The gut-brain connection: role of the gut microbioma in the outcome and development of the sporadic Parkinson's disease

Abstract

Parkinson's disease (PD) is a progressive neurodegenerative disease with devastating clinical manifestations. In PD, neuronal death is associated with intracellular accumulation of aggregated a-synuclein (a-syn), a synaptic protein, forming structures known as Lewy bodies. The disease is found in two main forms: familial PD, comprehending 10% of the cases; and sporadic PD, comprehending 90% of all cases. Although the cause of sporadic PD is not completely understood, abundant pathological and clinical evidences show that misfolded a-syn is found in enteric nerves before it appears in the brain. Thereby, this might suggest a hypothesis in which one possible cause of sporadic PD pathology is the misfolding and accumulation of a-syn in the gut, its migration throughout peripheric nerves and spreading to the central nervous system via cell-to-cell prion-like propagation, since misfolded a-synuclein initiates misfolding of native a-syn in recipient cells (seed hypothesis). It was recently shown that enteroendocrine cells (EECs), which are part of the gut epithelium, also possess many neuron-like properties and a direct connection to enteric nerves. In addition, since EECs face the gut lumen, these cells are in constant interaction with the gut microbiome, which might regulate much of their physiological and pathological processes. The gut/nutrient-centric nature of human evolutionary process proposes an important role for gut-associated microbiota in the maintenance of homeostasis and human health. Recent advances in microbiome research suggest that gastrointestinal microbiota might play an important role in pathogenesis of neurodegenerative disorders such as PD and also multiple sclerosis (MS). In fact, it was found that two bacteria groups, Acinetobacter and Akkermansia, were four times more abundant in MS patients than in individuals with no disease. Another group, Parabacteroides, was four times more abundant in healthy people. Therefore, the EECs, by their neuronal connection and interaction with the gut microbiome, might play a critical role in transmitting PD pathology from the gut to the brain. Therefore, understanding how the microbiome can influence the aggregation of ±-syn and how these amyloids are internalized by gut peripheric neurons will shed new light on innovative clinical interventions and drug discovery. This work will gather the efforts of national and international researchers with great experience in neurobiology, with the aim of exploring, in an unprecedented way in the country, to my knowledge, the influence of the microbioma on the misfolding of a-syn in intestinal cells and how this protein is able to reach peripheral nerve endings and migrate to ascending levels of the nervous system. (AU)