Indirect methods to increase SCFAs such as by faecal microbiota transplant or augmenting SCFA-producing bacteria alcohols role in gastrointestinal tract disorders pmc with specific probiotics (e.g., Clostridium butyricum) may also be beneficial. Butyricum in combination with Bifidobacterium infantis reduced symptoms of minimal hepatic encephalopathy in patients with hepatitis B cirrhosis as well as measures of gut permeability 66. However, supplementation with other probiotics (Bifidobacterium, Lactobacillus and Lactococcus genera) did not improve gut barrier function 67, suggesting the importance of targeting SCFA-producing species. Alcohol consumption may be expected to contribute toward an increased risk of or exacerbation of autoimmune diseases given its pro-inflammatory properties. In the following section, we will delineate the known alcohol dose-dependent effects on autoimmune diseases.
The main steps of the oxidative pathway are mediated by alcohol dehydrogenase (ADH) and acetaldehyde dehydrogenase (ALDH) that transform ethanol to acetaldehyde and acetaldehyde to acetate, respectively12. Acetaldehyde damages liver by directly triggering inflammation, extracellular matrix (ECM) remodeling and fibrogenesis13. Furthermore, it covalently binds to proteins and DNA leading to the production of immunogenic adducts (i.e., malondialdehyde) in the hepatocytes14. Finally, acetaldehyde stimulates transforming growth factor (TGF)-beta signaling in hepatic stellate cells that acquire a pro-fibrogenic and pro-inflammatory profile15. Changes in NADH/NAD+ ratio may affect biochemical reactions in the mitochondria and gene expression in nucleus. The burn of NADH requires additional oxygen amount in the mitochondria; the hepatocytes take up more than their normal share of oxygen from arterious blood but not enough to adequately supply all liver regions.
Factors affecting alcohol consumption and alcohol-related harm
- In an alcohol-fed rat model, Yazir et al48 recently demonstrated that chronic alcohol consumption impaired relaxant and contractile responses of both LES and tunica muscularis mucosae of the esophagus.
- Accordingly, alcoholic beverages with a low alcohol content (e.g., beer and wine) strongly increase gastric acid secretion and the release of gastrin, the gastric hormone that induces acid secretion.
- Most of the acetate produced enters the systemic circulation and is activated to acetyl coenzyme A (CoA), a key intermediate metabolite in peripheral tissues.
- Here, we review the effect of alcohol on the gut and liver, focusing on its interaction with micronutrients.
Similar to thyroid disease, diabetes and SLE, multiple epidemiological studies and several mechanistic studies support the protective role of light to moderate alcohol in RA in a J- or U-shaped dose-dependent manner8,15,45–54 (Table 1). Alcohol abuse; the most common and costly form of drug abuse, is a major contributing factor to many disease categories. The alcohol-attributable disease burden is closely related to the average volume of alcohol consumption, with dose-dependent relationships between amount and duration of alcohol consumption and the incidence of diabetes mellitus, hypertension, cardiovascular disease, stroke, and pneumonia.
Catalase, a peroxisomal enzyme, is the master regulator of non-oxidative metabolism of alcohol the final product of which is FAEE responsible for alcoholic steatosis9,11 and useful as biomarker of chronic alcohol consumption19,20. The metabolism of alcohol in the liver is key to understanding its role in the pathogenesis of alcohol-related liver disease. Alcohol is primarily metabolised in hepatocytes by alcohol dehydrogenase to acetaldehyde and then to acetate by aldehyde dehydrogenase.
The human body is able to metabolise and eliminate small volumes of alcohol without long-term sequelae. However, excessive alcohol use leads to alterations in the gut microbiome, metabolome, epithelial integrity and immune signalling culminating in progressive liver disease. Our recent improved understanding of these changes has identified potential new therapies to delay or reverse liver disease. Motility disorders, maldigestion, and malabsorption in alcoholics can result in digestive problems, such as anorexia, nausea, and abdominal pain. Alcohol abuse also promotes the development of cancers of the tongue, larynx, pharynx, and esophagus.
Other alternatives may be from impaired bile production, dysmotility, or altered gastric pH 58. Regenerating islet-derived protein 3 gamma (Reg3g) is a bactericidal protein secreted from Paneth cells and intestinal epithelial cells that can regulate bacterial overgrowth. Vitamin deficiencies, especially of vitamin C and D, in patients with alcohol-related liver disease are common. Vitamin supplementation may modulate the gut microbiome resulting in reduced dysbiosis, which may reduce gut permeability and liver inflammation; studies in healthy individuals have demonstrated beneficial shifts in microbial genera with vitamin C 78 and D 79.
A combined study enhancing both aerobic fitness and SCFA-producing bacteria in patients with alcohol-related liver disease may yield beneficial results. Alcohol inactivates peroxisome proliferator-activated-receptor (PPAR)-α, a nuclear hormone receptor that upregulates the expression of many genes involved in free fatty acid transport and oxidation. Acetaldehyde directly inhibits transcriptional activation activity and DNA binding of PPAR-α 43. Alcohol also indirectly inhibits PPAR-α via CYP2E1-derived oxidative stress, adenosine, the downregulation of adiponectin and zinc deficiency (a common state in patients with alcohol-related liver disease) 30,44.
Alcohol and Development of Inflammatory Bowel Disease
For example, small molecules, such as glycerol, gases (O2 and CO2), and products of dietary lipids digestion, becomes absorbed via simple diffusion. Some molecules, such as dietary fructose, enter the enterocyte via a facilitated diffusion process mediated by the GLUT-5 transporter. On the other hand, glutamine (B0AT1/SLCA19) and glucose (SGLT1/SLC5A1) are co-transported, along with sodium involving an active transport against a concentration gradient. The energy for this process is provided by the Na-K-ATPase pump in the basolateral membrane of the enterocyte 3,4,5. Alcohol abuse disrupts multiple cellular mechanisms, leading to altered organ function and disease.
- Vitamin supplementation may modulate the gut microbiome resulting in reduced dysbiosis, which may reduce gut permeability and liver inflammation; studies in healthy individuals have demonstrated beneficial shifts in microbial genera with vitamin C 78 and D 79.
- While this mechanism of action differed from what studies had previously established, that difference may have arisen from the dosage of ethanol used.
- Prostaglandins protect the gastric mucosa from damage by agents such as aspirin that break the gastric mucosal barrier without inhibiting acid secretion.
Alcohol’s pro- and anti-inflammatory effects on the immune system
Bile acids have been shown to be altered in both the serum and luminal contents of humans and rats consuming alcohol 12,14,27. Primary (synthesised by the liver) and secondary (from bacterial metabolism) bile acids perform a variety of functions predominantly in the small bowel and have crucial roles in lipid absorption, cholesterol homeostasis as well as hormonal actions through their steroid structure. In a healthy entero-hepatic circulation, primary bile acids are conjugated with either taurine or glycine to form bile salts that are secreted into the intestinal lumen. The intestinal microbiota then metabolises these to secondary bile acids, removing the taurine/glycine groups before recycling them back to the liver. Alcohol consumption appears to disrupt this by increasing the proportion of secondary bile acids and the total concentration of bile acids, as well as increasing the proportion conjugated with glycine instead of taurine 12,14.
Intestinal Bacterial Microflora
Acute ethanol administration in vivo, in man as well as in cats, transiently decreased lower esophageal sphinteric (LES) pressure, degree of contraction of the smooth muscle layer of the lower esophagus and mucosal clearance due to a primary and secondary peristalsis reduction45. In a cat model, neural decentralization (cervical vagotomy) or nerve block did not prevent the effects of acute ethanol administration suggesting a direct inhibitory effect of alcohol on esophageal muscle cells46,47. In an in vitro model, the pre-exposition of esophageal smooth muscle cells to ethanol significantly decreased carbachol-dependent shortening of the cells, thus confirming that ethanol directly inhibits the contractile activity of the esophageal muscle cells46. Paradoxically, chronic effect of alcohol on esophageal motility consisted in an increased tonus of the LES and reduced esophageal clearance45. In an alcohol-fed rat model, Yazir et al48 recently demonstrated that chronic alcohol consumption impaired relaxant and contractile responses of both LES and tunica muscularis mucosae of the esophagus. Increased prevalence of heartburn and increased risk of gastro-esophageal reflux disease (GERD) or erosive esophagitis have been reported in alcoholics39-42 as well as GERD patients are more likely to consume alcohol than controls43.
In brief, alcohol has been shown to increase the relative abundance of Proteobacteria, Enterobacteriacea and Streptococcus and decrease the abundance of Bacteroides, Akkermansia and Faecalibacterium 15. Many of the claims are based on the hypothesis that alcohol may modulate the microbiome and facilitate intestinal inflammation. This is corroborated by observations demonstrating that patients with alcohol abuse disorder have a similar microbial signature to that of patients with IBD,6-8 which, therefore, could facilitate IBD pathogenesis.
In this review, we will explore alcohol’s pro- and anti-inflammatory properties in human and animal autoimmune diseases, including autoimmune diabetes, thyroid disease, systemic lupus erythematosus, rheumatoid arthritis, experimental autoimmune encephalomyelitis and multiple sclerosis. We will also discuss potential mechanisms of alcohol’s anti-inflammatory effects mediated by the gut microbiome. In recent years, the field of alcohol consumption and its effect on intestinal nutrient absorption at the BBM of small intestine has continued to expand. Mounting studies reported ethanol effect on the absorption of array of macro and micronutrients, including glucose 73,74, glutamine 33 vitamin B2 90, vitamin C 95, vitamin B1 88,107, vitamin B9 92,94,109,129, iron 101,118,119,120,121,122, zinc 55,123, and selenium 104.
NO and PGE2 accelerate the flow of the gastric mucosal microcirculation, promote the secretion of bicarbonate, mediate the adaptive immune protective function, increase protein synthesis and cell renewal, and finally enhance the repair ability of the damaged gastric mucosa50. Pre-injection of an endothelin receptor antagonist significantly reduced ET-1-dependent gastric mucosal damage in rat. In addition, high ethanol intake rats had ET-1 plasma levels significantly higher and NO and PGE2 decreased in respect to the normal control group51. Taken together these data suggests that ethanol damages gastric mucosa and weakens its ability to repair by stimulating ET-1 secretion and inhibiting NO and PGE2 synthesis and secretion51. Alcohol-induced myocardial dysfunction results from oxidative stress, cardiomyocyte mitochondrial and sarcoplasmic reticulum damage, altered calcium dynamics, and cardiac fibrosis. Alcohol-mediated hypertension results from potentiation of the RAAS reflected in elevated circulating angiotensin II levels, cardiac angiotensin converting enzyme, and angiotensin type 1 (AT1) receptor expression.
Since the initial observation by Friedreich in 1878, growing evidence linked alcohol misuse and pancreatic damage. Because of difficulties in accurately identifying alcohol abuse, differences in the populations studied and classification of pancreatitis, based on morphology rather than on etiology, the proportion of cases of alcohol-related pancreatitis widely varies between and even in the same country. Overall, it has been estimated that prevalence of pancreatitis in alcoholics increased approximately 4-fold when compared with teetotalers27.