Gut, Microbiome, and Brain Regulatory Axis: Relevance to Neurodegenerative and Psychiatric Disorders

Abstract

It has become apparent that the molecular and biochemical integrity of interactive families, genera, and species of human gut microflora is critically linked to maintaining complex metabolic and behavioral processes mediated by peripheral organ systems and central nervous system neuronal groupings. Relatively recent studies have established intrinsic ratios of enterotypes contained within the human microbiome across demographic subpopulations and have empirically linked significant alterations in the expression of bacterial enterotypes with the initiation and persistence of several major metabolic and psychiatric disorders. Accordingly, the goal of our review is to highlight potential thematic/functional linkages of pathophysiological alterations in gut microbiota and bidirectional gut-brain signaling pathways with special emphasis on the potential roles of gut dysbiosis on the pathophysiology of psychiatric illnesses. We provide critical discussion of putative thematic linkages of Parkinson's disease (PD) data sets to similar pathophysiological events as potential causative factors in the development and persistence of diverse psychiatric illnesses. Finally, we include a concise review of preclinical paradigms that involve immunologically-induced GI deficits and dysbiosis of maternal microflora that are functionally linked to impaired neurodevelopmental processes leading to affective behavioral syndromes in the offspring.

Keywords: Antibiotics; Bacteria; Depression; FOXG1; Microbiome; Monoamines; Psychiatry.

Fig. 1

Bacterial intrinsic ratio perturbations are normal occurrences in the microbiome. In part, this phenomenon is monitored by the enteric microglia found in Auerbach’s and Meissner’s plexus. Macrophages freely travel via the circulatory system and gain entrance into the enteric nervous system and reside there fulfilling their sentinel function by transforming into microglia as also occurs in the brain. Clearly, as in the brain, various chemical messengers (e.g., LPS from bacteria) or toxins can activate these cellular sentinels turning them back into macrophages to meet the micro-environmental challenge. Activated macrophages originating from the enteric neuroimmune system may also enter the brain and by so doing activate central nervous system neurons and microglia. For example, the nucleus tractus solitarius is especially susceptible. This abnormal or normal activation may exert profound influences on regions of the brain, controlling our mental processes and consciousness because these activities are always on and thus subject to immediate modification. It is equally important to note that eukaryotic cell mitochondria may be part of this intricate communication between the host and the micro biota. Given the origin of mitochondria as a prokaryotic cell, its ability to communicate bidirectionally with a bacterium also exists and occurs

Fig. 2

By way of vagal enteric stimulation normal neural pathways may also be susceptible to abnormal microglial conversions into macrophages, inducing enhanced excitation at the peripheral level (e.g., enteric plexi). In this instance, this rapid neural response may also manifest itself via the nucleus tractus solitarius and locus coeruleus, which would influence the amygdala, hippocampus and the thalamus, and ultimately the cortex