Cytokines and Madness: A Unifying Hypothesis of Schizophrenia Involving Interleukin-22

Schizophrenia is a severe neuropsychiatric illness of uncertain etiopathogenesis in which antipsychotic drugs can attenuate the symptoms, but patients rarely return to the premorbid level of functioning. In fact, with each relapse, people living with schizophrenia progress toward disability and cognitive impairment. Moreover, our patients desire to live normal lives, to manage their daily affairs independently, date, get married, and raise and support a family. Those of us who work daily with schizophrenia patients know that these objectives are rarely met despite the novel and allegedly improved dopamine blockers. We hypothesize that poor outcomes in schizophrenia reflect the gray matter volume reduction, which continues despite antipsychotic treatment. We hypothesize further that increased gut barrier permeability, due to dysfunctional aryl hydrocarbon receptor (AhR), downregulates the gut barrier protectors, brain-derived neurotrophic factor (BDNF), and interleukin-22 (IL-22), facilitating microbial translocation into the systemic circulation, eventually reaching the brain. Recombinant human IL-22 could ameliorate the outcome of schizophrenia by limiting bacterial translocation and by initiating tissue repair. This short review examines the signal transducer and transcription-three (STAT3)/AhR axis and downregulation of IL-22 and BDNF with subsequent increase in gut barrier permeability. Based on the hypothesis presented here, we discuss alternative schizophrenia interventions, including AhR antagonists, mitochondrial transplant, membrane lipid replacement, and recombinant human IL-22.