Ioana Ciuperca

Severe mental illnesses, including schizophrenia and schizophrenia-like disorders, have been associated with premature neuronal and glial senescence, microglial activation, and gray matter volume reduction. These changes may drive clinical symptoms of schizophrenia, including cognitive impairment. Aryl hydrocarbon receptor, abundantly expressed in the intestinal and blood–brain barrier, is the master regulator of both tight junctions and cellular senescence. Under pathological circumstances, this receptor may promote premature gut aging, enabling the translocation of bacteria or their components from the gastrointestinal tract into systemic circulation and from there into the central nervous system. In this review article, we discuss a potential mechanism of schizophrenia–microorganismal migration, microglial activation, and gray matter volume reduction. We also focus on potential interventions for maintaining barrier function. These approaches include natural and synthetic modulators of the aryl hydrocarbon receptor as well as biophysical strategies to preserve barrier integrity and prevent central nervous system pathology.

Life is dependent on the separation of various body compartments from each other and the environment. The permeability of biological barriers, including the enhanced barriers of the gastrointestinal and blood-brain, depends on the integrity of cell or mitochondrial membranes and intercellular junctions. Severe mental illness and metabolic syndrome are characterized by premature cellular senescence that alters the permeability of biological membranes. Increased barrier permeability enables microbial migration outside the gastrointestinal tract, eventually reaching the brain, skeletal muscles, and adipose tissue. Immune responses to invading microorganisms or their components likely contribute to dysmetabolism and neuropathology. Entropy, a biophysical measure of randomness or disorder, may detect senescence-induced changes early, thus allowing for interventions to avert microbial translocation and the subsequent pathology. This highlights entropy as a potential screening tool for schizophrenia and metabolic disorders. This review consists of three parts. The first part introduces the reader to the entropy in biological systems and its screening role for neuropathology and dysmetabolism. The second part discusses cellular senescence and its importance for microbial migration outside the gastrointestinal tract. Part three focuses on biophysical interventions for restoring gut barrier homeostasis, such as membrane lipid replacement and plasmalogen replacement therapy, gamma wave entrainment, and other novel modalities.

Oxytocin, known as the “love hormone,” is produced in the posterior hypothalamus and participates in numerous physiological processes, including social intelligence, sexual activity, and metabolism. SARS-CoV-2 virus, the etiologic agent of the COVID-19 pandemic, has been shown to suppress oxytocin release from the intestinal epithelial cells, resulting in microbial migration outside of the gut lumen. Limosilactobacillus reuterii, a commensal known for producing oxytocin, normalizes the gut barrier function and exerts antiviral properties, including against the SARS-CoV-2 virus. This may explain the beneficial effect of oxytocin in schizophrenia, a condition associated with a dysfunctional gut barrier and microbial translocation from the gastrointestinal tract into the systemic circulation. The molecular underpinnings of oxytocin in the central nervous system are not entirely clear. However, as viruses target tight junctions, the molecular Velcro that holds the barrier cells together, oxytocin enhances the barrier function. In this mini-view, we summarize what is known about the role of oxytocin in schizophrenia and discuss natural and synthetic compounds that could optimize gut barrier permeability.