“Pseudoneurotransmission” and gut microbiome – brain communication in neuropsychiatric disorders

The gut microbiome, which comprises symbiotic bacteria colonizing the human digestive tract, undergoes dynamic changes during the lifespan, as evidenced by the fact that the number of species and the diversity of their composition decrease significantly with age. The aim of this review is to illuminate bilateral neuroimmunological pathways that determine the role of gut microbiome dysbiosis, not only as a cause but also as a byproduct of many neurodegenerative diseases of the CNS, such as Alzheimer's disease (AD) and Parkinson's disease (PD), but also in the frame of several behavioral and psychiatric pathological conditions such as depressive and anxiety disorders, schizophrenia, and autism spectrum disorder (ASD). Dysbiosis, in particular, reveals a model of "deceptive" mimicry of host molecules that might cause abnormal folding ("misfolding") and pathological aggregation of Aβ-peptide, leading to its dispersion through the gut-brain axis, precipitating microglia cell activation. By controlling myelination at the prefrontal cortex (PFC), a crucial area for multifaceted cognitive behavior, forecasting, and decision-making, the gut/microbiome-brain axis influences mood and social behavior, since major depressive disorder is correlated to white matter disturbance in the PFC, due to disregulations in the expression of myelin-related mRNA in this area. The gut microbiome is altered in psychosis compared to healthy controls, while medication with antipsychotics may result in reduced microbial community diversity. The vagus nerve, as a key element of the parasympathetic nervous system, regulating immune responses, may "detect" gut microbiome metabolites and transfer this intestinal information to the CNS, through its afferents, as in a "pseudo-neurotransmission" process. Scientific interest towards microbiome-based therapies increases as psychobiotics (which are strains of probiotics/prebiotics with specific properties to influence the gut-brain axis) appear to be able to exercise a beneficial effect in many CNS disorders. Lifestyle modifications, such as dietary interventions via psychobiotics intake that might enhance the gut microbiome's ability to produce beneficial metabolites that exert therapeutic effects on intestinal permeability, cognitive function, and immunity, may reveal new research pathways and therapeutic directions leading to a radical change of the "epistemology paradigm" as far as prevention and treatment of major neuro-psychiatric disorders is concerned.