The mode of cell death is likely to be influenced by the disease state, with apoptosis predominating in early alcohol-related liver disease but inflammasome activation driving pyroptosis and propagating liver injury in alcoholic hepatitis 50. The alcohol dehydrogenase pathway is efficient in metabolising alcohol in small quantities, but in chronic alcohol exposure, the pathway becomes saturated and there is significant induction of CYP2E1 32. ROS bind to proteins, changing their structural and functional properties, and may act as neoantigens. ROS can also bind directly to DNA, causing damage, or lead to lipid peroxidation products such as 4-hydroxynonenal (4-HNE) and malondialdehyde (MDA) that generate highly carcinogenic DNA adducts (Figure 2) 34. In addition, in chronic heavy alcohol ingestion, the antioxidant clearing system of the liver is impaired because of an acetaldehyde-mediated decrease in glutathione.
For example, the higher the concentration of the ingested alcohol, the more alcohol the mucosa absorbs. Other factors that may affect alcohol absorption include the type of alcoholic beverage, the drinker’s gender and body temperature, the presence of certain medications in the body, and the types of spices in the food (Bode 1980). For example, alcohol absorption occurs more slowly after the ingestion of beer than after the ingestion of an equal amount of alcohol in the form of whisky or brandy.
1.5. Vitamin C Absorption
Furthermore, in pregnant rats exposed to ethanol, zinc was conserved in the mothers, and zinc absorption was increased in the offspring. Such conservation of zinc in the mothers suggests that the human body will adapt to ethanol-dependent nutrient deficiencies during pregnancy 123. Extensive research has focused on the relationship between zinc and cellular junction regulation in the small intestine. Zinc plays a clear role in ethanol-mediated intestinal barrier disruption by decreasing the presence of cellular junction proteins, including claudin, ZO-1, and occluding 56. However, ethanol’s impact on the intestinal function and expression of zinc transporters requires further research.
Alcohol and the Liver
Alcohol-mediated disruption in HPA function has been implicated in the pathophysiology of pseudo-Cushing’s syndrome (19), addiction (48), dependence (48), and relapse of recovering alcoholics (3). Alcohol produces dose-, frequency-, and duration-specific effects on arginine vasopressin (AVP), leading to alterations in water balance and mean arterial blood pressure homeostasis (115). Acute alcohol intoxication increases magnocellular and parvocellular neuronal activity; whereas chronic alcohol abuse significantly reduces the number of AVP-producing neurons in the supraoptic nuclei (SON) (29) and suppresses circulating AVP levels (29). Our studies have shown that acute alcohol intoxication augments paraventricular nucleus nitric oxide inhibitory tone and suppresses the hypovolemia- but not hyperosmolarity-induced AVP release (127).
3. The Effect of Alcohol Consumption on Nutritional Status
It should also be noted that the intestinal microbiota also influences the immune phenotype that could in turn impact organ damage 55,56,57. SCFAs are a product of the bacterial digestion of dietary fibre and are essential to maintain gut epithelial integrity. Strategies to increase intestinal SCFA may reduce gut permeability and exposure of the liver to gut-derived toxins, thus preventing the progression of liver disease. Studies of SCFA treatment have yet to be conducted in patients with alcohol-related liver disease. Delivery of the SCFA butyrate by enema reduced gut oxidative stress and inflammation in patients with inflammatory bowel disease 65.
Protective effects of low-moderate alcohol on the gut microbiome in models of multiple sclerosis
Chronic alcohol consumption disrupts the hypothalamo-pituitary-gonadal (HPG) axis, manifesting in decreased gonadotropin release, abnormal menstrual cycles, infertility, and impotence (33, 37). In addition, alcohol abuse markedly diminishes the growth hormone (GH) insulin-like growth factor (IGF-I) axis at multiple levels, including release, signaling, and cellular responses (109). This suppression in the GH/IGF-I axis is critical during adolescence, a period of widespread alcohol abuse, as well as during disease states (104). Thus the acute and chronic effects of alcohol abuse can lead to a multitude of endocrine-related disorders. Alcohol abuse contributes to an impaired ability of the host to respond to challenges and maintain homeostasis, affecting the ability to respond to stress. In addition, the cumulative impact of alcohol on disease burden results in detrimental effects on thyroid, gonadal, and somatotropic axis functions that can contribute to conditions including hypothyroidism, decreased reproductive function, and growth retardation.
- Both animal and human studies have suggested that intestine-derived microbial factors and bacterial endotoxins are paramount in promoting the inflammatory process noted in the liver.
- Mechanistic studies on the impact of ethanol on intestinal iron transport demonstrated a complicated relationship between ethanol and iron absorption.
- However, recognition of alcohol as an underlying causal factor in comorbid conditions remains a challenge in the clinical setting (103).
- Several studies have established that chronic alcohol consumers have high concentrations of iron due to its increased absorption.
- Key components of the non-immunologic intestinal barrier include an unstirred water layer, mucosal surface hydrophobicity, surface mucous coat, endothelial factors 59, and epithelial factors (most importantly tight junctions).
Vitamin B7 in mammals is mostly acquired from exogenous sources (dietary and bacterial sources) through intestinal absorption, since most mammals cannot synthesize vitamin B7 endogenously. Although various biotin transporters exist, SLC5A6 (sodium-dependent multivitamin transporter, SMVT) is an intestinal-specific biotin transporter that transports biotin in the intestine 115,116. Al demonstrated that biotin uptake was significantly reduced during chronic alcohol exposure in the small and large intestines, and the reduction is due to a significant decrease in the transcription of the SLC5A6 transporter 107. It has also been demonstrated that chronic alcohol exposure inhibits small intestinal and colonic biotin uptake and SMVT expression in human differentiated enteroid and colonoid monolayers and in Caco-2 cells 108.
Understanding the role of the intestine in the pathogenesis of alcoholic liver disease can pose further avenues for pathogenic and treatment approaches. The average rate at which alcohol is eliminated from the body is ∼7 g/h, which translates to ∼1 drink/h. Alcohol is metabolized to acetaldehyde primarily by alcohol dehydrogenase (ALD) and the cytochrome P450 2E1 (CYP2E1). Acetaldehyde is converted to acetate in the mitochondria by the enzyme acetaldehyde dehydrogenase (ALDH) type 2.
- Thus a brief overview of salient aspects of alcohol metabolism and pharmacokinetics (reviewed in detail by Cederbaum and Khanna; Refs. 24, 61) is relevant to appreciate its significant role in organ injury.
- The increased intestinal permeability to macromolecules may account for the transient endotoxaemia described in healthy volunteers after acute alcohol consumption and in alcoholics with fatty liver24,68.
- Thus the authors caution against generalizations on the effects of alcohol described in some preclinical studies to those resulting from years of alcohol abuse in the clinical setting.
- The reason is unclear but a theory suggests that alcohol may decrease the intestinal motility resulting in an increase in luminal bacteria.
Oxidative stress is considered one of the principal mechanisms underlying alcohol-induced fibrosis. Oxidative stress stimulates the production of collagen by fibrogenic cells, including cardiac fibroblasts, leading to both interstitial and perivascular fibrosis (89). Studies from our group have shown that alcohol-induced transformation of fibroblasts to myofibroblasts results in excess deposition of collagen (36). In addition to the activation of fibrogenic cells, alcohol may promote fibrosis indirectly through cardiomyocyte apoptosis or necrosis and their replacement by collagen. In animal models, perfusion of jejunum with 6% ethanol triggered inflammatory reactions characterized by leukocyte infiltration and mast cells release of histamine and ROS63,72. The abstention from alcohol for up to 5 d increased the number of B-lymphocytes and halved the number of mononuclear macrophages in the lamina propria alcohols role in gastrointestinal tract disorders pmc of duodenal mucosa73.
Checkpoint inhibitors such as anti-PD-1 monoclonal antibodies improve the host immune response and have been licenced for the treatment of cancers. Such treatment may reduce PAMP-induced CD8+ T cell exhaustion 47 and improve the healing response in alcohol-related liver disease. Several studies have suggested that the decreased formation of hormone-like substances called prostaglandins might play a role in alcohol-induced mucosal injury (Bode et al. 1996). Prostaglandins protect the gastric mucosa from damage by agents such as aspirin that break the gastric mucosal barrier without inhibiting acid secretion.
Alcohol is well known for promoting systemic inflammation and aggravating multiple chronic health conditions. However, emerging data from human and animal studies suggest that alcohol may in fact be protective in autoimmune diseases. These studies point toward alcohol’s complex dose-dependent relationship in autoimmune diseases as well as potential modulation by duration and type of alcohol consumption, cultural background and sex.
Alcohol-Induced Intestinal Dysbiosis
Chronic alcohol abuse produces marked alterations in pulmonary function resulting from decreased GSH, increased ROS production, and marked alterations in lung host defense mechanisms. GM-CSF, granulocyte-macrophage colony-stimulating factor; RAAS, renin-angiotensin-aldosterone system; ARDS, acute respiratory distress syndrome. The most relevant clinical manifestations of alcohol-induced alterations in cardiopulmonary function are shown in the box. Cardiomyocyte damage resulting from chronic alcohol abuse is mediated by multiple mechanisms, including oxidative stress, alterations in calcium handling, and mitochondrial dysfunction. Alcohol abuse induces myocardial oxidative stress (89, 123) and depletes mitochondrial GSH, decreasing antioxidant capacity and enhancing myocyte susceptibility to oxidant injury and apoptosis (123). Moreover, chronic alcohol abuse reduces myofiber calcium sensitivity and alters cellular calcium transients, resulting in reduced contractile function (88).
Most of these factors probably inhibit or enhance alcohol absorption by affecting the movement of the stomach muscles (i.e., gastric motility) and small intestinal blood flow. Glucose absorption is the main source of energy, and its absorption has been extensively investigated during the initial wave of ethanol and intestinal transporter research. Among the first to describe an inhibition in glucose absorption were Ghirardi and colleagues in 1971 7. However, it was Dinda and colleagues in 1975 that elucidated the impact of ethanol on glucose absorption 10. Using a binge-dosage of ethanol equivalent to 450 mM in the jejunum of hamsters, investigators demonstrated that ethanol inhibited the active transport of glucose without a change in the net flux of sodium. Further experimentation, over many different studies and model systems, determined that ethanol decreased glucose absorption at the level of BBM in hamsters 10,14,47,65, rats 66,69,72,112, dogs 71, and more recently, chickens 73.
