The Immune System through the Lens of Alcohol Intake and Gut Microbiota

Abstract

The human gut is the largest organ with immune function in our body, responsible for regulating the homeostasis of the intestinal barrier. A diverse, complex and dynamic population of microorganisms, called microbiota, which exert a significant impact on the host during homeostasis and disease, supports this role. In fact, intestinal bacteria maintain immune and metabolic homeostasis, protecting our organism against pathogens. The development of numerous inflammatory disorders and infections has been linked to altered gut bacterial composition or dysbiosis. Multiple factors contribute to the establishment of the human gut microbiota. For instance, diet is considered as one of the many drivers in shaping the gut microbiota across the lifetime. By contrast, alcohol is one of the many factors that disrupt the proper functioning of the gut, leading to a disruption of the intestinal barrier integrity that increases the permeability of the mucosa, with the final result of a disrupted mucosal immunity. This damage to the permeability of the intestinal membrane allows bacteria and their components to enter the blood tissue, reaching other organs such as the liver or the brain. Although chronic heavy drinking has harmful effects on the immune system cells at the systemic level, this review focuses on the effect produced on gut, brain and liver, because of their significance in the link between alcohol consumption, gut microbiota and the immune system.

Keywords: alcohol; brain; dysbiosis; gut; immune system; liver; microbiota.

Figure 1

Relationships between the innate and the adaptive immune systems and gut microbiota. (A) The innate immune response is a very fast, pathogen-non-specific, first line of defense mechanism. It is mainly composed of macrophages, dendritic and natural killer cells, as well as different forms of granulocytes. The adaptive immune system is highly specific to a particular pathogen and is formed by B and T cells lymphocytes. (B) The gut microbiota is in close interaction with both the innate and the adaptive immune system. This interaction is frequently driven by SCFAs, which modulate local as well as systemic immune response. SCFAs can bind to G-protein-coupled receptors as FFAR2 and FFAR3 present on the surface of gut epithelial cells and immune cells including dendritic cells, macrophages and neutrophils, and are therefore important regulators of inflammatory response. SCFAs also promote the activation of B cells and the development of Treg CD4+T cells—for example, increasing secretion of IL-10 with important anti-inflammatory effects. Suppression of inflammatory factors like cytokines is further achieved by the inhibition of histone deacetylases (HDACs) activity. Finally, SCFAs have been shown to modulate immune inflammation responses in extraintestinal organs such as the brain, by acting on microglia and astrocytes.

Figure 2

Principal signaling pathway and molecules involved in the communication microbiota/gut to the brain and liver. Gut microbiota can signal to the brain and liver through multiple direct and indirect mechanisms. Microbiota produces neurotransmitters, tryptophan metabolites, fermentation metabolic by-products such as short-chain fatty acids (SCFAs), the release of cytokines by immune cells and gut hormone signaling. Some of these molecules can activate the vagus nerve or reach the brain and liver via systemic circulation. Alcohol consumption causes dysregulation in the intestinal microbiota, which leads to an alteration in this communication and subsequently causes alterations in brain and liver functions.

Figure 3

Effects of alcohol on the immune system. Alcohol consumption increases intestinal permeability through the suppression of intestinal tight junction protein expression. This alteration allows the translocation of bacterial products to the systemic circulation. The gut-derived bacterial components together with LPS activate the immune cells localized in the systemic circulation or in target organs such as liver and brain. This causes the increase in pro-inflammatory components that can lead to alcohol liver disease or increased states of neuroinflammation.