Evidence-Based Reviews

Gut microbiota and symptoms of psychosis: Is there a link?

Current Psychiatry. 2023 February;22(2):29-34 | doi: 10.12788/cp.0328

References

1. Bäckhed F, Ley RE, Sonnenburg JL, et al. Host-bacterial mutualism in the human intestine. Science. 2005;307(5717):1915-1920. doi:10.1126/science.1104816

2. Jackson SW. Galen—on mental disorders. J Hist Behav Sci. 1969;5(4):365-384. doi:10.1002/1520-6696(196910)5:4<365::AID-JHBS2300050408>3.0.CO;2-9

3. Zheng P, Zeng B, Liu M, et al. The gut microbiome from patients with schizophrenia modulates the glutamate-glutamine-GABA cycle and schizophrenia-relevant behaviors in mice. Sci Adv. 2019;5(2):eaau8317. doi:10.1126/sciadv.aau8317

4. Schizophrenia Working Group of the Psychiatric Genomics Consortium. Biological insights from 108 schizophrenia-associated genetic loci. Nature. 2014;511(7510):421-427. doi:10.1038/nature13595

5. Gill SR, Pop M, DeBoy RT, et al. Metagenomic analysis of the human distal gut microbiome. Science. 2006;312(5778):1355-1359. doi:10.1126/science.1124234

6. Alam R, Abdolmaleky HM, Zhou JR. Microbiome, inflammation, epigenetic alterations, and mental diseases. Am J Med Genet B Neuropsychiatr Genet. 2017;174(6):651-660. doi:10.1002/ajmg.b.32567

7. Cryan JF, O’Riordan KJ, Cowan CSM, et al. The microbiota-gut-brain axis. Physiol Rev. 2019;99(4):1877-2013. doi:10.1152/physrev.00018.2018

8. Mueller NT, Bakacs E, Combellick J, et al. The infant microbiome development: mom matters. Trends Mol Med. 2015;21(2):109-117. doi:10.1016/j.molmed.2014.12.002

9. Fouhy F, Watkins C, Hill CJ, et al. Perinatal factors affect the gut microbiota up to four years after birth. Nat Commun. 2019;10(1):1517. doi:10.1038/s41467-019-09252-4

10. Sharon G, Sampson TR, Geschwind DH, et al. The central nervous system and the gut microbiome. Cell. 2016;167(4):915-932. doi:10.1016/j.cell.2016.10.027

11. Hill CJ, Lynch DB, Murphy K, et al. Evolution of gut microbiota composition from birth to 24 weeks in the INFANTMET Cohort. Microbiome. 2017;5:4. doi:10.1186/s40168-016-0213-y

12. Gareau MG, Wine E, Rodrigues DM, et al. Bacterial infection causes stress-induced memory dysfunction in mice. Gut. 2011;60(3):307-317. doi:10.1136/gut.2009.202515

13. Bokulich NA, Chung J, Battaglia T, et al. Antibiotics, birth mode, and diet shape microbiome maturation during early life. Sci Transl Med. 2016;8(343):343ra82. doi:10.1126/scitranslmed.aad7121

14. Mancabelli L, Milani C, Lugli GA, et al. Meta-analysis of the human gut microbiome from urbanized and pre-agricultural populations. Environ Microbiol. 2017;19(4):1379-1390. doi:10.1111/1462-2920.13692

15. Stilo SA, Murray RM. Non-genetic factors in schizophrenia. Curr Psychiatry Rep. 2019;21(10):100. doi:10.1007/s11920-019-1091-3

16. Buscaino VM. Patologia extraneurale della schizofrenia: fegato, tubo digerente, sistema reticolo-endoteliale. Acta Neurologica. 1953;VIII:1-60.

17. Hemmings G. Schizophrenia. Lancet. 2004;364(9442):1312-1313. doi:10.1016/S0140- 6736(04)17181-X

18. Hooper LV, Gordon JI. Commensal host-bacterial relationships in the gut. Science. 2001;292(5519):1115-1118. doi:10.1126/science.1058709

19. Ewaschuk JB, Diaz H, Meddings L, et al. Secreted bioactive factors from Bifidobacterium infantis enhance epithelial cell barrier function. Am J Physiol-Gastrointest Liver Physiol. 2008;295(5):G1025-G1034. doi:10.1152/ajpgi.90227.2008

20. Alhasson F, Das S, Seth R, et al. Altered gut microbiome in a mouse model of Gulf War Illness causes neuroinflammation and intestinal injury via leaky gut and TLR4 activation. PLoS One. 2017;12(3):e0172914. doi:10.1371/journal.pone.0172914

21. Fillman SG, Cloonan N, Catts VS, et al. Increased inflammatory markers identified in the dorsolateral prefrontal cortex of individuals with schizophrenia. Mol Psychiatry. 2013;18(2):206-214. doi:10.1038/mp.2012.110

22. Miller BJ, Buckley P, Seabolt W, et al. Meta-analysis of cytokine alterations in schizophrenia: clinical status and antipsychotic effects. Biol Psychiatry. 2011;70(7):663-671. doi:10.1016/j.biopsych.2011.04.013

23. Al-Amin M, Uddin MMN, Reza HM. Effects of antipsychotics on the inflammatory response system of patients with schizophrenia in peripheral blood mononuclear cell cultures. Clin Psychopharmacol Neurosci. 2013;11(3):144-151. doi:10.9758/cpn.2013.11.3.144

24. Yuan X, Zhang P, Wang Y, et al. Changes in metabolism and microbiota after 24-week risperidone treatment in drug naïve, normal weight patients with first episode schizophrenia. Schizophr Res. 2018;201:299-306. doi:10.1016/j.schres.2018.05.017

25. Maier L, Pruteanu M, Kuhn M, et al. Extensive impact of non-antibiotic drugs on human gut bacteria. Nature. 2018;555(7698):623-628. doi:10.1038/nature25979

26. Dickerson FB, Stallings C, Origoni A, et al. Effect of probiotic supplementation on schizophrenia symptoms and association with gastrointestinal functioning: a randomized, placebo-controlled trial. Prim Care Companion CNS Disord. 2014;15(1):PCC.13m01579. doi:10.4088/PCC.13m01579

27. David LA, Maurice CF, Carmody RN, et al. Diet rapidly and reproducibly alters the human gut microbiome. Nature. 2014;505(7484):559-563. doi:10.1038/nature12820

28. Bien J, Palagani V, Bozko P. The intestinal microbiota dysbiosis and Clostridium difficile infection: is there a relationship with inflammatory bowel disease? Ther Adv Gastroenterol. 2013;6(1):53-68. doi:10.1177/1756283X12454590

29. Cryan JF, O’Riordan KJ, Sandhu K, et al. The gut microbiome in neurological disorders. Lancet Neurol. 2020;19(2):179-194. doi:10.1016/S1474-4422(19)30356-4

30. Jones CA, Watson DJG, Fone KCF. Animal models of schizophrenia. Br J Pharmacol. 2011;164(4):1162-1194. doi:10.1111/j.1476-5381.2011.01386.x

31. Schmidt MJ, Mirnics K. Neurodevelopment, GABA system dysfunction, and schizophrenia. Neuropsychopharmacology. 2015;40(1):190-206. doi:10.1038/npp.2014.95

32. Nasrallah, HA. The daunting challenge of schizophrenia: hundreds of biotypes and dozens of theories. Curr. Psychiatry 2018;17(12):4-6,50.

33. Nocera A, Nasrallah HA. The association of the gut microbiota with clinical features in schizophrenia. Behav Sci (Basel). 2022;12(4):89. doi:10.3390/bs12040089

34. Schwarz E, Maukonen J, Hyytiäinen T, et al. Analysis of microbiota in first episode psychosis identifies preliminary associations with symptom severity and treatment response. Schizophr Res. 2018;192:398-403. doi:10.1016/j.schres.2017.04.017

35. Nguyen TT, Kosciolek T, Maldonado Y, et al. Differences in gut microbiome composition between persons with chronic schizophrenia and healthy comparison subjects. Schizophr Res. 2019;204:23-29. doi:10.1016/j.schres.2018.09.014

36. Li S, Zhuo M, Huang X, et al. Altered gut microbiota associated with symptom severity in schizophrenia. PeerJ. 2020;8:e9574. doi:10.7717/peerj.9574

37. Chen X, Xu J, Wang H, et al. Profiling the differences of gut microbial structure between schizophrenia patients with and without violent behaviors based on 16S rRNA gene sequencing. Int J Legal Med. 2021;135(1):131-141. doi:10.1007/s00414-020-02439-1

38. Manchia M, Fontana A, Panebianco C, et al. Involvement of gut microbiota in schizophrenia and treatment resistance to antipsychotics. Biomedicines. 2021;9(8):875. doi:10.3390/biomedicines9080875

39. Zhu C, Zheng M, Ali U, et al. Association between abundance of haemophilus in the gut microbiota and negative symptoms of schizophrenia. Front Psychiatry. 2021;12:685910. doi:10.3389/fpsyt.2021.685910

40. Flowers SA, Evans SJ, Ward KM, et al. Interaction between atypical antipsychotics and the gut microbiome in a bipolar disease cohort. Pharmacotherapy. 2017;37(3):261-267. doi:10.1002/phar.1890

41. Yatsunenko T, Rey FE, Manary MJ, et al. Human gut microbiome viewed across age and geography. Nature. 2012;486(7402):222-227. doi:10.1038/nature11053

42. Buchanan RW. Persistent negative symptoms in schizophrenia: an overview. Schizophr Bull. 2007;33(4):1013-1022. doi:10.1093/schbul/sb1057

43. Liu JCW, Gorbovskaya I, Hahn MK, et al. The gut microbiome in schizophrenia and the potential benefits of prebiotic and probiotic treatment. Nutrients. 2021;13(4):1152. doi:10.3390/nu13041152

44. Biedermann L, Zeitz J, Mwinyi J, et al. Smoking cessation induces profound changes in the composition of the intestinal microbiota in humans. PloS One. 2013;8(3):e59260. doi:10.1371/journal.pone.0059260

45. Leclercq S, Matamoros S, Cani PD, et al. Intestinal permeability, gut-bacterial dysbiosis, and behavioral markers of alcohol-dependence severity. Proc Natl Acad Sci. 2014;111(42):e4485-e4493. doi:10.1073/pnas.1415174111

46. Hernández-Quiroz F, Nirmalkar K, Villalobos-Flores LE, et al. Influence of moderate beer consumption on human gut microbiota and its impact on fasting glucose and ß-cell function. Alcohol. 2020;85:77-94. doi:10.1016/j.alcohol.2019.05.006

47. Panee J, Gerschenson M, Chang L. Associations between microbiota, mitochondrial function, and cognition in chronic marijuana users. J Neuroimmune Pharmacol. 2018;13(1):113-122. doi:10.1007/s11481-017-9767-0

48. Wu GD, Chen J, Hoffmann C, et al. Linking long-term dietary patterns with gut microbial enterotypes. Science. 2011;334(6052):105-108. doi:10.1126/science.1208344

49. Rezac S, Kok CR, Heermann M, et al. Fermented foods as a dietary source of live organisms. Front Microbiol. 2018;9:1785. doi:10.3389/fmicb.2018.01785

50. Chen X, Zhang Y, Wang H, et al. The regulatory effects of lactic acid on neuropsychiatric disorders. Discover Ment Health. 2022;2(1). doi:10.1007/s44192-022-00011-4

51. Karbownik MS, Mokros Ł, Dobielska M, et al. Association between consumption of fermented food and food-derived prebiotics with cognitive performance, depressive, and anxiety symptoms in psychiatrically healthy medical students under psychological stress: a prospective cohort study. Front Nutr. 2022;9:850249. doi:10.3389/fnut.2022.850249

52. Romano S, Savva GM, Bedarf JR, et al. Meta-analysis of the Parkinson’s disease gut microbiome suggests alterations linked to intestinal inflammation. NPJ Parkinsons Dis. 2021;7(1):27. doi:10.1038/s41531-021-00156-z

53. Bourassa MW, Alim I, Bultman SJ, et al. Butyrate, neuroepigenetics and the gut microbiome: can a high fiber diet improve brain health? Neurosci Lett. 2016;625:56-63. doi:10.1016/j.neulet.2016.02.009

54. Matt SM, Allen JM, Lawson MA, et al. Butyrate and dietary soluble fiber improve neuroinflammation associated with aging in mice. Front Immunol. 2018;9:1832. doi:10.3389/fimmu.2018.01832

55. Mittal VA, Vargas T, Osborne KJ, et al. Exercise treatments for psychosis: a review. Curr Treat Options Psychiatry. 2017;4(2):152-166. doi:10.1007/s40501-017-0112-2

56. Estaki M, Pither J, Baumeister P, et al. Cardiorespiratory fitness as a predictor of intestinal microbial diversity and distinct metagenomic functions. Microbiome. 2016;4(1):42. doi:10.1186/s40168-016-0189-7

57. Karl JP, Margolis LM, Madslien EH, et al. Changes in intestinal microbiota composition and metabolism coincide with increased intestinal permeability in young adults under prolonged physiological stress. Am J Physiol-Gastrointest Liver Physiol. 2017;312(6):G559-G571. doi:10.1152/ajpgi.00066.2017

58. Claus SP, Guillou H, Ellero-Simatos S. The gut microbiota: a major player in the toxicity of environmental pollutants? NPJ Biofilms Microbiomes. 2016;2:16003. doi:10.1038/npjbiofilms.2016.3

Clinical symptoms of psychosis and the gut microbiome

Previous literature has grouped patients with schizophrenia spectrum disorders as 1 unified study group. But as is the case with many psychiatric conditions, there is a great deal of heterogeneity in neurobiology, genetics, and microbiome composition among individuals with schizophrenia.³²

Researchers have begun to investigate ways in which the gut microbiome varies regarding the clinical symptoms of psychosis.³³ The Table^3,34-39 provides an overview of 7 human studies of gut microbiome changes relating to clinical features of schizophrenia. In these studies, researchers have found correlations between the gut microbiome and a tendency toward violence,³⁷ cognitive deficits,^34-36,39 depressive symptoms,^35,39 and numerous other clinical features of psychosis. Most of these correlations have not yet been replicated by further studies. But among studies with similar clinical questions, 3 reported changes in gut microbiome correlated with overall symptom severity, and 4 studies correlated changes with negative symptom severity. In 2 studies,^3,34 Lachnospiraceae was correlated with worsened symptom severity. However, this may have been the result of poor control for antipsychotic use, as 1 study in bipolar patients found that Lachnospiraceae was increased in those taking antipsychotics compared to those who were not treated with antipsychotics.⁴⁰ The specific shifts in bacteria seen for overall symptom and negative symptom severity were not consistent across studies. This is not surprising because the gut microbiome varies with diet and geographic region,⁴¹ and patients in these studies were from a variety of regions. Multiple studies demonstrated gut microbiome alterations for patients with more severe negative symptoms. This is particularly interesting because negative symptoms are often difficult to treat and do not respond to antipsychotics.⁴² This research suggests the gut microbiome may be helpful in developing future treatments for patients with negative symptoms that do not respond to existing treatments.

Research of probiotic supplementation for ameliorating symptoms of schizophrenia has yielded mixed results.⁴³ It is possible that studies of probiotic supplementation have failed to consider the variations in the gut microbiome among individuals with schizophrenia. A better understanding of the variations in gut microbiome may allow for the development of more personalized interventions.

Recommendations for a healthy gut microbiome

In addition to antipsychotics, many other evidence-based interventions can be used to help restore a healthy gut microbiome in patients with schizophrenia. To improve the gut microbiome, we suggest discussing the following changes with patients:

Quitting smoking. Smoking is common among patients with schizophrenia but decreases gut microbiome diversity.⁴⁴
Avoiding excessive alcohol use. Excessive alcohol use contributes to dysbiosis and increased intestinal permeability.⁴⁵ Moderate alcohol consumption does not appear to have the same harmful effects on the microbiome.⁴⁶
Avoiding the use of recreational drugs, including marijuana, which impact the gut microbiome.⁴⁷
Consuming a diet rich in fiber.⁴⁸ Presently, there is not enough evidence to recommend probiotic supplementation to reduce symptoms of schizophrenia.⁴¹ Similar to probiotics, fermented foods contain Lactobacillus, a bacterial species that produces lactic acid.⁴⁹ Lactobacillus is enriched in the gut microbiome in some neurodegenerative diseases, and lactic acid can be neurotoxic at high levels.^50-52 Therefore, clinicians should not explicitly recommend fermented foods under the assumption of improved brain health. A diet rich in soluble fiber has been consistently shown to promote anti-inflammatory bacteria and is much more likely to be beneficial.^53,54 Soluble fiber is found in foods such as fruits, vegetables, beans, and oats.
Exercising can increase microbiome diversity and provide anti-inflammatory effects in the gut.^55,56 A recent review found that steady-state aerobic and high-intensity exercise interventions have positive effects on mood, cognition, and other negative symptoms in patients with schizophrenia.⁵⁵
Minimizing stress. Psychological stress and physiological stress from untreated medical conditions are toxic to healthy gut bacteria and weaken the gut barrier.⁵⁷
Mitigating exposure to pollution. Environmental pollution, including exposures to air pollution, heavy metals, and pesticides, disrupts the gut microbiome.⁵⁸

The American Heart Association publishes lifestyle recommendations for individuals with heart disease and the National Institutes of Health publishes lifestyle recommendations for patients with chronic kidney disease. This leads us to question why the American Psychiatric Association has not published lifestyle recommendations for those with severe mental illness. The effects of lifestyle on both the gut microbiome and symptom mitigation is critical. With increasingly shortened appointments, standardized guidelines would benefit psychiatrists and patients alike.

Bottom Line

The gut microbiome is connected to the clinical symptoms of psychosis via a variety of hormonal, neuroimmune, and metabolic mechanisms active across the lifespan. Despite advances in research, there is still much to be understood regarding this relationship. Clinicians should discuss with patients ways to promote a healthy gut microbiome, including consuming a diet rich in fiber, avoiding use of recreational drugs, and exercising regularly.

Related Resources

Nocera A, Nasrallah HA. The association of the gut microbiota with clinical features in schizophrenia. Behav Sci. 2022;12(4):89.
Nasrallah HA. It takes guts to be mentally ill: microbiota and psychopathology. Current Psychiatry. 2018;17(9):4-6.