The gut-brain axis
Another advance in understanding the potential role of infections and inflammation in brain disorders are research findings that suggest the brain does not exist as an isolated organ but rather interacts with many other organ systems in the body. The gastrointestinal tract is the best characterized brain-interacting organ system. Numerous studies indicate that the gastrointestinal tract and the brain interact with each other by means of a series of networks categorized as the gut-brain-axis.
Clinical manifestations of the gut-brain axis have been long noted by clinicians who observed a high rate of gastrointestinal symptoms in individuals with psychiatric disorders and a correspondingly high rate of psychiatric symptoms in individuals with gastrointestinal disorders, particularly immune-based gastrointestinal disorders such as inflammatory bowel diseases. Alterations in gut-based immune markers have been found in several psychiatric disorders including schizophrenia, bipolar disorder, and major depressive disorder as well as in individuals who had a recent suicide attempt.
Recent studies have also shown that genetic differences can modulate the individual response to infectious agents. Many components of the immune system display individual variation based on genetic elements that comprise the human leukocyte antigen (HLA) and other immune networks. This immune variation is likely to explain much of the individual variation in response to infectious agents. For example, not every person who is exposed to the protozoan Toxoplasma gondii is at an increased risk for a psychiatric disorder—some of the variation apparently results from genetic differences.7
In the case of Epstein Barr virus, increased risk of schizophrenia appears to be associated with an altered immune response to viral proteins, some of which is likely to be under genetic control. Furthermore, many microbial agents also have their own genomes, which can vary and define differing degrees of pathogenicity. For example, some strains of Toxoplasma gondii appear to be more associated with psychiatric disorders than others.
Interestingly, many of the genetic regions associated with increased risk of psychiatric disorders have been shown to encode components of the immune system and other immune active proteins. This finding suggests that some of the genetic risk of psychiatric disorders lies in variations in the immune response to infectious agents. In this scenario, many cases of psychiatric disorders represent an environmental exposure occurring in a genetically susceptible individual in a manner characterized as representing gene-environmental interactions.
Dr Yolken is Theodore and Vada Stanley Distinguished Professor of Neurovirology in Pediatrics, Johns Hopkins University, Baltimore, MD; Ms Shwartz is a Psychiatric-Mental Health Nurse Practitioner, Telecare Corporation, Alameda County, CA; and Dr Quanbeck is Associate Medical Director, Cordilleras Mental Health Rehabilitation Center, San Mateo County Health, Redwood City, CA.
1. Bakhshi K, Chance SA. The neuropathology of schizophrenia: a selective review of past studies and emerging themes in brain structure and cytoarchitecture. Neurosci. 2015;303:82-102.
2. Severance EG, Xiao J, Jones-Brando L, et al.Toxoplasma gondii-A gastrointestinal pathogen associated with human brain diseases. Int Rev Neurobiol. 2016;131:143-163.
3. Khandaker GM, Cousins L, Deakin J, et al. Inflammation and immunity in schizophrenia: implications for pathophysiology and treatment. Lancet Psychiatry. 2015;2:258-270.
4. Müller N. Immunological aspects of the treatment of depression and schizophrenia. Dial Clin Neurosci. 2017;19:55-63.
5. Tronel C, Largeau B, Santiago Ribeiro MJ, et al. Molecular targets for PET imaging of activated microglia: the current situation and future expectations. Int J Mol Sci. 2017;18:802.
6. Tay TL, Béchade C, D’Andrea I, et al. Microglia gone rogue: impacts on psychiatric disorders across the lifespan. Front Mol Neurosci. 2017;10:421.
7. Wang AW, Avramopoulos D, Lori A, et al. Genome-wide association study in two populations to determine genetic variants associated with Toxoplasma gondii infection and relationship to schizophrenia risk. Prog Neuropsychopharmacol Biol Psychiatry. 2019;8;92:133-147.
8. Dickerson F, Adamos M, Katsafanas E, et al. Adjunctive probiotic microorganisms to prevent rehospitalization in patients with acute mania: a randomized controlled trial. Bipolar Disord. 2018;20:614-621.
9. 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. February 2014;16 [Epub].
10. Köhler-Forsberg O, Petersen L, Gasse C, et al. A nationwide study in Denmark of the association between treated infections and the subsequent risk of treated mental disorders in children and adolescents. JAMA Psychiatry. 2019;76:271-279.