Redes de interação proteína-proteína para avaliar a associação entre microbiota e ação neuroinflamatória na depressão

Abstract

INTRODUCTION: Major depressive disorder (MDD) has a heritability of 37% and is one of the most common, costly and disabling mental health conditions worldwide with lifetime prevalence estimates of 19% among adults. There is evidence of MDD alterations correlated with bidirectional communication between CNS and microbiota. Considered as the “second brain”, the microbiota plays a key role in regulating the central nervous system (CNS) and immune system. Analysis of the network of proteins encoded by genes associated with MDD and the microbiota can help to elucidate the molecular systems involved. METHODS: To establish the relationships between intestinal microbiota and MDD, protein-protein interaction networks (PPIN) were constructed from human genetic variants identified in the literature. The R Studio v 4.0.2 interface, the STRING v11 database and Cytoscape v 3.7.2. were used for the generation and visualization of networks. The protein from each gene was connected to 10 other proteins at three successive levels. An intersection network was generated between PPIN built from microbiota-associated variants and PPIN from MDD variants. RESULTS: One of the main biological processes was the exocytosis of proteins from the lumen of azurophile granules (code: HSA:6798751, p-corrected: 2.20E-18). The proteins that act on this phenomenon interact with proteins encoded by the DENND1A and DENND1B genes, which are associated with MDD. DISCUSSION: Exocytosis of proteins from the lumen of azurophilic neutrophil granules are involved in the first immune response when the permeability of the intestinal barrier is altered, which can be caused by dysbiosis. Additionally, alterations in proteins encoded by variants of DENND1A and DENND1B genes could deregulate neutrophil degranulation, altering the organism's inflammatory response. CONCLUSION: Understanding the interaction between the gut-brain axis and MDD are important steps to elucidate the inflammatory pathway present in depression and the immune dysregulation associated with this pathology.