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Trimethylamine N-oxide (TMAO) as a link among gut dysbiosis, immune system activation and vascular dysfunction induced by ethanol consumption

Grant number: 20/11339-2
Support type:Scholarships in Brazil - Post-Doctorate
Effective date (Start): August 01, 2021
Effective date (End): July 31, 2023
Field of knowledge:Health Sciences - Pharmacy
Principal researcher:Rita de Cassia Aleixo Tostes Passaglia
Grantee:Carla Brigagão Pacheco da Silva
Home Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
Associated research grant:13/08216-2 - CRID - Center for Research in Inflammatory Diseases, AP.CEPID

Abstract

Cardiovascular diseases (CVDs) are the leading cause of death and disability in developed, emerging and underdeveloped countries. Risk factors such as sex, ageing, genetic, diet, sedentary lifestyle, metabolic diseases and excessive alcohol consumption, contribute to CVDs. Recent studies showed that alterations of gut microbiota composition or gut microbiota-dependent metabolites also contribute to the pathogenesis of CVDs, which potentially lead to activation of pro-inflammatory responses in the cardiovascular system. Furthermore, dysregulation of the innate and adaptive immune systems has been reported in chronic alcohol drinkers. Despite studies showing that both ethanol consumption and gut dysbiosis activate the immune system, and the overactivation of immune system is associated to cardiovascular dysfunction, the mechanisms underlying these events are not fully understood. Elevated levels of trimethylamine N-oxide (TMAO), a biologically active molecule generated by the gut microbiota, have been linked to vascular inflammation, cardiac remodeling, endothelial dysfunction and, consequently, contribute to the development of CVDs. However, there are no studies showing whether vascular dysfunction induced by ethanol consumption results from dysbiosis, enhanced TMAO levels and overactivation of the immune system, in other words, the increase of TMAO mediated by gut dysbiosis is the mechanisms underlying the immune system activation and vascular dysfunction induced by ethanol consumption. Therefore, the hypothesis of the present study is that excessive ethanol consumption alters the gut microbiota composition/function, leading to gut dysbiosis, and these alterations play an important role in the modulation of immune response. In addition, the consequent exacerbated inflammatory response is key to ethanol consumption-mediated vascular dysfunction. Thus, this study will determine whether the gut microbiota, via TMAO and activation of the immune system, plays a role on vascular dysfunction induced by excessive ethanol consumption. We will determine whether the experimental model of ethanol consumption induces vascular dysfunction, gut dysbiosis and alteration of immune response; as well as possible mechanisms underlying in the immune response activation and vascular dysfunction induced by excessive ethanol consumption, focusing on the role of the gut microbiota in these events. (AU)

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