Alcohol Use in Patients With Inflammatory Bowel Disease

As ethanol travels from the mouth and down the esophagus to the stomach, it increases the risk of mouth, esophageal, and gastric cancer 27,29,30,31. In the stomach, ethanol undergoes first pass metabolism through the primary ethanol enzymatic reaction via alcohol dehydrogenase 1 and 3 34. After first pass metabolism, ethanol is assimilated primarily in the upper small intestine 35. Due to its amphiphilic nature, ethanol’s absorption occurs via passive diffusion through the plasma membrane of intestinal epithelial cells called enterocytes 36,37. Several variables influence the rate of ethanol absorption, including, but not limited to, ethanol dosage, amount of ingested food, gastric emptying rate, ethanol concentration, intestinal motility, intestinal wall permeability, and blood flow 34,38.

4. Alcohol-Induced Fibrosis and Cirrhosis

Secretary IgA is amongst the most abundant class of antibodies found in the intestinal lumen and it protects the intestinal epithelium from enteric toxin and pathogenic damage 61,62,63. Indeed, IgA appears to exert its anti-inflammatory effects by reducing bacterial pro-inflammatory pathways and limiting LPS-induced cytokine release (e.g., IL1 and TNFα). Several studies have shown that IgA level is increased in alcoholics which might be a compensatory protective mechanism for limiting alcohol-induced damage 61,64,65.

Alcohol’s Impact on the Gut and Liver

Studies have shown that net calcium absorption was inhibited in rats given moderate (2 g/kg) ethanol, but the treatment also increased alcohols role in gastrointestinal tract disorders pmc calcium secretion, leading to no net change in calcium serum levels 71,96. So far, no alterations in magnesium absorption have been shown at the nutrient transporter level, but hypomagnesaemia is common in chronic alcoholics 1. MicroRNAs (miRNAs) are small non-coding RNAs that have a role in the post-transcriptional regulation of their target genes. MiRNA-155, a key regulator of inflammation, is increased in the liver and circulation in mouse models of alcohol-related liver disease 51. Chronic alcohol consumption increases the expression of miRNA-155 in Kupffer cells, which contributes to increased LPS-triggered TNF production 52. MiR-181b-3p, a negative regulator of TLR4 signalling in Kupffer cells, is downregulated in patients with alcohol-related liver disease 53.

2. Short-Chain Fatty Acids

In human, a significantly increased intestinal permeability for macromolecules such as PEG 4.000 Mr and Mr has been reported in actively drinking alcoholics24. 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. The increased permeability of the gut mucosa reported in alcoholics since the early stage of liver disease, further supports the hypothesis that it is caused by ethanol itself and is not a consequence of advanced ALD. The gastrointestinal system participates in alcohol absorption and metabolism, and is an important target for alcohol-induced pathophysiology including esophageal and gastric dysmotility, altered acid secretion, impaired nutrient absorption, and disrupted intestinal barrier function.

Alcohol and Inflammatory Bowel Disease Symptoms

Alcohol itself is a carcinogen and in the context of HCC plays specific roles in its development through ROS-induced damage, inflammatory mechanisms and its reactive metabolite, acetaldehyde. The excessive consumption of alcoholic beverages interferes with the normal function and structure of the gastrointestinal (GI) tract. The relationship between alcohol and the GI tract is a two-way street, however, and the GI tract plays a role in the absorption, metabolism, and production of alcohol.

Vitamin B12 absorption is of critical importance because deficiency of this vitamin leads to macrocytic anemia 117. In one study, rats fed a liquid ethanol diet composed of 35% ethanol displayed decreased vitamin B12 absorption, but this was not due to the binding of the vitamin B12 complex to the BBM receptors 40,110. Further research is needed to understand the mechanistic details of the effect of ethanol on the absorption and availability of this vital nutrient. The GI tract’s functions are to physically and chemically break down ingested food, allow the absorption of nutrients into the bloodstream, and excrete the waste products generated. The GI tract can be viewed as one continuous tube extending from the mouth to the anus (figure 1), which is subdivided into different segments with specific functions. Alcohol metabolism reflected by dehydrogenase (ADH) activity in rat tissues was compiled from Riveros-Rosas et al. and Raskin and Sokoloff.

• For example, alcohol—even in relatively small doses—can alter gastric acid secretion, induce acute gastric mucosal injury, and interfere with gastric and intestinal motility.
• Furthermore, chronic alcohol abuse can induce fibrosis of the intestinal mucosa by increasing number of myofibroblast-like cells in the duodenal mucosa67.
• Additionally, further research has focused on the molecular mechanism of ethanol’s action on nutrient absorption, more particularly on the nutrient transporter.
• 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.
• One of these enzymes is lactase, which breaks down the milk sugar lactose; lactase deficiency results in lactose intolerance.

Alcohol can permeate to virtually all tissues in the body, resulting in alterations in significant multi-systemic pathophysiological consequences. Approximately 3.4% of global noncommunicable disease-related burden of deaths, 5% of net years of life lost, and 2.4% of net disability-adjusted life years can be attributed to alcohol abuse, with higher burden for cancer and liver cirrhosis (86). Thus alcohol abuse is the third leading lifestyle-related cause of death in the United States. Dose-dependent relationships between alcohol consumption and incidence of diabetes mellitus, hypertension, ischemic heart disease, dysrhythmias, stroke, pneumonia, and fetal alcohol syndrome have been reported (95).

1. Microbiome

Chronic alcohol abuse disrupts multiple factors involved the balance between anabolic and catabolic mechanisms in bone and muscle. The underlying mechanisms include nutritional deficiencies, decreased growth factor availability and responsiveness, increased ubiquitin proteasome pathway activation, upregulation of negative regulators of skeletal muscle growth, and disruption of bone remodeling. Chronic alcohol abuse produces marked alterations in adipocyte function, resulting in fat mass redistribution, dyslipidemia, and altered pattern of adipokine release. The potential clinical implications of alcohol’s effects on skeletal muscle, bone, and adipose tissue are summarized in the box. Alcohol disrupts responsiveness of the hypothalamo-pituitary-adrenal (HPA) axis to psychological and physical stressors, and this has been implicated in the pathophysiology of pseudo-Cushing’s syndrome, addiction, dependence, and relapse of recovering alcoholics. Alcohol produces dose-, frequency-, and duration-specific effects on arginine vasopressin (AVP), leading to alterations in water balance and mean arterial blood pressure homeostasis.

Finally, the results of recent epidemiological studies indicate an association between alcohol consumption and the development of colorectal cancer. Alcohol-related dysbiosis inevitably affects the gut metabolome, and dramatic alterations in short-chain fatty acids (SCFAs), amino acids and bile acids have been documented. Alcohol can interfere with the activity of many enzymes that are essential for intestinal functioning. One of these enzymes is lactase, which breaks down the milk sugar lactose; lactase deficiency results in lactose intolerance. Alcohol also interferes with some of the enzymes involved in transporting nutrients from the intestine into the bloodstream and inhibits important enzymes that participate in the metabolism of drugs and other foreign organic substances in the gut (for reviews, see Mezey 1985; Bode 1980). In the stomach, the chemical degradation of the food continues with the help of gastric acid and various digestive enzymes.

• 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.
• The GI tract’s functions are to physically and chemically break down ingested food, allow the absorption of nutrients into the bloodstream, and excrete the waste products generated.
• While alcohol is a necessary component in the development of alcoholic liver disease and cirrhosis, only a subset of alcoholics develop cirrhosis and liver failure 20.
• A combined study enhancing both aerobic fitness and SCFA-producing bacteria in patients with alcohol-related liver disease may yield beneficial results.
• Furthermore, in pregnant rats exposed to ethanol, zinc was conserved in the mothers, and zinc absorption was increased in the offspring.

In the duodenum, selenomethionine absorption was increased following heavy ethanol dosages (20% v/v) in Wistar rat offspring for four weeks 104. Exposure to heavy ethanol levels significantly increased the affinity of the transporter (Km). This is one of the few studies that focused on the impact of gestational and lactational ethanol treatment on intestinal nutrient absorption, and further research using this model system is necessary 104. Low doses of ethanol stimulate gastric acid secretion while high doses either exert or not inhibitory effect38.

However, recognition of alcohol as an underlying causal factor in comorbid conditions remains a challenge in the clinical setting (103). 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. 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. Moreover, the existing comorbid conditions, dietary habits, and additional drugs consumed by most individuals who abuse alcohol are not directly replicated in animal studies. This too should be taken into consideration when the existing preclinical literature is interpretted.

Indeed, alcohol affects MUC-2 protein expression 66, which is one of the key components of intestinal mucus layer 67. Other potential means for alcohol to cause gut leakiness is to increase trans-epithelial passage of molecules. Since it is well-established that alcohol can increase cellular membrane fluidity 68, it is plausible that alcohol abuse results in disrupted intestinal epithelial cell membrane fluidity leading to gut leakiness. While these factors are all important, components of the biochemical/physical barrier, the epithelial layer of intestinal barrier may very well be the most important factor in mediating barrier integrity.

While this mechanism of action differed from what studies had previously established, that difference may have arisen from the dosage of ethanol used. Overall, further research is needed, both at varying ethanol dosages and at the molecular signaling level, to better understand ethanol’s impact on this vital sodium-glucose co-transporter 74. Ethanol’s impact on intestinal vitamin B2 absorption was not discussed in previous reviews because the link between ethanol and the essential dietary coenzyme vitamin B2, riboflavin, was not described until 2013.