Ethanol: striking the cardiovascular system by harming the gut microbiota

Abstract

Ethanol consumption represents a significant public health problem, and excessive ethanol intake is a risk factor for cardiovascular disease (CVD), one of the leading causes of death and disability worldwide. The mechanisms underlying the effects of ethanol on the cardiovascular system are complex and not fully comprehended. The gut microbiota and their metabolites are indispensable symbionts essential for health and homeostasis and therefore, have emerged as potential contributors to ethanol-induced cardiovascular system dysfunction. By mechanisms that are not completely understood, the gut microbiota modulates the immune system and activates several signaling pathways that stimulate inflammatory responses, which in turn, contribute to the development and progression of CVD. This review summarizes preclinical and clinical evidence on the effects of ethanol in the gut microbiota and discusses the mechanisms by which ethanol-induced gut dysbiosis leads to the activation of the immune system and cardiovascular dysfunction. The cross talk between ethanol consumption and the gut microbiota and its implications are detailed. In summary, an imbalance in the symbiotic relationship between the host and the commensal microbiota in a holobiont, as seen with ethanol consumption, may contribute to CVD. Therefore, manipulating the gut microbiota, by using antibiotics, probiotics, prebiotics, and fecal microbiota transplantation might prove a valuable opportunity to prevent/mitigate the deleterious effects of ethanol and improve cardiovascular health and risk prevention.

Keywords: cardiovascular system; dysbiosis; ethanol; gut microbiota; immune system.

Figure 1.

Oxidative metabolism of alcohol. The enzymes alcohol dehydrogenase (ADH), cytochrome P450 2E1 (CYP2E1), and catalase convert alcohol (i.e., ethanol) to acetaldehyde, a highly reactive and toxic byproduct. Acetaldehyde is metabolized by aldehyde dehydrogenase (ALDH) in the mitochondria to form acetate and NADH. Increased reactive oxygen species (ROS) generation, NADH:NAD⁺ ratio and acetaldehyde adducts formation are observed during the metabolism of ethanol, which contributes to oxidative stress and organs/tissues damage. H⁺, hydrogen proton; H₂O, water; H₂O₂, hydrogen peroxide; NAD⁺, nicotinamide adenine dinucleotide; NADH, reduced nicotinamide adenine dinucleotide; NADP⁺, nicotinamide adenine dinucleotide phosphate; NADPH, reduced nicotinamide adenine dinucleotide phosphate; O₂, molecular oxygen.

Figure 2.

Schematic illustration of possible mechanisms whereby excessive ethanol consumption leads to gut dysbiosis and affects various organs and tissues. Ethanol-induced gut dysbiosis is related to decreased antimicrobial peptides (Reg3b and Reg3g) and increased levels of pathogen-associated molecular patterns (PAMPs), such as lipopolyssacaride (LPS), which are recognized by pattern recognition receptors (PRRs), including Toll-like receptors (TLRs) and NOD-like receptors (NLRs), leading to proinflammatory pathways activation. Furthermore, ethanol induces epithelial barrier disruption by decreasing tight junction protein (Ocln, Cldn4, and Tjp1) expression, promoting increased gut permeability and endotoxemia. These events are accompanied by enhancement in proinflammatory mediators, including cytokines and chemokines, and proinflammatory immune cells in the systemic circulation. Systemic inflammation, exacerbated proinflammatory and immune responses, and oxidative stress in different organs and tissues are linked to ethanol effects. Altogether, these mechanisms can contribute to cardiovascular dysfunction induced by excessive ethanol consumption. Cldn4, claudin 4; CXCL-1/KC, chemokine CXCL-1/KC; IL-1β, interleukin-1β; NLR, NOD-like receptor; Ocln, occludin; Reg3b/Reg3g, C-type regenerating islet derived-3; Th17, T helper 17 cells; Tjp1, tight junction protein 1; TLR, Toll-like receptor; TNF-α, tumor necrosis factor-α.

Figure 3.

Potential mechanisms associated with ethanol-induced imbalances in the symbiotic relationship between the host and the gut microbiota, which can lead to the development and progression of cardiovascular disease (CVD). The immune system hypothesis (1) suggests that ethanol-induced dysbiosis increases inflammatory processes and immune cell infiltration, especially in the perivascular adipose tissue (PVAT), culminating in adipocyte hypertrophy and oxidative stress in the vascular endothelium. In addition, it is hypothesized that the interference of ethanol in the gut microbiota causes an imbalance in hepatic and adipose tissue homeostasis (2), increasing the levels of vasoactive metabolites. The increase in secondary bile acids (3) is associated with decreased expression of the farnesoid X-activated receptor (FXR) and increase of important genes in the synthesis of these acids, events associated with the consumption of ethanol. The consequences are decreased heart rate and systemic inflammation. The consumption of ethanol decreases the production of short-chain fatty acids (SCFAs), such as butyrate and acetate (4), by the gut microbiota and thus inhibits regulatory mechanisms of inflammation and favors hypertension. The excess of N-oxide-trimethylamine (TMAO) derived from the imbalanced microbiota (5) may activate Toll-like receptors (TLRs), nuclear factor-kappa B (NF-κB), and inflammasome, inducing inflammatory processes and endothelial dysfunction, in addition to favoring the accumulation of fat in macrophages. Ethanol consumption can also increase the levels of formylated peptides derived from the gut microbiota and mitochondria (6), which, when interacting with the formyl peptide receptor 1 (FPR-1), contribute to increased vascular permeability and the occurrence of hypertension.