A Schizophrenia Hypothesis Based Onmicrobial Translocation and Aberrant Microglial Activation

Severe mental illness, including schizophrenia and schizophrenia-like disorders, have been associated with premature cellular senescence and gray matter volume reduction but these findings have not been adequately explored. We hypothesize that dysfunctional aryl hydrocarbon receptor, the master regulator of both tight junctions and cellular senescence, disrupts intestinal and blood-brain barriers, enabling the translocation of gut microbes or their components into the systemic circulation and from there in the brain. We hypothesize further that intestinal bacteria and/or their molecules activate microglia, leading to the aberrant phagocytosis of healthy neurons and synapses with resultant gray matter volume reduction, a hallmark of schizophrenia. In this article, we discuss intestinal epithelial cell senescence, microorganismal translocation outside the gut lumen, microglial activation, and gray matter volume depletion. We also highlight potential interventions for optimization of gut barrier, suggesting that several established antipsychotic drugs oppose microbial translocation.