In addition, alcohol abuse is an important cause of bleeding (i.e., hemorrhagic) gastric lesions that can destroy parts of the mucosa. Although low or moderate alcohol doses do not cause such damage in healthy subjects, even a single episode of heavy drinking can induce mucosal inflammation and hemorrhagic lesions. Nonsteroidal anti-inflammatory drugs (e.g., aspirin and ibuprofen) may aggravate the development of alcohol-induced acute gastric lesions. The impact of alcohol consumption on nutrient absorption along the small intestine have been extensively studied 1,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26. In this review, we have attempted to update recent research regarding the mechanisms of alcohol’s effect on nutrient absorption along the small intestine and its alterations in disease conditions. Understanding the underlying mechanisms of alcohol in the alteration of nutrient absorption is vital, as elucidating these mechanisms can lead to a better understanding of alcohol-dependent malnutrition, as well as other nutrition-related disease states.
Ethanol inhibits the absorption of amino acids, such as alanine 111, glycine 6, leucine 80,81,82,112, and glutamine. However, more research is necessary to clarify the reported null effect of low concentration of ethanol, below 200 mM, on glycine and leucine absorption 70, including more investigations of the mechanisms underlying these effects. Dipeptides and tripeptides are absorbed primarily in the proximal small intestine using proton-coupled oligopeptide transporters.
Alcohol’s pro- and anti-inflammatory effects on the immune system
The most sensitive organ with respect to alcohol exposure is the female breast, and for alcohol-mediated breast cancer no threshold dose exists. Although not addressed in any detail in this issue, it should be mentioned that early alcohol drinking in life at the age of 12–15 years increases breast cancer risk in later life significantly 3. There are potentially two ways in which low-to-moderate alcohol consumption can modulate SCFA production. As alcohol is largely metabolized within the GI tract, it is a prime factor to impact gut microbiome composition, gut immune system and downstream systemic immune communications with other organs. In the following section, we will focus on alcohol’s effects on the gut, gut immune system and gut metabolism of fatty acids and how these effects may translate into pro-inflammatory vs protective effects in autoimmune diseases. Recent studies have demonstrated that ethanol directly affect the intestinal vitamin C co-transporter 95.
Even if the liver has been for long time considered the major victim of the harmful use of alcohol, the likelihood of systemic effects parallels the severity of liver damage dependent on the alcohol abuse. According to the World Health Organization Report on Alcohol and Health (2011), alcohol abuse is responsible for at least 60 major types of systemic diseases. Furthermore, alcohol consumption significantly increases the overall risk of developing cancer1. Several studies have described that ethanol could exert varied effects on lipid absorption along the small intestine.
Alcohol-Induced Intestinal Dysbiosis
Mechanistic studies on the effect of ethanol on nutrient transporters could be better achieved by utilizing the recently developed ex vivo model of human intestinal organoid culture 136,137,138,139. The sustained culture of human intestinal organoids, three-dimensional cell cultures derived from human biopsy tissues, can be used to study the effects of ethanol on nutrient absorption 140. Moreover, this model system proves to be advantageous, as biopsies can be derived from patients with different disease characteristics, including obese and IBD patients 142,143. Overall, additional extensive research is required to fully comprehend the intricate balance of nutrient homeostasis and the impact of ethanol consumption on this malleable system. Zinc transporter mRNA expressions were inhibited in the duodenum of male rodents exposed to ethanol via six-weeks of the Lieber DeCarli ethanol diet (SLC39A1; SLC39A4; SLC30A4) 55.
Environmental Co-Factors for Alcohol-Induced Dysbiosis and Barrier Dysfunction
- 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.
- Moreover, the existing comorbid conditions, dietary habits, and additional drugs consumed by most individuals who abuse alcohol are not directly replicated in animal studies.
- Our recent improved understanding of these changes has identified potential new therapies to delay or reverse liver disease.
- Subramanian and colleagues demonstrated that long-term exposure to ethanol via the Lieber DeCarli ethanol diet inhibits intestinal vitamin B2 absorption (SLC52A1 and SLC52A3).
Finally, alcohol can increase the permeability of the mucosal micro-vessels with enhanced transcapillary fluid filtration and disruption of the epithelial continuity58. If the damaging effect of acute alcohol exposure is clear, whether or not chronic alcohol ingestion damages the mucosa of the small intestine remains controversial. Duodenal biopsies of chronic alcohol abusers either had normal histology or showed reduced villus height, increase in the number of intra-epithelial mononuclear cells, goblet cell hyperplasia and gastric metaplasia58,66. Furthermore, chronic alcohol abuse can induce fibrosis of the intestinal mucosa by increasing number of myofibroblast-like cells in the duodenal mucosa67. The loss of the anatomical integrity of the mucosa can, at least in part, account for the alcohol-related increased intestinal permeability. In animal models it has been reported that alcohol exposition can induce increased permeability for hemoglobin, horseradish peroxidase and polyethyleneglycol (PEG) 1500 Mr58.
Intestinal Bacterial Microflora
- 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).
- Ethanol’s inhibitory action was also shown at the level of the vitamin B1 transporter’s transcriptional promoter activity in human intestinal epithelial HuTu-80 cells (SLC19A2–3) 89.
- Clearly, alcohol metabolism and the generation of ROS, depletion of reducing equivalents, particularly GSH, and the resulting alteration in cellular redox state contribute to tissue injury in several organ systems including the liver, lung, muscle, and brain (FIGURE 2).
- Because often this is based on evidence derived from preclinical studies, it is important to take into consideration the context of alcohol administration (acute vs. chronic), the route of administration (oral, intraperitoneal, vapor), and the specific outcome studied under each condition.
While, at this point, ethanol is distributed evenly throughout the body, it nonetheless continues to interact with the rest of the GI tract 35. Ethanol is distributed to the distal small intestine and colon through the mesenteric vasculature. Additionally, it affects the tissues of alcohols role in gastrointestinal tract disorders pmc the lower GI tract through the basolateral membrane (BLM) of enterocytes 39,40,41. Ethanol’s effect on the BLM has been detailed in several studies 1,30,41,42, with the most convincing study showing luminal changes in the terminal small intestine following intraperitoneal injections of ethanol in mice 41.
For example, three to four weeks of 36% ethanol inhibited dietary absorption of fats in rats 75. Decreased absorption of fatty acid, arachidonic acid, and linoleic acid was reported in the jejunum of chronic alcoholics following heavy ethanol consumption (100 mM) 79,106. There have been very few studies that are pertinent to ethanol exposure on intestinal vitamin B7 absorption.
In some people, long-term alcohol misuse results in liver disease progressing from fatty liver to cirrhosis and hepatocellular carcinoma, and results in over half of all deaths from chronic liver disease, over half a million globally per year. In this review, we will describe the effect of alcohol on the gut, the gut microbiome and liver function and structure, with a specific focus on micronutrients and areas for future research. As pointed out above, alcoholic liver disease (ALD), pancreatitis, and cancers are the most important diseases caused by alcohol use. Therefore, epidemiology, clinical features, diagnostics, and therapy for these alcohol-mediated diseases are focused on in this review 2. Over the last decades, it has been shown that the susceptibility towards alcohol and the risk of disease depend not only on the amount of alcohol consumed but also on the target organ as well as on genetic and non-genetic risk factors.
Alcohol Use and Gastrointestinal Diseases
Such clotting may lead to an impaired transport of fluids across the capillaries; fluid accumulation under the tips of the villi; and, eventually, destruction of the tips of the villi. The resulting lesions allow large molecules, such as endotoxins and other bacterial toxins, to enter the bloodstream and the lymph. Third, as in the stomach, decreased prostaglandin synthesis may contribute to changes in the capillaries and to the development of mucosal injury. Chronic alcohol abuse leads to an increased incidence not only of heartburn but also of esophageal mucosal inflammation (i.e., esophagitis) and other injuries that may induce mucosal defects (i.e., esophagitis with or without erosions). In addition, alcoholics make up a significant proportion of patients with Barrett’s esophagus. This condition, which occurs in 10 to 20 percent of patients with symptomatic gastroesophageal reflux disease (Wienbeck and Berges 1985), is characterized by changes in the cell layer lining the esophagus (i.e., the epithelium) that lead to abnormal acid production.
ROS generation leads to lipid peroxidation, alterations in plasma and intracellular membranes, and release of proinflammatory and profibrotic mediators. Alcohol and its metabolites disrupt intestinal barrier function by affecting the integrity of tight junctions, promoting the dissociation and redistributing proteins like ZO-1, claudin, and occludin. Increased paracellular permeability leads to increased bacterial toxin translocation from the gut lumen and disseminated to the systemic circulation via the portal vein and the lymphatic route. This later route of dissemination may be significant, since alcohol intoxication has been shown to promote lymphatic pumping. GSH, reduced glutathione; ROS, reactive oxygen species; HCV, hepatitis C virus; LES, lower esophageal sphincter. The potential clinical consequences of alcohol abuse and its impact on the endocrine system are shown in the box.
Furthermore, gastric first-pass metabolism decreases with long-term alcohol consumption, partly because of diminished ADH activity (Gentry et al. 1994). Throughout the GI tract, alcohol absorption into the bloodstream occurs through a process called simple diffusion. The rate at which this process occurs depends on several factors, primarily the difference between the alcohol concentrations in the GI organs and in the adjacent small blood vessels, the regional blood flow, and the permeability of the GI tract lining (i.e., the mucosa) in question.