Bipolar disorder is a psychiatric label for recurrent episodes of mania or hypomania and depression. Standard care uses mood stabilizers, antipsychotics, and psychotherapy. Gut microbial composition differs in bipolar cohorts, and adjunctive probiotics after mania hospitalization cut psychiatric rehospitalization risk in a randomized trial.

Bipolar disorder
Synonyms Manic-depressive illness, BD
Classification Psychiatric
Metabolic driver Gut microbiome and inflammation
Standard treatment Mood stabilizers, antipsychotics, psychotherapy
Ray's verdict

Gut microbiota

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A narrative review of the gut-brain axis in bipolar disorder reports altered gut bacterial composition in many bipolar cohorts and discusses immune, metabolic, and neurotransmitter routes by which gut microbes may shape mood-episode biology.[1]

Probiotic rehospitalization trial

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In a randomized, placebo-controlled trial, 66 patients discharged after hospitalization for mania received 24 weeks of adjunctive Lactobacillus rhamnosus GG plus Bifidobacterium animalis subsp. lactis Bb12, or placebo. Placebo arms had 24 psychiatric rehospitalizations versus 8 on probiotics. The probiotic group had a 74% lower hazard of psychiatric rehospitalization and spent fewer days back in hospital. The probiotic effect was larger when baseline systemic inflammation was higher.[2]

This is an adjunctive prevention trial after acute mania, not a stand-alone bipolar cure. It sits with the wiki caution on treating diagnoses as purely psychological while ignoring gut and inflammation chemistry.


Faecal microbiota transplantation

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In an uncontrolled 2020 case letter, a woman with bipolar I disorder and 10 prior public-sector psychiatric hospitalizations received nine faecal microbiota transplants (FMT) over 11 months, using stool from her husband, who had no psychiatric history. Within six months she was free of depression. She had no mania after September 2017, came off lithium, lamotrigine and quetiapine under her psychiatrist's supervision, lost 33 kg, and went on to run a small business and publish two books.[3] The letter appeared in March 2020, about two and a half years after the last reported manic episode. A single case report cannot separate a treatment effect from placebo, natural course, or other changes made at the same time.

A second uncontrolled case report followed a 28-year-old man with bipolar II disorder and possible mild ADHD, who had earlier noticed symptom relief from over-the-counter probiotics. After FMT in September 2020 he stopped valproate within two months and cut quetiapine from 250 mg to 50 mg a day by 12 months, then stopped it; he charted his mood daily from September 2020 to January 2022. Before the FMT he had taken rifaximin plus vancomycin, eaten a low-fiber diet, and undergone microdacyn colonic irrigation. His own account in the report credits FMT with much milder ADHD symptoms. The discussion section weighs the placebo risk of an intensive, high-expectation procedure.[4]

A 2026 pilot double-blind parallel-arm RCT randomized 35 adults in a bipolar depressive episode who had not responded to standard treatment. Each received a single colonoscopy dose of allogenic FMT from a healthy donor (n = 17) or autologous FMT from their own stool (n = 18), on top of standard therapy. MADRS depression scores improved in both arms (allogenic -16.74 points, autologous -15.4) with no significant difference between them (t = -0.47, P = 0.64). Among completers, 9 of 11 allogenic and 11 of 16 autologous participants reached remission, again with no significant difference. Only the allogenic arm shifted toward the donor's microbiota and gained bacterial diversity at six months. Autologous FMT is not an inert placebo, and the trial report calls for a true placebo arm in a larger study. Several authors hold patents or equity in a company developing bacterial therapies for bipolar disorder.[5]

Insulin signaling

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A review proposes that lithium works in bipolar disorder by acting on the PI3K/Akt insulin signaling pathway, through its effects on GSK3 and the phosphatidylinositol cycle. It names energy dysregulation as a core deficit and notes the frequent co-occurrence of bipolar disorder with type 2 diabetes and other forms of impaired glucose metabolism. The hypothesis has not yet been tested in patients.[6]

Calcium and parathyroid hormone

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In 199 patients with bipolar disorder, parathyroid hormone (PTH) levels correlated with bipolar I diagnosis, psychotic symptoms, lithium treatment, suicidality, number of acute episodes, number of hospitalizations and seasonality. Higher PTH was predicted by earlier age at onset, more hospitalizations, aggressive behavior, higher childhood trauma scores and lithium treatment.[7]

MTHFR

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MTHFR C677T tracks with bipolar risk in pooled data, though more weakly than with schizophrenia. In a meta-analysis, carrying two copies of the T variant raised bipolar risk by about a quarter, an effect significant mainly in Asian and African subgroups.[8] Across schizophrenia, bipolar disorder, and unipolar depression combined, 677TT carriers showed a shared genetic vulnerability. The A1298C AA genotype carried about double the odds specifically for bipolar disorder.[9]

These odds ratios are modest and ethnicity-dependent. They sit with lower blood folate in psychosis cohorts and with the one-carbon / methylation framing on Depression and Schizophrenia, not as a single-gene bipolar diagnosis.

Autoimmune disease

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In a cohort of 3.57 million Danish births followed through national registers from 1977 to 2006 (9,920 bipolar cases), a personal history of any of 30 autoimmune diseases carried a bipolar relative risk of 1.7 in the first four years after the autoimmune diagnosis and 1.2 after five or more years. Autoimmune disease in parents or siblings did not raise bipolar risk overall (relative risk 1.0); pernicious anemia was the one familial exception (1.7).[10] In a cross-sectional study of a large Israeli health-insurer database, bipolar disorder was present in 0.62% of 5,018 patients with systemic lupus versus 0.26% of 25,090 age- and sex-matched controls, and lupus stayed associated with bipolar disorder in a multivariate model that included smoking.[11] In the UK Our Future Health cohort, people reporting an autoimmune condition had about 1.5 times the odds of a self-reported bipolar diagnosis.[12] All three are observational and cannot establish that autoimmunity causes bipolar disorder.

Practice

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Mood-stabilizer and antipsychotic regimens remain first-line for bipolar disorder. The mania rehospitalization trial and gut-microbiota reviews favor checking gut barrier, infection, and inflammatory load alongside psychiatry. See Mental health, Gut, and Inflammation.

See also

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References

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  1. ↑ Zhang P, Kong L, Huang H, et al. "Gut microbiota," Front Neurosci. 2022;16:830748. doi:10.3389/fnins.2022.830748. PMID 35401095. PMC8984199.
  2. ↑ Dickerson F, Adamos M, Katsafanas E, et al. "Probiotic rehospitalization," Bipolar Disord. 2018;20(7):614-621. doi:10.1111/bdi.12652. PMID 29693757. Time to rehospitalization HR 0.26 (95% CI 0.10–0.69); mean days rehospitalized 2.8 vs 8.3.
  3. ↑ Hinton R. "A case report looking at the effects of faecal microbiota transplantation in a patient with bipolar disorder," Aust N Z J Psychiatry. 2020;54(6):649-650. doi:10.1177/0004867420912834. PMID 32228039.
  4. ↑ Parker G, Spoelma MJ, Rhodes N. "Faecal microbiota transplantation for bipolar disorder: A detailed case study," Bipolar Disord. 2022;24(5):559-563. doi:10.1111/bdi.13187. PMID 35165993. PMC9545285.
  5. ↑ Shekarriz S, Vigod SN, Bianco T, et al. "The Safety, Efficacy, and Feasibility of Fecal Microbiota Transplantation in a Population With Bipolar Disorder During Depressive Episodes: A Pilot Parallel Arm Randomized Controlled Trial," Can J Psychiatry. 2026;71(9):675-690. doi:10.1177/07067437261420877. PMID 41785480. PMC12962988.
  6. ↑ Campbell IH, Campbell H, Smith DJ. "Insulin signaling as a therapeutic mechanism of lithium in bipolar disorder," Transl Psychiatry. 2022;12(1):350. doi:10.1038/s41398-022-02122-6. PMID 36038539.
  7. ↑ Steardo L, Luciano M, Sampogna G, Carbone EA, et al. "Clinical Severity and Calcium Metabolism in Patients with Bipolar Disorder," Brain Sci. 2020;10(7):417. doi:10.3390/brainsci10070417. PMID 32630307.
  8. ↑ Hu CY, Qian ZZ, Gong FF, et al. "Methylenetetrahydrofolate reductase (MTHFR) polymorphism susceptibility to schizophrenia and bipolar disorder," J Neural Transm. 2015;122(2):307-320. PMID 24938371. 38 articles; recessive model TT vs CT+CC OR 1.26 (95% CI 1.00–1.59).
  9. ↑ Peerbooms OL, van Os J, Drukker M, et al. "Meta-analysis of MTHFR gene variants," Brain Behav Immun. 2011;25(8):1530-1543. PMID 21185933. 677TT vs CC across disorders OR 1.26 (95% CI 1.09–1.46); A1298C AA vs CC in bipolar OR 2.03 (95% CI 1.07–3.86).
  10. ↑ Eaton WW, Pedersen MG, Nielsen PR, Mortensen PB. "Autoimmune diseases, bipolar disorder, and non-affective psychosis," Bipolar Disord. 2010;12(6):638-46. doi:10.1111/j.1399-5618.2010.00853.x. PMID 20868462. PMC2950824. Register cohort.
  11. ↑ Tiosano S, Nir Z, Gendelman O, Comaneshter D, Amital H, Cohen AD, Amital D. "The association between systemic lupus erythematosus and bipolar disorder: a big data analysis," Eur Psychiatry. 2017;43:116-119. doi:10.1016/j.eurpsy.2017.03.006. PMID 28525775. Cross-sectional study.
  12. ↑ Mudra Rakshasa-Loots A, Swiffen D, Steyn C, Marwick KFM, Smith DJ. "Affective disorders and chronic inflammatory conditions: analysis of 1.5 million participants in Our Future Health," BMJ Ment Health. 2025;28(1):e301706. doi:10.1136/bmjment-2025-301706. PMID 40494639. PMC12161381. Cross-sectional cohort analysis. 1,563,155 adults; bipolar adjusted OR 1.49 (95% CI 1.32–1.68).