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 Opportunities: Scholarships in Brazil - Post-Doctoral
• Start date: August 01, 2021
• End date: July 31, 2025
• Field of knowledge: Health Sciences - Pharmacy
• Principal Investigator: Rita de Cassia Aleixo Tostes Passaglia
• Grantee: Carla Brigagão Pacheco da Silva
• Host 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
• Associated scholarship(s): 22/12426-1 - Ethanol effects on cardiovascular system: the role of gut microbiota and fMLP/FPR-1, BE.EP.PD

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)

Scientific publications

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

BRIGAGAO PACHECO DA SILVA, CARLA; NASCIMENTO-SILVA, EDSON ALEXANDRE; ZARAMELA, LIVIA SOARES; DA COSTA, BRUNO RUIZ BRANDAO; RODRIGUES, VANESSA FERNANDES; DE MARTINIS, BRUNO SPINOSA; CARLOS, DANIELA; TOSTES, RITA C.. Drinking pattern and sex modulate the impact of ethanol consumption on the mouse gut microbiome. Physiological Genomics, v. 57, n. 3, p. 16-pg., 2025-03-07. (20/08554-9, 20/11339-2, 13/08216-2)