In this review, we will examine alcohol’s dose-dependent effects and potential mechanisms in autoimmune diseases in human and animal studies with a focus on the role of alcohol in modulating the gut microbiome in autoimmunity. This is not the first study to show the potential benefits of moderate alcohol consumption. Earlier this year, Medical News Today reported on a study suggesting that consuming a glass of wine a day may reduce the risk of depression, while other research suggests a compound found in red wine could help treat cancer. Additional studies in rodents assessed the effects of alcohol on the effectiveness of bacillus Calmette-Guérin (BCG) vaccination, which protects against tuberculosis. The studies found that when animals consumed ethanol before BCG vaccination, they were not protected against a subsequent pulmonary challenge with M.
Responses to Infections
Rodents have a much shorter life span and often require forced (i.e., not initiated by the animal) exposure to alcohol, which is stressful. Moreover, a recent systematic comparison examining gene expression changes found that temporal gene response patterns to trauma, burns, and endotoxemia in mouse models correlated poorly with the human conditions (Seok, Warren et al. 2013). Nonhuman primates, on the other hand, voluntarily consume different amounts of alcohol and allow us to conduct studies in an outbred species that shares significant physiological and genetic homology with humans while maintaining rigorous control over diet and other environmental cues. Moreover, immune systems of several nonhuman how to wean off alcohol and safely taper drinking primate species are similar to those of humans and these animals are susceptible to several clinically important pathogens making them a valuable model to study the impact of ethanol on immunity (Hein and Griebel 2003). Costly requirements such as dedicated facilities to house the animals, experienced personnel to perform specialized procedures, and compliance with high standards of care must be considered. Recently, it was reported that a single episode of binge alcohol consumption in alcohol-experienced human volunteers (men and women) initially (within the first 20 min) increased total number of peripheral blood monocytes and LPS-induced TNF-α production when blood alcohol levels were ~130mg/dL.
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Recent studies suggest that the increase in IgA levels may be mediated by an ethanol-induced elevation of the enzyme neuronal nitric oxide synthase (nNOS) in the animals’ intestine, because inhibition of nNOS before ethanol injection suppressed the IgA increase (Budec et al. 2013). However, additional studies are needed to fully uncover the mechanisms that underlie increased Ig production while B-cell numbers are reduced. Alcohol abuse also leads to a significant elevation of activated CD8 T cells, measured by increased expression of human leukocyte antigen (HLA)-DR in adult males who consumed an average of 23 drinks/day for approximately 27 years that persisted for up to 10 days of abstinence (Cook, Garvey et al. 1991). Similarly, an increased percentage of CD8 T cells expressing HLA-DR and CD57 was reported in the group of male alcoholics with self reported average alcohol consumption of approximately 400g/day for approximately 26 years (Cook, Ballas et al. 1995). Mice that consumed 20% (w/v) ethanol in water for up to 6 months, also showed an increased percentage of activated T cells as measured by increased expression of CD43, Ly6C, rapid IFN-γ response, and increased sensitivity to low levels of TCR stimulation (Song, Coleman et al. 2002, Zhang and Meadows 2005). Taken together, these studies suggest that chronic alcohol-induced T cell lymphopenia increases T cell activation and homeostatic proliferation resulting in increased proportion of memory T cells relative to naïve T cells.
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Several lines of evidence suggest that alcohol consumption exerts a dose-dependent impact on the host response to infection. Chronic alcohol abuse leads to increased susceptibility to bacterial and viral infections, most notably a 3 to 7-fold increase in susceptibility (Schmidt and De Lint 1972) and severity (Saitz, Ghali et al. 1997) of bacterial pneumonia compared with control subjects. Similarly, the incidence of Mycobacterium tuberculosis infection among alcoholics is increased (Sabot and Vendrame 1969, Hudolin 1975, Kline, Hedemark et al. 1995, Panic and Panic 2001). Alcohol use has also been shown to drive disease progression in chronic viral infections such as human immunodeficiency virus (HIV) (Baum, Rafie et al. 2010) and Hepatitis C (Bhattacharya and Shuhart 2003).
When you drink too much alcohol, it can throw off the balance of good and bad bacteria in your gut. If alcohol continues to accumulate in your system, it can destroy cells and, eventually, damage your organs. The World Health Organization (WHO) and U.S. surgeon general have warned people to avoid drinking too much alcohol during the COVID-19 pandemic. One study found that people who got less than 7 hours of sleep were nearly three times more likely to develop a cold compared with those who got 8 or more hours of sleep. According to the Cleveland Clinic, once you take a sip of alcohol, your body prioritizes breaking down alcohol over several other bodily functions. The body doesn’t have a way to store alcohol like it does with carbohydrates and fats, so it has to immediately send it to the liver, where it’s metabolized.
- In addition, alcohol markedly affects the differentiation of dendritic cells in blood and tissues (Ness et al. 2008).
- Your body breaks alcohol down into a chemical called acetaldehyde, which damages your DNA.
- Several studies have demonstrated the dose-dependent effect that alcohol has on preventing both monocytes and macrophages from binding to the bacterial cell wall component lipopolysaccharide (LPS).
Liver failure
Consequently, deficiency in vitamin A results in the impairment of mucosal responses (Mora, Iwata et al. 2008). Vitamin D has long been known to have a critical role in calcium and phosphorous homeostasis. In addition, antigen presenting cells convert vitamin D to 1,25(OH)2VD3, a physiologically active form of vitamin D that is highly concentrated in lymphoid tissues (Mora, Iwata et al. 2008) where it can modulate function of T and B cells which express vitamin D receptors. Vitamin D deficiency results in reduced differentiation, phagocytosis and oxidative burst, by monocytes as well as defective bactericidal activity by keratinocytes (Fabri, Stenger et al. 2011, Djukic, Onken et al. 2014). Alcoholic beverages are energy dense and often become the primary energy source in those with AUD, leading to malnutrition.
Frequent and heavy alcohol consumption can suppress the immune system, making the body vulnerable to viruses and infections. Alcohol misuse can cause short-term effects such as the common cold or gastrointestinal complications, but it can also lead to more serious conditions such as cancer, septicemia, or, liver disease. While binge drinking is typically more harmful than occasional drinking, any amount of alcohol can have adverse effects on the body and its ability to fight infections and diseases. Drinking every day or drinking too much alcohol at a time may affect the immune system more than drinking every other day or every few days, but the healthiest thing to do is abstain from drinking completely.
Thus, mice that were chronically fed ethanol generated a weaker antibody response following vaccination with HCV compared with control mice (Encke and Wands 2000). Abstinence partially restored antibody responses against hepatitis antigens in a mouse model (Encke and Wands 2000). These clinical observations were confirmed with cultured cells as well as in rodent studies. Treatment of a mouse cell line (i.e., A78-G/A7 hybridoma cells) with different concentrations of ethanol (25, 50, 100, and 200mM) for 48 hours resulted in a linear increase in IgM levels (Muhlbauer et al. 2001). Moreover, spontaneous IgA synthesis by peripheral blood mononuclear cells (PBMCs)— a mixed population of various white blood cells that also includes B cells—was higher in PBMCs isolated from alcoholic patients with liver disease compared with controls (Wands et al. 1981). IgA concentrations also were increased in a layer (i.e., the lamina propria) of the mucous membranes lining the intestine of adult female Wistar rats after acute ethanol administration (4g/kg intraperitoneally) for 30 minutes (Budec et al. 2007).
Each T cell expresses a unique T-cell receptor (TCR) that confers specificity for one particular foreign molecule (i.e., antigen). Early studies already had indicated that chronic alcohol abuse (i.e., for 12 to 15 years) resulted in reduced numbers of peripheral T cells (Liu 1973; McFarland and Libre 1963). More recent studies confirmed this observation and showed that the lack of lymphocytes (i.e., lymphopenia) was as severe in people who engaged in a short period of binge drinking as it was in individuals who drank heavily for 6 months (Tonnesen et al. 1990).
Similarly, most rodent studies to date have focused on acute/short-term binge models utilizing high concentration of ethanol (20% ethanol) as the sole source of fluid, a possible stressor in itself. Therefore, there is a pressing need for in depth studies that examine dose-dependent effects of chronic ethanol consumption on immunity in vivo to allow for the complex interactions between ethanol, its metabolites, HPA signaling, nutritional deficiencies, and the immune system. For instance, IL-1 induces HPA axis activation and glucocorticoid release that suppresses the immune system (Sapolsky, Rivier et al. 1987). Cytokines are also proposed to cross the blood-brain barrier and produce sickness behavior (Watkins, Maier et al. 1995), which is comorbid with AUD (Dantzer, Bluthe et al. 1998). Ethanol administration (4g/kg) in male rats increased IL-6 but decreased TNF-α expression in PVN, an effect that was blunted or reversed after long-term ethanol self-administration (Doremus-Fitzwater, Buck et al. 2014).
Future studies aimed at uncovering the mechanisms underlying dose-dependent modulation of immune function should also investigate changes in gene expression patterns, as well as factors that regulate gene expression including microRNAs and epigenetic changes within specific immune cell populations. Additionally, the role of alcohol-induced changes in the microbiome on immunity should be studied. Recent studies have shown that the microbiome modulates immunity in the gut, and in turn, immunity modulates the microbiome in the gut (Belkaid and Hand 2014). Only two studies have examined alcohol-induced changes in colonic (Mutlu, Gillevet et al. 2012) and fecal microbiomes (Chen, Yang et al. 2011), and both studies focused on individuals with AUD.
For example, the acetaldehyde that is formed during alcohol metabolism can interact with other proteins in the cells, interfering with their function. Therefore, it is possible that acetaldehyde also interacts with antibodies and thereby may alter antibody responses; however, this remains to be established (Thiele et al. 2008). Similarly, more work is needed to determine whether alcohol inhibits specific aspects of B-cell differentiation, salvia extent of use, effects, and risks such as immunoglobulin class switching and cell survival. The consequences of impaired gut structural integrity are significant (see figure 1). The white blood cells, tissues and organs that make up our body’s immune system are designed to fight off infections, disease and toxins. To this end, heavy drinkers have been shown to exhibit an increase in both IgA and IgM levels when compared to both moderate and light male drinkers.
These findings suggest that ethanol pretreatment can sensitize T cells to AICD (Kapasi et al. 2003). Similarly, in vitro exposure of peripheral T cells to a physiologically relevant concentration of 25mM ethanol significantly enhanced the activation of a protein that mediates apoptosis (i.e., caspase-3) as well as promoted DNA fragmentation (which is a hallmark of apoptosis) when the cells were stimulated (Kelkar et al. 2002). In vivo studies in humans confirmed these observations, demonstrating that binge drinking (i.e., consuming 5 to 7 drinks within 90 to 120 minutes) promoted T-cell apoptosis and decreased Bcl-2 expression (Kapasi et al. 2003). Alcohol has a broad range of effects on the structural, cellular, and humoral components of the immune system.
After this period, the moderate-drinking participants exhibited down-regulation of a transcription factor (i.e., NF-Kappa B), modulation of pathways of antigen presentation, altered B- and T-cell receptor signaling, and reduced IL-15. Another aspect of cell-mediated immunity that is affected by ethanol consumption is the delayed-type hypersensitivity (DTH) response. DTH refers to a cutaneous T-cell–mediated inflammatory reaction that takes 2 to 3 days to develop. One early study (Lundy et al. 1975) showed defects in cell-mediated immunity in male alcoholic patients admitted for detoxification, in response both to a new antigen and to an antigen to which they had previously been exposed. A more recent study (Smith et al. 2004) reported that a negative correlation existed between the amount of alcohol consumed by the participants and the size of DTH skin test responses to a specific antigen (i.e., keyhole limpet hemocyanin).
Specifically, people who had consumed 30.9 ± 18.7 alcoholic drinks/day for approximately 25.6 ± 11.5 years exhibited a decreased frequency of naïve (i.e., CD45RA+) CD4 and CD8 T cells, as well as an increased frequency of memory T cells (i.e., CD45RO+) (Cook et al. 1994). Another study conducted in humans with self-reported average alcohol consumption of approximately 400 g/day also found an increase in the percentage of both CD45RO+ memory CD4 cells and CD8 cells (Cook et al. 1995). Thus, studies in C57BL/6 mice demonstrated that chronic dmt dimethyltryptamine abuse signs and symptoms of dmt abuse ethanol consumption (20 percent ethanol in water for up to 6 months) decreased the frequency of naïve T cells and increased the percentage of memory T cells (Song et al. 2002; Zhang and Meadows 2005). This loss of naïve T cells could result from decreased T-cell production in the thymus; increased cell death (i.e., apoptosis) of naïve T cells; or increased homeostatic proliferation. Additional analyses detected evidence that T-cell proliferation in the spleen was increased in alcohol-consuming mice (Zhang and Meadows 2005).
Moreover, these B-cell subpopulations did not recover to normal levels until 3 to 4 weeks of life (Moscatello et al. 1999; Wolcott et al. 1995). Other studies were conducted using a precursor cell type called oligoclonal-neonatal-progenitor (ONP) cells, which in vitro can differentiate either into B lymphocytes or into other white and red blood cells (i.e., myeloid cells), depending on the cytokines to which they are exposed. Similarly, ONP cells isolated from newborn mice and cultured in vitro in the presence of 100 mM ethanol for 12 days failed to respond to IL-7 and commit to the B lineage, suggesting intrinsic defects (Wang et al. 2011). Additional investigations demonstrated that alcohol affects ONP cell differentiation into B lineage at a late stage by down-regulating the expression of several transcription factors (e.g., EBF and PAX5) and cytokine receptors, such as the IL-7 receptor (IL-7Ra) (Wang et al. 2009). Finally, primary alveolar macrophages isolated from female mice cultured in 25–100mM ethanol for 24 hours prior to addition of apoptotic cells showed a dose-dependent decrease in efferocytosis, the process of clearing dying cells that is critical to resolution of the inflammatory process after infection.
It can also lead to complications after surgery and poor recovery from injuries such as broken bones. “When you’re feeling run down or like you might get sick, you want to be well hydrated so that all the cells in your body have enough fluid in them and can work really well,” Favini says. Cellulitis is a bacterial infection of the skin’s deeper layers that causes pain, swelling, and, redness in the skin’s infected area. It’s a common infection, but it can cause serious health complications if left untreated and spread breaks in the skin, such as cuts, bites, ulcers, and puncture wounds, which can allow bacteria into the skin. This condition occurs when bacteria enter the chest cavity’s pleural space, typically due to pneumonia or a post-surgery infection. When alcohol damages the gastrointestinal tract’s barrier, bacteria and toxins can enter the bloodstream easily, potentially leading to septicemia and sepsis.