Alcohol, intestinal bacterial growth, intestinal permeability to endotoxin, and medical consequences: Summary of a symposium

Division of Metabolism and Health Effects, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, 5635 Fishers Lane, Room 2035, MSC 9304, Bethesda, MD 20892-9304, USA.
Alcohol (Impact Factor: 2.01). 09/2008; 42(5):349-61. DOI: 10.1016/j.alcohol.2008.03.131
Source: PubMed


This report is a summary of the symposium on Alcohol, Intestinal Bacterial Growth, Intestinal Permeability to Endotoxin, and Medical Consequences, organized by National Institute on Alcohol Abuse and Alcoholism, Office of Dietary Supplements, and National Institute of Diabetes and Digestive and Kidney Diseases of National Institutes of Health in Rockville, Maryland, October 11, 2006. Alcohol exposure can promote the growth of Gram-negative bacteria in the intestine, which may result in accumulation of endotoxin. In addition, alcohol metabolism by Gram-negative bacteria and intestinal epithelial cells can result in accumulation of acetaldehyde, which in turn can increase intestinal permeability to endotoxin by increasing tyrosine phosphorylation of tight junction and adherens junction proteins. Alcohol-induced generation of nitric oxide may also contribute to increased permeability to endotoxin by reacting with tubulin, which may cause damage to microtubule cytoskeleton and subsequent disruption of intestinal barrier function. Increased intestinal permeability can lead to increased transfer of endotoxin from the intestine to the liver and general circulation where endotoxin may trigger inflammatory changes in the liver and other organs. Alcohol may also increase intestinal permeability to peptidoglycan, which can initiate inflammatory response in liver and other organs. In addition, acute alcohol exposure may potentiate the effect of burn injury on intestinal bacterial growth and permeability. Decreasing the number of Gram-negative bacteria in the intestine can result in decreased production of endotoxin as well as acetaldehyde which is expected to decrease intestinal permeability to endotoxin. In addition, intestinal permeability may be preserved by administering epidermal growth factor, l-glutamine, oats supplementation, or zinc, thereby preventing the transfer of endotoxin to the general circulation. Thus reducing the number of intestinal Gram-negative bacteria and preserving intestinal permeability to endotoxin may attenuate alcoholic liver and other organ injuries.

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Available from: David A Brenner, Nov 13, 2014
    • "inflammation, and it is widely accepted that immune system activation is relevant for alcoholic steatohepatitis pathogenesis and ALD progression. Gram-negative bacteria lipopolysaccharides reaches portal blood and stimulates liver Kupffer cells, by activation of Toll-like receptor 4 and CD14 (Purohit et al., 2008; Thurman, 1998). This causes a downstream cascade of intracellular events, namely the activation of nuclear factor kappa B, activator protein 1, interferon (IFN) regulatory factors, and the alteration of pro-caspases 3 and 8 and c-Jun N-terminal kinase. "

    No preview · Article · Sep 2015 · Alcoholism Clinical and Experimental Research
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    • "Alcoholic liver disease (ALD) is one of the leading causes of liver diseases and a major cause of morbidity and mortality in the United States and worldwide [1]. The gut–liver interactions have emerged as a critical component in the progression of alcohol-induced liver disease both in patients and in experimental models [2] [3] [4]. Increasing evidence demonstrates that the elevated portal endotoxin level is an important etiological factor in the pathogenesis of ALD [5] [6] [7] [8]. "
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    ABSTRACT: Alcoholic liver disease (ALD) is a major healthcare challenge worldwide. Emerging evidence reveals that ethanol administration disrupts the intestinal epithelial tight junction (TJ) complexes; this defect allows for the paracellular translocation of gut-derived pathogenic molecules to reach the liver to cause inflammation and progressive liver injury. We have previously demonstrated a causative role of impairments in liver transmethylation reactions in the pathogenesis of ALD. We have further shown that treatment with betaine, a methylation agent that normalizes liver methylation potential, can attenuate ethanol-induced liver injury. Herein, we explored whether alterations in methylation reactions play a causative role in disrupting intestinal mucosal barrier function by employing an intestinal epithelial cell line. Monolayers of Caco-2 cells were exposed to ethanol or a-pan methylation reaction inhibitor, tubercidin, in the presence and absence of betaine. The structural and functional integrity of intestinal epithelial barrier was then examined. We observed that exposure to either ethanol or tubercidin disrupted TJ integrity and function by decreasing the localization of TJ protein occludin-1 to the intracellular junctions, reducing transepithelial electrical resistance and increasing dextran influx. All these detrimental effects of ethanol and tubercidin were attenuated by co-treatment with betaine. We further show that the mechanism of betaine protection was through BHMT-mediated catalysis. Collectively, our data suggest a novel mechanism for alcohol-induced gut leakiness and identifies the importance of normal methylation reactions in maintaining TJ integrity. We also propose betaine as a potential therapeutic option for leaky gut in alcohol-consuming patients who are at the risk of developing ALD. Copyright © 2015. Published by Elsevier Inc.
    Full-text · Article · Apr 2015 · Biochemical pharmacology
    • "In comparison to the AS group, in which ADH activity/output transiently increased at the 15th day but was still significantly lower at the 30th day than in controls, the ADH values at the 30th day in the ANS group were already restored (no statistical difference from the control group). It was reported that alcohol drinking and smoking can induce repopulation/overgrowth of some microbial species (e.g., Neisseria) of the alimentary tract, which can induce changes in the ADH mRNA, protein, and ADH activity, for example, via an endotoxin pathway (Chang et al., 2012; Crabb, Matsumoto, Chang, & You, 2004; Purohit et al., 2008). However, the saliva in our study was centrifuged to remove cells and debris. "
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    ABSTRACT: Increasing attention to the importance of saliva testing is not surprising because smoking and alcohol drinking act synergistically on oral tissues, and their metabolite levels, e.g., acetaldehyde, are much higher in saliva than in blood. The activity of salivary alcohol dehydrogenase (ADH) comes from oral microbiota, mucosa, and salivary glands. The purpose of this study was to investigate the involvement of ADH in the oral health pathology of smoking (AS) and non-smoking (ANS) alcohol-dependent males. The results indicated that the AS group had a more significant and longer duration (until the 30th day of alcohol abstinence) decrease in ADH activity and output than the ANS group (until the 15th day of alcohol abstinence) compared to controls (social drinkers; C). The decreased salivary flow (SF) in alcoholics was observed longer in the ANS group (until the 30th day of alcohol abstinence), whereas in the AS group SF normalized at the 15th day, probably due to the irritating effect of tobacco smoke on the oral mucosa. Because saliva was centrifuged to remove cells and debris (including microbial cells), the detected salivary ADH activity was derived from salivary glands and/or oral mucosa. A more profound and longer decrease in ADH activity/output in smoking than non-smoking alcoholics was likely due to the damaged salivary glands and/or oral mucosa, caused by the synergistic effect of alcohol drinking and smoking. The lower values of salivary ADH in smoking than non-smoking alcoholics might also be partly due to the reversed/inhibited ADH reaction by high levels of accumulated acetaldehyde.
    No preview · Article · Sep 2014 · Alcohol
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