, W24, Lactococcus Lactis W19, and Lc. Lactis W58 – reduces depressive-like behaviour
  • L. helveticus – resilience to depressive symptoms

However, other studies have shown no benefit from supplementing bacteria known to be reduced in subjects with depression and a 2020 meta-analysis showed no clear effect of either prebiotic or probiotic supplements on depression.2 

Most reported studies have demonstrated some correlation between the gut microbiota and depression

Most reported studies though have demonstrated some correlation between the gut microbiota and depression,3 and it is worth remembering that the interplay between genes, diet, lifestyle, environment, microbiota, and mental health is a complex one that begs for further research, and that the effects of supplementation on particular illnesses is likely to be dependent on the species-disease interaction.

Gut health and anxiety

Recent research now suggests that the microbiome plays a role in regulating mood, anxiety, and stress.

In a review of 21 studies[1] (extracted from a search yielding 3334 articles), 11 studies showed a positive effect on anxiety symptoms by regulating intestinal microbiota (by supplementation or dietary interventions). Interestingly, non-probiotic (dietary interventions) appear to be more effective for regulating the microbiome and reducing anxiety.4

The gut, IBS and anxiety

Anxiety and depression, and irritable bowel syndrome (IBS) are common, and around 40-90% of those with anxiety share these conditions. In a review of 17 human and animal trials indicated that people with IBS and anxiety had lower diversity of bacteria and higher abundance of Proteobacteria, Prevotella/Prevotellaceae, Bacteroides and lower levels of Lachnospiraceae relative to healthy controls.5

Gut differences in depression and bipolar disorder

Depression and bipolar disorder may show differing microbiota.6

In both depression and bipolar disorder, increased numbers of Firmicutes and Actinobacteria and decreased Bacteroidetes have been found, and at the genus level, Bacteroides, Clostridium, Bifidobacterium, Oscillibacter and Streptococcus were significantly increased compared to controls. Between people with depression and bipolar disorder, depressive patients had greater abundance of Prevotellaceae including Prevotella denticola F0289, Prevotella intermedia 17, Prevotella ruminicola, and Prevotella intermedia. While in the bipolar patients, Fusobacteriaceae, Escherichia blattae DSM 4481 and Klebsiella oxytoca were significantly increased, whereas the Bifidobacterium longum subsp. infantis ATCC 15697 = JCM 1222 was decreased compared with the depression group.7

Bipolar disorder

Many conditions related to gut-health are co-morbid with bipolar disorder, including inflammation, irritable bowel disease and antibiotic induced mania.8 People with bipolar disorder also have a greater incidence of gastrointestinal illnesses and inflammatory bowel diseases which are linked to microbiome status.9 The microbiota of people with bipolar disorder and schizophrenia also differ from controls and GI inflammation is known to be increased in both conditions.10, 11 In particular, Flavonifractor has been associated with having a newly diagnosed bipolar disorder (and also with smoking).11

People with bipolar disorder have a greater incidence of gastrointestinal illnesses which are linked to microbiome status

People with bipolar disorder may also have reduced bacterial diversity in the microbiome, lower Faecalbacetrium (as a proportion of total bacteria),12 and a greater abundance of Clostridiaceae among bipolar type 1 subjects and Collinsella among bipolar type 2 subjects.13

There was a lower Bifidobacteria to Enterobacteriaceae ratio (which represents microbial colonization resistance) than control subjects. Treatment with the drug quetiapine increased the levels of Eubacterium rectale, Bifidobacteria, and B/E ratio.14  Greater representation of Faecalibacterium in people with bipolar disorder is associated with better self-reported health outcomes (including for sleep, mood, and anxiety).12

There may also be interactions between specific microbiota and metabolites, causing increased oxidative stress and nitric oxide production in bipolar disorder,15 possibly also related to increased gut permeability (leaky gut) related to poor gut health.16

Studies also suggest increased intestinal inflammation and permeability, which may be among the principal mechanisms by which microbial dysbiosis impacts systemic physiological functioning and mental health.17


1.         Hélѐne-Zanin J. Gut feelings: a thematic review of the links between acute gastrointestinal illness and anxiety and depressive disorders. Global Health: Annual Review. 2015;1(1).

2.         Vaghef-Mehrabany E, Maleki V, Behrooz M, Ranjbar F, Ebrahimi-Mameghani M. Can psychobiotics “mood” ify gut? An update systematic review of randomized controlled trials in healthy and clinical subjects, on anti-depressant effects of probiotics, prebiotics, and synbiotics. Clinical Nutrition. 2020;39(5):1395-410.

3.         Yang Z, Li J, Gui X, Shi X, Bao Z, Han H, et al. Updated review of research on the gut microbiota and their relation to depression in animals and human beings. Molecular Psychiatry. 2020.

4.         Yang B, Wei J, Ju P, Chen J. Effects of regulating intestinal microbiota on anxiety symptoms: A systematic review. Gen Psychiatr. 2019;32(2):e100056-e.

5.         Simpson CA, Mu A, Haslam N, Schwartz OS, Simmons JG. Feeling down? A systematic review of the gut microbiota in anxiety/depression and irritable bowel syndrome. Journal of Affective Disorders. 2020;266:429-46.

6.         Zheng P, Yang J, Li Y, Wu J, Liang W, Yin B, et al. Gut Microbial Signatures Can Discriminate Unipolar from Bipolar Depression. Advanced Science. 2020;7(7):1902862.

7.         Rong H, Xie X-h, Zhao J, Lai W-t, Wang M-b, Xu D, et al. Similarly in depression, nuances of gut microbiota: Evidences from a shotgun metagenomics sequencing study on major depressive disorder versus bipolar disorder with current major depressive episode patients. Journal of psychiatric research. 2019;113:90-9.

8.         Gondalia S, Parkinson L, Stough C, Scholey A. Gut microbiota and bipolar disorder: a review of mechanisms and potential targets for adjunctive therapy. Psychopharmacology. 2019;236(5):1433-43.

9.         Flowers SA, Ward KM, Clark CT. The Gut Microbiome in Bipolar Disorder and Pharmacotherapy Management. Neuropsychobiology. 2020;79(1-2):43-9.

10.       Dickerson F, Severance E, Yolken R. The microbiome, immunity, and schizophrenia and bipolar disorder. Brain, behavior, and immunity. 2017;62:46-52.

11.       Coello K, Hansen TH, Sørensen N, Munkholm K, Kessing LV, Pedersen O, et al. Gut microbiota composition in patients with newly diagnosed bipolar disorder and their unaffected first-degree relatives. Brain, behavior, and immunity. 2019;75:112-8.

12.       Evans SJ, Bassis CM, Hein R, Assari S, Flowers SA, Kelly MB, et al. The gut microbiome composition associates with bipolar disorder and illness severity. Journal of psychiatric research. 2017;87:23-9.

13.       McIntyre RS, Subramaniapillai M, Shekotikhina M, Carmona NE, Lee Y, Mansur RB, et al. Characterizing the gut microbiota in adults with bipolar disorder: a pilot study. Nutritional neuroscience. 2019:1-8.

14.       Lu Q, Lai J, Lu H, Ng C, Huang T, Zhang H, et al. Gut Microbiota in Bipolar Depression and Its Relationship to Brain Function: An Advanced Exploration. Frontiers in Psychiatry. 2019;10(784).

15.       Maes M, Simeonova D, Stoyanov D, Leunis JC. Upregulation of the Nitrosylome in Bipolar Disorder Type 1 (BP1), but not BP2, and Major Depression: Increased IgM Antibodies to Nitrosylated Conjugates are Associated with Indicants of Leaky Gut. 2019.

16.       Simeonova D, Stoyanov D, Leunis JC, Carvalho AF, Kubera M, Murdjeva M, et al. Increased Serum Immunoglobulin Responses to Gut Commensal Gram-Negative Bacteria in Unipolar Major Depression and Bipolar Disorder Type 1, Especially When Melancholia Is Present. Neurotoxicity Research. 2020;37(2):338-48.

17.       Nguyen TT, Kosciolek T, Eyler LT, Knight R, Jeste DV. Overview and systematic review of studies of microbiome in schizophrenia and bipolar disorder. Journal of Psychiatric Research. 2018;99:50-61.

[1] n = 1503

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