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Zhang D, Liu Z, Bai F. Roles of Gut Microbiota in Alcoholic Liver Disease. Int J Gen Med 2023; 16:3735-3746. [PMID: 37641627 PMCID: PMC10460590 DOI: 10.2147/ijgm.s420195] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2023] [Accepted: 08/10/2023] [Indexed: 08/31/2023] Open
Abstract
Alcoholic liver disease (ALD)-one of the most common liver diseases - involves a wide range of disorders, including asymptomatic hepatic steatosis, alcoholic hepatitis (AH), liver fibrosis, and cirrhosis. Alcohol consumption induces a weakened gut barrier and changes in the composition of the gut microbiota. The presence of CYP2E1 and its elevated levels in the gastrointestinal tract after alcohol exposure lead to elevated levels of ROS and acetaldehyde, inducing inflammation and oxidative damage in the gut. At the same time, the influx of harmful molecules such as the bacterial endotoxin LPS and peptidogly from gut dysbiosis can induce intestinal inflammation and oxidative damage, further compromising the intestinal mucosal barrier. In this process, various oxidative stress-mediated post-translational modifications (PTMs) play an important role in the integrity of the barrier, eg, the presence of acetaldehyde will result in the sustained phosphorylation of several paracellular proteins (occludin and zona occludens-1), which can lead to intestinal leakage. Eventually, persistent oxidative stress, LPS infiltration and hepatocyte damage through the enterohepatic circulation will lead to hepatic stellate cell activation and hepatic fibrosis. In addition, probiotics, prebiotics, synbiotics, fecal microbial transplantation (FMT), bioengineered bacteria, gut-restricted FXR agonists and others are promising therapeutic approaches that can alter gut microbiota composition to improve ALD. In the future, there will be new challenges to study the interactions between the genetics of individuals with ALD and their gut microbiome, to provide personalized interventions targeting the gut-liver axis, and to develop better techniques to measure microbial communities and metabolites in the body.
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Affiliation(s)
- Daya Zhang
- Graduate School, Hainan Medical University, Haikou, People’s Republic of China
| | - ZhengJin Liu
- Department of Gastroenterology, The Second Affiliated Hospital of Hainan Medical University, Haikou, People’s Republic of China
| | - Feihu Bai
- Department of Gastroenterology, The Second Affiliated Hospital of Hainan Medical University, Haikou, People’s Republic of China
- The Gastroenterology Clinical Medical Center of Hainan Province, Haikou, People’s Republic of China
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Waris S, Habib S, Khan S, Kausar T, Naeem SM, Siddiqui SA, Moinuddin, Ali A. Molecular docking explores heightened immunogenicity and structural dynamics of acetaldehyde human immunoglobulin G adduct. IUBMB Life 2019; 71:1522-1536. [PMID: 31185142 DOI: 10.1002/iub.2078] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2019] [Accepted: 05/08/2019] [Indexed: 12/19/2022]
Abstract
Acetaldehyde is a metabolite of ethanol, an important constituent of tobacco pyrolysis and the aldehydic product of lipid peroxidation. Acetaldehyde induced toxicity is mainly due to its binding to cellular macromolecules resulting in the formation of stable adducts accompanied by oxidative stress. The aim of this study was to characterize structural and immunological alterations in human immunoglobulin G (IgG) modified with acetaldehyde in the presence of sodium borohydride, a reducing agent. The IgG modifications were studied by various physicochemical techniques such as fluorescence and CD spectroscopy, free amino group estimation, 2,2-azobis 2-amidinopropane (AAPH) induced red blood cell hemolysis as well as transmission electron microscopy. Molecular docking was also employed to predict the preferential binding of acetaldehyde to IgG. The immunogenicity of native and acetaldehyde-modified IgG was investigated by immunizing female New Zealand white rabbits using native and modified IgG as antigens. Binding specificity and cross reactivity of rabbit antibodies was screened by competitive inhibition ELISA and band shift assays. The modification of human IgG with acetaldehyde results in quenching of the fluorescence of tyrosine residues, decrease in free amino group content, a change in the antioxidant property as well as formation of cross-linked structures in human IgG. Molecular docking reveals strong binding of IgG to acetaldehyde. Moreover, acetaldehyde modified IgG induced high titer antibodies (>1:12800) in the experimental animals. The antibodies exhibited high specificity in competitive binding assay toward acetaldehyde modified human IgG. The results indicate that acetaldehyde induces alterations in secondary and tertiary structure of IgG molecule that leads to formation of neo-epitopes on IgG that enhances its immunogenicity.
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Affiliation(s)
- Sana Waris
- Department of Biochemistry, Faculty of Medicine, J. N. Medical College, Aligarh Muslim University, Aligarh, Uttar Pradesh, India
| | - Safia Habib
- Department of Biochemistry, Faculty of Medicine, J. N. Medical College, Aligarh Muslim University, Aligarh, Uttar Pradesh, India
| | - Shifa Khan
- Department of Biochemistry, Faculty of Medicine, J. N. Medical College, Aligarh Muslim University, Aligarh, Uttar Pradesh, India
| | - Tasneem Kausar
- Department of Chemistry, Aligarh Muslim University, Aligarh, Uttar Pradesh, India
| | - Shahid M Naeem
- Department of Chemistry, Aligarh Muslim University, Aligarh, Uttar Pradesh, India
| | - Shahid A Siddiqui
- Department of Radiotherapy, Faculty of Medicine, J. N. Medical College, Aligarh Muslim University, Aligarh, Uttar Pradesh, India
| | - Moinuddin
- Department of Biochemistry, Faculty of Medicine, J. N. Medical College, Aligarh Muslim University, Aligarh, Uttar Pradesh, India
| | - Asif Ali
- Department of Biochemistry, Faculty of Medicine, J. N. Medical College, Aligarh Muslim University, Aligarh, Uttar Pradesh, India
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3
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Zhou Z, Zhong W. Targeting the gut barrier for the treatment of alcoholic liver disease. LIVER RESEARCH 2017; 1:197-207. [PMID: 30034913 PMCID: PMC6051712 DOI: 10.1016/j.livres.2017.12.004] [Citation(s) in RCA: 69] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Alcohol consumption remains one of the predominant causes of liver disease and liver-related death worldwide. Intriguingly, dysregulation of the gut barrier is a key factor promoting the pathogenesis of alcoholic liver disease (ALD). A functional gut barrier, which consists of a mucus layer, an intact epithelial monolayer and mucosal immune cells, supports nutrient absorption and prevents bacterial penetration. Compromised gut barrier function is associated with the progression of ALD. Indeed, alcohol consumption disrupts the gut barrier, increases gut permeability, and induces bacterial translocation both in ALD patients and in experimental models with ALD. Moreover, alcohol consumption also causes enteric dysbiosis with both numerical and proportional perturbations. Here, we review and discuss mechanisms of alcohol-induced gut barrier dysfunction to better understand the contribution of the gut-liver axis to the pathogenesis of ALD. Unfortunately, there is no effectual Food and Drug Administration-approved treatment for any stage of ALD. Therefore, we conclude with a discussion of potential strategies aimed at restoring the gut barrier in ALD. The principle behind antibiotics, prebiotics, probiotics and fecal microbiota transplants is to restore microbial symbiosis and subsequently gut barrier function. Nutrient-based treatments, such as dietary supplementation with zinc, niacin or fatty acids, have been shown to regulate tight junction expression, reduce intestinal inflammation, and prevent endotoxemia as well as liver injury caused by alcohol in experimental settings. Interestingly, saturated fatty acids may also directly control the gut microbiome. In summary, clinical and experimental studies highlight the significance and efficacy of the gut barrier in treating ALD.
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Affiliation(s)
- Zhanxiang Zhou
- Center for Translational Biomedical Research, School of Health and Human Sciences, University of North Carolina at Greensboro, Kannapolis, NC, USA
- Department of Nutrition, School of Health and Human Sciences, University of North Carolina at Greensboro, Greensboro, NC, USA
| | - Wei Zhong
- Center for Translational Biomedical Research, School of Health and Human Sciences, University of North Carolina at Greensboro, Kannapolis, NC, USA
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4
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Zhao M, Howard EW, Parris AB, Guo Z, Zhao Q, Yang X. Alcohol promotes migration and invasion of triple-negative breast cancer cells through activation of p38 MAPK and JNK. Mol Carcinog 2016; 56:849-862. [PMID: 27533114 DOI: 10.1002/mc.22538] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2016] [Revised: 08/05/2016] [Accepted: 08/15/2016] [Indexed: 12/26/2022]
Abstract
Although alcohol is an established breast cancer risk factor, the underlying mechanisms remain unclear. Previous studies examined the general association between alcohol consumption and breast cancer risk; however, the risk for different breast cancer subtypes has been rarely reported. Triple-negative breast cancer (TNBC) is a subtype of breast cancer lacking hormone receptors and HER2 expression, and having poor prognosis. Understanding the molecular mechanisms of TNBC etiology remains a significant challenge. In this study, we investigated cellular responses to alcohol in two TNBC cell lines, MDA-MB-231 and MDA-MB-468. Our results showed that alcohol at low concentrations (0.025-0.1% v/v) induced cell proliferation, migration, and invasion in 1% FBS-containing medium. Molecular analysis indicated that these phenotypic changes were associated with alcohol-induced reactive oxygen species production and increased p38 and JNK phosphorylation. Likewise, p38 or JNK inhibition attenuated alcohol-induced cell migration and invasion. We revealed that alcohol treatment activated/phosphorylated NF-κB regulators and increased transcription of NF-κB-targeted genes. While examining the role of acetaldehyde, the major alcohol metabolite, in alcohol-associated responses in TNBC cells, we saw that acetaldehyde induced cell migration, invasion, and increased phospho-p38, phospho-JNK, and phospho-IκBα in a pattern similar to alcohol treatment. Taken together, we established that alcohol promotes TNBC cell proliferation, migration, and invasion in vitro. The underlying mechanisms involve the induction of oxidative stress and the activation of NF-κB signaling. In particular, the activation of p38 and JNK plays a pivotal role in alcohol-induced cellular responses. These results will advance our understanding of alcohol-mediated development and promotion of TNBC. © 2016 Wiley Periodicals, Inc.
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Affiliation(s)
- Ming Zhao
- Department of Biology, Julius L. Chambers Biomedical/Biotechnology Research Institute, North Carolina Central University, Kannapolis, North Carolina
| | - Erin W Howard
- Department of Biology, Julius L. Chambers Biomedical/Biotechnology Research Institute, North Carolina Central University, Kannapolis, North Carolina
| | - Amanda B Parris
- Department of Biology, Julius L. Chambers Biomedical/Biotechnology Research Institute, North Carolina Central University, Kannapolis, North Carolina
| | - Zhiying Guo
- Department of Biology, Julius L. Chambers Biomedical/Biotechnology Research Institute, North Carolina Central University, Kannapolis, North Carolina
| | - Qingxia Zhao
- Department of Biology, Julius L. Chambers Biomedical/Biotechnology Research Institute, North Carolina Central University, Kannapolis, North Carolina
| | - Xiaohe Yang
- Department of Biology, Julius L. Chambers Biomedical/Biotechnology Research Institute, North Carolina Central University, Kannapolis, North Carolina
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Modulation of Intestinal Barrier and Bacterial Endotoxin Production Contributes to the Beneficial Effect of Nicotinic Acid on Alcohol-Induced Endotoxemia and Hepatic Inflammation in Rats. Biomolecules 2015; 5:2643-58. [PMID: 26501337 PMCID: PMC4693251 DOI: 10.3390/biom5042643] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2015] [Revised: 09/21/2015] [Accepted: 09/23/2015] [Indexed: 12/12/2022] Open
Abstract
Alcohol consumption causes nicotinic acid deficiency. The present study was undertaken to determine whether dietary nicotinic acid supplementation provides beneficial effects on alcohol-induced endotoxin signaling and the possible mechanisms at the gut-liver axis. Male Sprague-Dawley rats were pair-fed the Lieber-DeCarli liquid diets containing ethanol or isocaloric maltose dextrin for eight weeks, with or without dietary supplementation with 750 mg/liter nicotinic acid. Chronic alcohol feeding elevated the plasma endotoxin level and activated hepatic endotoxin signaling cascade, which were attenuated by nicotinic acid supplementation. Alcohol consumption remarkably decreased the mRNA levels of claudin-1, claudin-5, and ZO-1 in the distal intestine, whereas nicotinic acid significantly up-regulated these genes. The concentrations of endotoxin, ethanol, and acetaldehyde in the intestinal contents were increased by alcohol exposure, and niacin supplementation reduced the intestinal endotoxin and acetaldehyde levels. Nicotinic acid supplementation upregulated the intestinal genes involved in aldehyde detoxification via transcriptional regulation. These results demonstrate that modulation of the intestinal barrier function and bacterial endotoxin production accounts for the inhibitory effects of nicotinic acid on alcohol-induced endotoxemia and hepatic inflammation.
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Bagyánszki M, Bódi N. Gut region-dependent alterations of nitrergic myenteric neurons after chronic alcohol consumption. World J Gastrointest Pathophysiol 2015; 6:51-57. [PMID: 26301118 PMCID: PMC4540706 DOI: 10.4291/wjgp.v6.i3.51] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/28/2015] [Revised: 03/27/2015] [Accepted: 06/02/2015] [Indexed: 02/06/2023] Open
Abstract
Chronic alcohol abuse damages nearly every organ in the body. The harmful effects of ethanol on the brain, the liver and the pancreas are well documented. Although chronic alcohol consumption causes serious impairments also in the gastrointestinal tract like altered motility, mucosal damage, impaired absorption of nutrients and inflammation, the effects of chronically consumed ethanol on the enteric nervous system are less detailed. While the nitrergic myenteric neurons play an essential role in the regulation of gastrointestinal peristalsis, it was hypothesised, that these neurons are the first targets of consumed ethanol or its metabolites generated in the different gastrointestinal segments. To reinforce this hypothesis the effects of ethanol on the gastrointestinal tract was investigated in different rodent models with quantitative immunohistochemistry, in vivo and in vitro motility measurements, western blot analysis, evaluation of nitric oxide synthase enzyme activity and bio-imaging of nitric oxide synthesis. These results suggest that chronic alcohol consumption did not result significant neural loss, but primarily impaired the nitrergic pathways in gut region-dependent way leading to disturbed gastrointestinal motility. The gut segment-specific differences in the effects of chronic alcohol consumption highlight the significance the ethanol-induced neuronal microenvironment involving oxidative stress and intestinal microbiota.
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7
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Spacek LA, Mudalel ML, Lewicki R, Tittel FK, Risby TH, Stoltzfus J, Munier JJ, Solga SF. Breath ammonia and ethanol increase in response to a high protein challenge. Biomarkers 2015; 20:149-56. [PMID: 26043432 DOI: 10.3109/1354750x.2015.1040840] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Quantifying changes in ammonia and ethanol in blood and body fluid assays in response to food is cumbersome. We used breath analysis of ammonia, ethanol, hydrogen (an accepted standard of gut transit) and acetone to investigate gastrointestinal physiology. In 30 healthy participants, we measured each metabolite serially over 6 h in control and high protein trials. Two-way repeated measures ANOVA compared treatment (control versus intervention), change from baseline to maximum and interaction of treatment and time change. Interaction was significant for ammonia (p < 0.0001) and hydrogen (p < 0.0001). We describe the dynamic measurement of multiple metabolites in response to an oral challenge.
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Affiliation(s)
- Lisa A Spacek
- Department of Medicine, School of Medicine, Johns Hopkins University , Baltimore, MD , USA
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8
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Singh S, Arcaroli J, Thompson DC, Messersmith W, Vasiliou V. Acetaldehyde and retinaldehyde-metabolizing enzymes in colon and pancreatic cancers. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2015; 815:281-94. [PMID: 25427913 DOI: 10.1007/978-3-319-09614-8_16] [Citation(s) in RCA: 55] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Colorectal cancer (CRC) and pancreatic cancer are two very significant contributors to cancer-related deaths. Chronic alcohol consumption is an important risk factor for these cancers. Ethanol is oxidized primarily by alcohol dehydrogenases to acetaldehyde, an agent capable of initiating tumors by forming adducts with proteins and DNA. Acetaldehyde is metabolized by ALDH2, ALDH1B1, and ALDH1A1 to acetate. Retinoic acid (RA) is required for cellular differentiation and is known to arrest tumor development. RA is synthesized from retinaldehyde by the retinaldehyde dehydrogenases, specifically ALDH1A1, ALDH1A2, ALDH1A3, and ALDH8A1. By eliminating acetaldehyde and generating RA, ALDHs can play a crucial regulatory role in the initiation and progression of cancers. ALDH1 catalytic activity has been used as a biomarker to identify and isolate normal and cancer stem cells; its presence in a tumor is associated with poor prognosis in colon and pancreatic cancer. In summary, these ALDHs are not only biomarkers for CRC and pancreatic cancer but also play important mechanistic role in cancer initiation, progression, and eventual prognosis.
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Affiliation(s)
- S Singh
- Department of Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Mail Stop C238-P20, 12850 E Montview Blvd, Aurora, CO, 80045, USA
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Vonlaufen A, Spahr L, Apte MV, Frossard JL. Alcoholic pancreatitis: A tale of spirits and bacteria. World J Gastrointest Pathophysiol 2014; 5:82-90. [PMID: 24891979 PMCID: PMC4025076 DOI: 10.4291/wjgp.v5.i2.82] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/28/2013] [Accepted: 04/29/2014] [Indexed: 02/06/2023] Open
Abstract
Alcohol is a major cause of chronic pancreatitis. About 5% of alcoholics will ever suffer from pancreatitis, suggesting that additional co-factors are required to trigger an overt disease. Experimental work has implicated lipopolysaccharide, from gut-derived bacteria, as a potential co-factor of alcoholic pancreatitis. This review discusses the effects of alcohol on the gut flora, the gut barrier, the liver-and the pancreas and proposes potential interventional strategies. A better understanding of the interaction between the gut, the liver and the pancreas may provide valuable insight into the pathophysiology of alcoholic pancreatitis.
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10
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Elamin EE, Masclee AA, Dekker J, Jonkers DM. Ethanol metabolism and its effects on the intestinal epithelial barrier. Nutr Rev 2013; 71:483-99. [PMID: 23815146 DOI: 10.1111/nure.12027] [Citation(s) in RCA: 132] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Ethanol is widely consumed and is associated with an increasing global health burden. Several reviews have addressed the effects of ethanol and its oxidative metabolite, acetaldehyde, on the gastrointestinal (GI) tract, focusing on carcinogenic effects or alcoholic liver disease. However, both the oxidative and the nonoxidative metabolites of ethanol can affect the epithelial barrier of the small and large intestines, thereby contributing to GI and liver diseases. This review outlines the possible mechanisms of ethanol metabolism as well as the effects of ethanol and its metabolites on the intestinal barrier. Limited studies in humans and supporting in vitro data have indicated that ethanol as well as mainly acetaldehyde can increase small intestinal permeability. Limited evidence also points to increased colon permeability following exposure to ethanol or acetaldehyde. In vitro studies have provided several mechanisms for disruption of the epithelial barrier, including activation of different cell-signaling pathways, oxidative stress, and remodeling of the cytoskeleton. Modulation via intestinal microbiota, however, should also be considered. In conclusion, ethanol and its metabolites may act additively or even synergistically in vivo. Therefore, in vivo studies investigating the effects of ethanol and its byproducts on permeability of the small and large intestines are warranted.
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Affiliation(s)
- Elhaseen E Elamin
- Top Institute Food and Nutrition (TIFN), Wageningen, The Netherlands
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11
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Suzuki T. Regulation of intestinal epithelial permeability by tight junctions. Cell Mol Life Sci 2013; 70:631-59. [PMID: 22782113 PMCID: PMC11113843 DOI: 10.1007/s00018-012-1070-x] [Citation(s) in RCA: 953] [Impact Index Per Article: 79.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2012] [Revised: 06/19/2012] [Accepted: 06/21/2012] [Indexed: 12/13/2022]
Abstract
The gastrointestinal epithelium forms the boundary between the body and external environment. It effectively provides a selective permeable barrier that limits the permeation of luminal noxious molecules, such as pathogens, toxins, and antigens, while allowing the appropriate absorption of nutrients and water. This selective permeable barrier is achieved by intercellular tight junction (TJ) structures, which regulate paracellular permeability. Disruption of the intestinal TJ barrier, followed by permeation of luminal noxious molecules, induces a perturbation of the mucosal immune system and inflammation, and can act as a trigger for the development of intestinal and systemic diseases. In this context, much effort has been taken to understand the roles of extracellular factors, including cytokines, pathogens, and food factors, for the regulation of the intestinal TJ barrier. Here, I discuss the regulation of the intestinal TJ barrier together with its implications for the pathogenesis of diseases.
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Affiliation(s)
- Takuya Suzuki
- Department of Biofunctional Science and Technology, Graduate School of Biosphere Science, Hiroshima University, 1-4-4, Kagamiyama, Higashi-Hiroshima, 739-8528, Japan.
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12
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Ferrari P, McKay JD, Jenab M, Brennan P, Canzian F, Vogel U, Tjønneland A, Overvad K, Tolstrup JS, Boutron-Ruault MC, Clavel-Chapelon F, Morois S, Kaaks R, Boeing H, Bergmann M, Trichopoulou A, Katsoulis M, Trichopoulos D, Krogh V, Panico S, Sacerdote C, Palli D, Tumino R, Peeters PH, van Gils CH, Bueno-de-Mesquita B, Vrieling A, Lund E, Hjartåker A, Agudo A, Suarez LR, Arriola L, Chirlaque MD, Ardanaz E, Sánchez MJ, Manjer J, Lindkvist B, Hallmans G, Palmqvist R, Allen N, Key T, Khaw KT, Slimani N, Rinaldi S, Romieu I, Boffetta P, Romaguera D, Norat T, Riboli E. Alcohol dehydrogenase and aldehyde dehydrogenase gene polymorphisms, alcohol intake and the risk of colorectal cancer in the European Prospective Investigation into Cancer and Nutrition study. Eur J Clin Nutr 2012; 66:1303-8. [PMID: 23149980 DOI: 10.1038/ejcn.2012.173] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
Abstract
BACKGROUND/OBJECTIVES Heavy alcohol drinking is a risk factor of colorectal cancer (CRC), but little is known on the effect of polymorphisms in the alcohol-metabolizing enzymes, alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) on the alcohol-related risk of CRC in Caucasian populations. SUBJECTS/METHODS A nested case-control study (1269 cases matched to 2107 controls by sex, age, study centre and date of blood collection) was conducted within the European Prospective Investigation into Cancer and Nutrition (EPIC) to evaluate the impact of rs1229984 (ADH1B), rs1573496 (ADH7) and rs441 (ALDH2) polymorphisms on CRC risk. Using the wild-type variant of each polymorphism as reference category, CRC risk estimates were calculated using conditional logistic regression, with adjustment for matching factors. RESULTS Individuals carrying one copy of the rs1229984(A) (ADH1B) allele (fast metabolizers) showed an average daily alcohol intake of 4.3 g per day lower than subjects with two copies of the rs1229984(G) allele (slow metabolizers) (P(diff)<0.01). None of the polymorphisms was associated with risk of CRC or cancers of the colon or rectum. Heavy alcohol intake was more strongly associated with CRC risk among carriers of the rs1573496(C) allele, with odds ratio equal to 2.13 (95% confidence interval: 1.26-3.59) compared with wild-type subjects with low alcohol consumption (P(interaction)=0.07). CONCLUSIONS The rs1229984(A) (ADH1B) allele was associated with a reduction in alcohol consumption. The rs1229984 (ADH1B), rs1573496 (ADH7) and rs441 (ALDH2) polymorphisms were not associated with CRC risk overall in Western-European populations. However, the relationship between alcohol and CRC risk might be modulated by the rs1573496 (ADH7) polymorphism.
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Affiliation(s)
- P Ferrari
- International Agency for Research on Cancer (IARC-WHO), Lyon, France.
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13
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Duryee MJ, Klassen LW, Schaffert CS, Tuma DJ, Hunter CD, Garvin RP, Anderson DR, Thiele GM. Malondialdehyde-acetaldehyde adduct is the dominant epitope after MDA modification of proteins in atherosclerosis. Free Radic Biol Med 2010; 49:1480-6. [PMID: 20696236 PMCID: PMC2952714 DOI: 10.1016/j.freeradbiomed.2010.08.001] [Citation(s) in RCA: 81] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/08/2010] [Revised: 07/14/2010] [Accepted: 08/02/2010] [Indexed: 11/20/2022]
Abstract
Antibodies to malondialdehyde (MDA)-modified macromolecules (adducts) have been detected in the serum of patients with atherosclerosis and correlate with the progression of this disease. However, the epitope and its formation have not been characterized. Studies have shown that excess MDA can be degraded to acetaldehyde, which combines with proteins to from a stable dihydropyridine adduct. To investigate, mice were immunized with MDA adducts in the absence of adjuvant and showed an increase in antibodies to MDA adducts and the carrier protein as the concentration of MDA was increased. In fact, a number of the commercially available antibodies to MDA-modified proteins were able to be inhibited by a chemical analogue, hexyl-MAA. Also, MDA-MAA adducts were detected in the serum and aortic tissue of JCR diabetic/atherosclerotic rats. These studies determined that commercially available antibodies to MDA predominantly react with the MAA adduct and are present in the JCR model of atherosclerosis in both the serum and the aortic tissue. Therefore, the immune response to MDA-modified proteins is most probably to the dihydropyridine structure (predominant epitope in MAA), which suggests that MAA adducts may play a role in the development and/or progression of atherosclerosis.
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Affiliation(s)
- Michael J Duryee
- Experimental Immunology Laboratory, Section of Rheumatology, Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68198, USA.
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Salaspuro M. Acetaldehyde as a common denominator and cumulative carcinogen in digestive tract cancers. Scand J Gastroenterol 2010; 44:912-25. [PMID: 19396661 DOI: 10.1080/00365520902912563] [Citation(s) in RCA: 58] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
The key issue in cancer prevention is the identification of specific aetiologic factors. Acetaldehyde, the first metabolite of ethanol oxidation, is carcinogenic in animals. ADH and ALDH2 gene mutations provide an exceptional human model to estimate the long-term effects of acetaldehyde exposure in man. These models provide strong evidence for the local carcinogenic potential of acetaldehyde also in humans. Ethanol is metabolized to acetaldehyde by both mucosal and microbial enzymes. Many microbes produce acetaldehyde from ethanol, but their capacity to eliminate acetaldehyde is low, which leads to the accumulation of acetaldehyde in saliva during an alcohol challenge. Acetaldehyde is the most abundant carcinogen in tobacco smoke, and it readily dissolves into saliva during smoking. Fermented food and many alcoholic beverages can also contain significant amounts of acetaldehyde. Thus acetaldehyde, derived from mucosal or microbial oxidation of ethanol, tobacco smoke, and/or diet, appears to act as a cumulative carcinogen in the upper digestive tract of humans. The evidence strongly suggests the importance of world-wide screening of acetaldehyde and ethanol levels in many beverages and foodstuffs, as well as an urgent need for regulatory measures and consumer guidance. Screening of the risk groups with enhanced acetaldehyde exposure, e.g. people with ADH and ALDH2 gene polymorphisms and hypochlorhydric atrophic gastritis, should also be seriously considered. Most importantly, the GRAS (generally regarded as safe) status of acetaldehyde, which allows it to be used as a food additive, should be re-evaluated, and the classification of acetaldehyde as a carcinogen should be upgraded.
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Affiliation(s)
- Mikko Salaspuro
- Research Unit on Acetaldehyde and Cancer, Faculty of Medicine, Biomedicum Helsinki, University of Helsinki, Helsinki, Finland.
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15
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Yang H, Zhou Y, Zhou Z, Liu J, Yuan X, Matsuo K, Takezaki T, Tajima K, Cao J. A novel polymorphism rs1329149 of CYP2E1 and a known polymorphism rs671 of ALDH2 of alcohol metabolizing enzymes are associated with colorectal cancer in a southwestern Chinese population. Cancer Epidemiol Biomarkers Prev 2009; 18:2522-7. [PMID: 19706845 DOI: 10.1158/1055-9965.epi-09-0398] [Citation(s) in RCA: 43] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
BACKGROUND To screen for tagging single nucleotide polymorphisms (tagSNP) in the major alcohol metabolizing enzymes: ADH1B, ALDH2, and CYP2E1, and to evaluate the association between these tagSNPs and colorectal cancer (CRC) in a southwestern Chinese population. METHODS A hospital-based case-control study of 440 CRC patients and 800 cancer-free controls was conducted. Personal information was collected by a Semi-Quantitative Food Frequency Questionnaire. The tagSNPs were screened in the HapMap with Haploview by setting the minor allele frequency at 0.03 with the highest score of r(2) form each block. Genotypes were identified by using the SNPLex System. Both crude and adjusted odds ratio (OR) and 95% confidence interval (CI) were used to evaluate the risk of each SNP. RESULTS Sixteen tagSNPs were selected, and 13 were successfully genotyped. A novel CYP2E1 locus rs1329149 and a known ALDH2 locus rs671 were found to be significantly associated with CRC risk. The adjusted OR was 1.86 (95% CI, 1.12-3.09) for the rs671 A/A genotype and 4.04 for the rs1329149 T/T genotype (95% CI, 2.44-6.70), compared with their common homozygous genotypes. Interaction was found between alcohol consumption and gene polymorphisms on CRC, the adjusted OR was 7.17 (95% CI, 2.01-25.53) for drinking habits combined with rs671 A/A or rs1329149 T/T genotype. CONCLUSION The results of this study suggest that rs671 A/A and the first reported locus rs1329149 T/T genotypes increase the susceptibility to CRC, and gene-environmental interaction between the two loci and alcohol use existed for CRC in Southwestern Chinese. Larger studies are warranted to verify our findings.
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Affiliation(s)
- Huan Yang
- Department of Hygienic Toxicology, College of Preventive Medicine, Third Military Medical University, Chongqing 400038, China
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Marietta C, Thompson LH, Lamerdin JE, Brooks P. Acetaldehyde stimulates FANCD2 monoubiquitination, H2AX phosphorylation, and BRCA1 phosphorylation in human cells in vitro: implications for alcohol-related carcinogenesis. Mutat Res 2009; 664:77-83. [PMID: 19428384 PMCID: PMC2807731 DOI: 10.1016/j.mrfmmm.2009.03.011] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2009] [Revised: 02/27/2009] [Accepted: 03/27/2009] [Indexed: 02/01/2023]
Abstract
According to a recent IARC Working Group report, alcohol consumption is causally related to an increased risk of cancer of the upper aerodigestive tract, liver, colorectum, and female breast [R. Baan, K. Straif, Y. Grosse, B. Secretan, F. El Ghissassi, V. Bouvard, A. Altieri, V. Cogliano, Carcinogenicity of alcoholic beverages, Lancet Oncol. 8 (2007) 292-293]. Several lines of evidence indicate that acetaldehyde (AA), the first product of alcohol metabolism, plays a very important role in alcohol-related carcinogenesis, particularly in the esophagus. We previously proposed a model for alcohol-related carcinogenesis in which AA, generated from alcohol metabolism, reacts in cells to generate DNA lesions that form interstrand crosslinks (ICLs) [J.A. Theruvathu, P. Jaruga, R.G. Nath, M. Dizdaroglu, P.J. Brooks, Polyamines stimulate the formation of mutagenic 1,N2-propanodeoxyguanosine adducts from acetaldehyde, Nucleic Acids Res. 33 (2005) 3513-3520]. Since the Fanconi anemia-breast cancer associated (FANC-BRCA) DNA damage response network plays a crucial role in protecting cells against ICLs, in the present work we tested this hypothesis by exposing cells to AA and monitoring activation of this network. We found that AA exposure results in a concentration-dependent increase in FANCD2 monoubiquitination, which is dependent upon the FANC core complex. AA also stimulated BRCA1 phosphorylation at Ser1524 and increased the level of gammaH2AX, with both modifications occurring in a dose-dependent manner. However, AA did not detectably increase the levels of hyperphosphorylated RPA34, a marker of single-stranded DNA exposure at replication forks. These results provide the initial description of the AA-DNA damage response, which is qualitatively similar to the cellular response to mitomycin C, a known DNA crosslinking agent. We discuss the mechanistic implications of these results, as well as their possible relationship to alcohol-related carcinogenesis in different human tissues.
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Affiliation(s)
- Cheryl Marietta
- Section on Molecular Neurobiology, Laboratory of Neurogenetics, National Institute on Alcohol Abuse and Alcoholism, 5625 Fishers Lane, Room 3S32, Rockville, MD 20852
| | - Larry H. Thompson
- Biosciences and Biotechnology Division, L452, Lawrence Livermore National Laboratory, P.O. Box 808, Livermore, CA 94551-0808
| | - Jane E. Lamerdin
- Biosciences and Biotechnology Division, L452, Lawrence Livermore National Laboratory, P.O. Box 808, Livermore, CA 94551-0808
| | - P.J. Brooks
- Section on Molecular Neurobiology, Laboratory of Neurogenetics, National Institute on Alcohol Abuse and Alcoholism, 5625 Fishers Lane, Room 3S32, Rockville, MD 20852
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Homann N, König IR, Marks M, Benesova M, Stickel F, Millonig G, Mueller S, Seitz HK. Alcohol and Colorectal Cancer: The Role of Alcohol Dehydrogenase 1C Polymorphism. Alcohol Clin Exp Res 2009; 33:551-6. [DOI: 10.1111/j.1530-0277.2008.00868.x] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/01/2022]
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Koivisto H, Hietala J, Anttila P, Niemelä O. Co-occurrence of IgA antibodies against ethanol metabolites and tissue transglutaminase in alcohol consumers: correlation with proinflammatory cytokines and markers of fibrogenesis. Dig Dis Sci 2008; 53:500-5. [PMID: 17597408 DOI: 10.1007/s10620-007-9874-5] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/12/2007] [Accepted: 05/09/2007] [Indexed: 01/26/2023]
Abstract
IgA antibodies to tissue transglutaminase have been suggested to be specific indicators of celiac disease. However, no studies have addressed the relationships between such antibodies and alcohol abuse, which is also a common cause of IgA-isotype immune responses and tissue injury in the gastrointestinal tract and liver. Here, measurements of specific IgAs against tissue transglutaminase and proteins modified by acetaldehyde, the first metabolite of ethanol, showed significantly higher levels of both antibodies in alcoholic liver disease patients than in healthy controls or heavy drinkers without liver disease. These antibodies also significantly co-occurred in heavy drinkers without liver disease, moderate drinkers, and abstainers, and correlated with biomarkers of alcohol consumption, proinflammatory cytokines and markers of fibrogenesis. The data suggests a link between such immune responses, perturbations in cytokine profiles and fibrogenesis, which should be implicated in studies on the pathogenesis and diagnosis of ethanol-induced tissue injury and celiac disease.
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Affiliation(s)
- Heidi Koivisto
- Medical Research Unit and Department of Laboratory Medicine, Seinäjoki Central Hospital, Seinajoki 60220, Finland
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19
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Abstract
Approximately 3.6% of cancers worldwide derive from chronic alcohol drinking, including those of the upper aerodigestive tract, the liver, the colorectum and the breast. Although the mechanisms for alcohol-associated carcinogenesis are not completely understood, most recent research has focused on acetaldehyde, the first and most toxic ethanol metabolite, as a cancer-causing agent. Ethanol may also stimulate carcinogenesis by inhibiting DNA methylation and by interacting with retinoid metabolism. Alcohol-related carcinogenesis may interact with other factors such as smoking, diet and comorbidities, and depends on genetic susceptibility.
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Affiliation(s)
- Helmut K Seitz
- Department of Medicine and Laboratory of Alcohol Research, Liver Disease and Nutrition, Salem Medical Centre, University of Heidelberg, Heidelberg, Germany.
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20
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Hietala J, Koivisto H, Latvala J, Anttila P, Niemelä O. IgAs against acetaldehyde-modified red cell protein as a marker of ethanol consumption in male alcoholic subjects, moderate drinkers, and abstainers. Alcohol Clin Exp Res 2006; 30:1693-8. [PMID: 17010136 DOI: 10.1111/j.1530-0277.2006.00204.x] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
BACKGROUND Alcohol abuse has been shown to result in the production of antibodies against acetaldehyde-modified epitopes in proteins. However, as yet, only limited information has been available on the clinical usefulness of such responses as markers of hazardous drinking. METHODS We developed an ELISA to measure specific IgAs against acetaldehyde-protein adducts. This method was evaluated in cross-sectional and follow-up studies on male heavy drinkers with a current ethanol consumption of 40 to 540 g/d (n=40), moderate drinkers consuming 1 to 40 g/d (n=25), and abstainers (n=16). The clinical assessments included detailed interviews on the amounts and patterns of ethanol consumption and various biochemical markers of alcohol abuse and liver function. RESULTS The mean antiadduct IgAs (198+/-28 U/L) in the alcohol abusers were significantly higher than those in the moderate drinkers (58+/-11 U/L, p<0.001) or abstainers (28+/-8 U/L, p<0.001). The values of moderate drinkers were also higher than those in abstainers (p<0.05). The amount of ethanol consumed during the period of 1 month preceding blood sampling correlated strongly with antiadduct IgAs (r=0.67, p<0.001). The sensitivity (73%) and specificity (94%) of this marker were found to exceed those of the conventional laboratory markers of alcohol abuse in comparisons contrasting heavy drinkers with abstainers although not in comparisons contrasting heavy drinkers with moderate drinkers. During abstinence, antiadduct IgAs disappeared with a mean rate of 3% per day. In additional analyses of possible marker combinations, antiadduct IgAs, together with CDT, were found to provide the highest sensitivity and specificity. CONCLUSIONS Measurements of antiadduct IgAs may provide a new clinically useful marker of alcohol abuse, providing a close relationship between marker levels and the actual amounts of recent ethanol ingestion.
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Affiliation(s)
- Johanna Hietala
- Department of Laboratory Medicine and Medical Research Unit, Seinäjoki Central Hospital, Seinäjoki, Finland
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21
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Ferrier L, Bérard F, Debrauwer L, Chabo C, Langella P, Buéno L, Fioramonti J. Impairment of the intestinal barrier by ethanol involves enteric microflora and mast cell activation in rodents. THE AMERICAN JOURNAL OF PATHOLOGY 2006; 168:1148-54. [PMID: 16565490 PMCID: PMC1606551 DOI: 10.2353/ajpath.2006.050617] [Citation(s) in RCA: 197] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
Alcohol hepatic toxicity in heavy drinkers is associated with high endotoxin blood levels and increased intestinal permeability. Because endotoxins can cross damaged mucosa, we investigated the mechanisms through which ethanol impairs the colonic epithelium of rats submitted to acute alcohol intake. Colonic permeability to (51)Cr-ethylenediamintetraacetic acid was increased 24 hours after 3.0 g/kg ethanol intake (3.2 +/- 0.2% versus 2.2 +/- 0.2%) and was associated with significant endotoxemia. Antibiotics and doxantrazole (a mast cell membrane stabilizer) significantly inhibited the effect of ethanol. Two hours after intake, plasma concentrations of ethanol were twofold higher in antibiotic-treated rats than in controls (155.8 +/- 9.3 mg/dl versus 75.7 +/- 7.6 mg/dl, P < 0.001). Lumenal concentrations of acetaldehyde were markedly increased after ethanol intake (132.6 +/- 31.6 micromol/L versus 20.8 +/- 1.4 micromol/L, P < 0.05) and antibiotics diminished this increase (86.2 +/- 10.9 micromol/L). In colonic samples mounted in Ussing chambers, acetaldehyde but not ethanol increased dextran flux across the mucosa by 54%. Doxantrazole inhibited the effect of acetaldehyde. This study demonstrates that an acute and moderate ethanol intake alters the epithelial barrier through ethanol oxidation into acetaldehyde by the colonic microflora and downstream mast cell activation. Such alterations that remain for longer periods could result in excessive endotoxin passage, which could explain the subsequent endotoxemia frequently observed in patients with alcoholic liver disease.
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Affiliation(s)
- Laurent Ferrier
- Unité de Neuro-Gastroentérologie et Nutrition, Institut National de la Recherche Agronomique, 180 Chemin de Tournefeuille, B.P. 3, 31931 Toulouse Cedex 9, France.
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22
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Latvala J, Hietala J, Koivisto H, Järvi K, Anttila P, Niemelä O. Immune Responses to Ethanol Metabolites and Cytokine Profiles Differentiate Alcoholics with or without Liver Disease. Am J Gastroenterol 2005; 100:1303-10. [PMID: 15929761 DOI: 10.1111/j.1572-0241.2005.41509.x] [Citation(s) in RCA: 64] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
OBJECTIVES Excessive alcohol consumption is associated with the generation of antibodies against neoantigens induced by ethanol metabolism. However, the associations between such immune responses, ethanol consumption, and liver injury remain unclear. METHODS Eight-six male alcoholics with (n=54) or without (n=32) liver disease, and 20 male volunteers (6 abstainers, 14 moderate drinkers) underwent clinical, morphological, and biochemical assessments of liver status and ethanol consumption. RESULTS Antiacetaldehyde adduct IgAs in both groups of alcoholics were significantly higher than those in the controls. Elevated IgGs occurred in patients with liver disease, whereas IgMs were high in the heavy drinkers without apparent liver disease. Liver disease patients had high levels of both proinflammatory (IL-2, IL-6, IL-8, TNF-alpha) and antiinflammatory (IL-10) cytokines, whereas those without liver disease showed elevated IL-6, IL-8, and IL-10 only. Ethanol consumption correlated significantly with antiadduct IgA and IL-6 levels, which also showed parallel changes upon abstinence. CONCLUSIONS Alcoholic liver disease is associated with the generation of IgAs and IgGs against acetaldehyde-derived antigens and enhanced levels of both pro- and antiinflammatory cytokines, whereas elevated IgA, IL-6, and IL-10 characterize alcoholics without liver disease. These data suggest that immunological mechanisms may play a role in the sequence of events leading to liver disease in some patients with excessive drinking.
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Affiliation(s)
- Jaana Latvala
- Department of Laboratory Medicine and Addiction Research Unit, EP Central Hospital, Seinäjoki, and University of Tampere, Finland
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23
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Sheth P, Seth A, Thangavel M, Basuroy S, Rao RK. Epidermal growth factor prevents acetaldehyde-induced paracellular permeability in Caco-2 cell monolayer. Alcohol Clin Exp Res 2004; 28:797-804. [PMID: 15166657 DOI: 10.1097/01.alc.0000125358.92335.90] [Citation(s) in RCA: 37] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
BACKGROUND Intestinal permeability and endotoxemia play a crucial role in the pathogenesis of alcoholic liver disease. Previous studies showed that acetaldehyde disrupts intestinal epithelial barrier function and increases paracellular permeability by a tyrosine kinase-dependent mechanism. In the present study, the role of epidermal growth factor (EGF) in protection of epithelial barrier function from acetaldehyde was evaluated in Caco-2 intestinal epithelial cell monolayer. METHODS Caco-2 cells on Transwell inserts were exposed to acetaldehyde in the absence or presence of EGF, and the paracellular permeability was evaluated by measuring transepithelial electrical resistance and unidirectional flux of inulin. Integrity of epithelial tight junctions and adherens junctions was analyzed by confocal immunofluorescence microscopy and immunoblot analysis of occludin, zonula occludens (ZO)-1, E-cadherin, and beta-catenin in the actin cytoskeleton. Reorganization of actin cytoskeletal architecture was examined by confocal microscopy. RESULTS Acetaldehyde increased paracellular permeability to inulin and lipopolysaccharide, and EGF significantly reduced these effects of acetaldehyde in a time- and dose-dependent manner. EGF prevented acetaldehyde-induced reorganization of occludin, ZO-1, E-cadherin, and beta-catenin from the cellular junctions to the intracellular compartments. Acetaldehyde treatment induced a reorganization of actin cytoskeletal network and reduced the levels of occludin, ZO-1, E-cadherin, and beta-catenin associated with the actin cytoskeleton. EGF effectively prevented acetaldehyde-induced reorganization of actin cytoskeleton and the interaction of occludin, ZO-1, E-cadherin, and beta-catenin with the actin cytoskeleton. CONCLUSION These results indicate that EGF attenuates acetaldehyde-induced disruption of tight junctions and adherens junctions and prevents acetaldehyde-induced reorganization of actin cytoskeleton and its interaction with occludin, ZO-1, E-cadherin, and beta-catenin.
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Affiliation(s)
- P Sheth
- Department of Physiology, University of Tennessee Health Science Center, Memphis, Tennessee, USA
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24
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Zidi SH, Linderborg K, Väkeväinen S, Salaspuro M, Jokelainen K. Lactulose Reduces Intracolonic Acetaldehyde Concentration and Ethanol Elimination Rate in Rats. Alcohol Clin Exp Res 2003; 27:1459-62. [PMID: 14506407 DOI: 10.1097/01.alc.0000086061.31875.c8] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
BACKGROUND Normal colonic bacteria possessing alcohol dehydrogenase activity can oxidize ethanol to acetaldehyde. Acetaldehyde recently has been shown to be a local carcinogen in humans. The aim of the study was to examine the effect of lactulose feeding on fecal and cecal pH, intracolonic acetaldehyde concentration, and total ethanol elimination rate in rats. METHODS Sixty Wistar rats were divided into four groups. Groups 2 and 4 received lactulose daily (11 g/kg body weight for 14 days). On days 7 and 14, groups 1 and 2 received ethanol (1.5 g/kg body weight) intraperitoneally, whereas groups 3 and 4 received saline. RESULTS Fecal and cecal pH values decreased significantly after lactulose treatment compared with the controls. Lactulose feeding reduced the total ethanol elimination rate by 13.8% (257 +/- 0.008 mg/kg/hr vs. 298 +/- 0.003 mg/kg/hr, p < 0.001) and the intracecal acetaldehyde concentration by 66.2% after ethanol (49 +/- 29 microM vs. 145 +/- 47 microM, p = 0.03) compared with the controls. CONCLUSION Lactulose feeding to rats significantly reduces ethanol elimination rate and intraluminal acetaldehyde concentration in the colon after ethanol administration. This prebiotic thus could be used as an effective agent to block the microbial production of carcinogenic acetaldehyde in the large intestine.
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Affiliation(s)
- Sémia H Zidi
- Research Unit of Substance Abuse Medicine, Biomedicum Helsinki, Helsinki University Central Hospital, Finland
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Abstract
Excessive alcohol consumption and heavy smoking are the main risk factors for upper digestive tract cancers. Cancer risk is dose-dependent and alcohol and smoking have synergistic effects. Alcohol is not carcinogenic. However, its first metabolite-acetaldehyde-has recently been shown to be a local carcinogen in humans. Microbes representing normal human gut flora are able to produce acetaldehyde from ethanol. This results in high local acetaldehyde concentrations in the saliva and contents of the large intestine. Asian heavy drinkers with a genetic deficiency for detoxifying acetaldehyde form an exceptional human 'knockout' model for long-term acetaldehyde exposure. The risk of alcohol-related digestive tract cancers is particularly high among this population. All mechanisms that have an effect on salivary or intracolonic acetaldehyde concentration are of importance. The message for prevention is that one should take care to have good oral hygiene and to avoid smoking, heavy drinking and drinking to intoxication.
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Affiliation(s)
- Mikko P Salaspuro
- Research Unit of Substance Abuse Medicine, University Central Hospital of Helsinki, Biomedicum Helsinki, PL 700, 00029 HUS, Helsinki, Finland.
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Abstract
Excessive alcohol consumption and heavy smoking are the main risk factors of upper digestive tract cancer in industrialized countries. The association between heavy drinking and cancer appears to he particularly prominent in Asian individuals who have an inherited deficient ability to detoxify the first metabolite of ethanol oxidation, acetaldehyde. Alcohol itself is not carcinogenic. However, according to cell culture and animal experiments acetaldehyde is highly toxic, mutagenic, and carcinogenic. In addition to somatic cells, microbes representing normal human gut flora are also able to produce acetaldehyde from ethanol. After the ingestion of alcoholic beverages, this results in high local acetaldehyde concentrations in the saliva, gastric juice, and the contents of the large intestine. In addition, microbes may produce acetaldehyde endogenously without alcohol administration. This review summarizes the epidemiological, genetic, and biochemical evidence supporting the role of locally produced acetaldehyde in the pathogenesis of digestive tract cancer. Special emphasis is given to those factors that regulate local acetaldehyde concentration in the contents of the gastrointestinal tract. The new evidence presented in this review may open a microbiological approach to the pathogenesis of digestive tract cancer and may have an influence on future preventive strategies.
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Affiliation(s)
- Mikko P Salaspuro
- Research Unit of Substance Abuse Medicine, University Central Hospital of Helsinki, Biomedicum Helsinki, PL 700, 00029 HUS, Helsinki, Finland.
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Atkinson KJ, Rao RK. Role of protein tyrosine phosphorylation in acetaldehyde-induced disruption of epithelial tight junctions. Am J Physiol Gastrointest Liver Physiol 2001; 280:G1280-8. [PMID: 11352822 DOI: 10.1152/ajpgi.2001.280.6.g1280] [Citation(s) in RCA: 128] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Acetaldehyde-induced cytotoxicity is an important factor in pathogenesis of alcohol-related diseases; however, the mechanism of this toxicity is unknown. We recently showed that acetaldehyde increases epithelial paracellular permeability. We asked whether protein tyrosine phosphorylation via modulation of tyrosine kinases and/or PTPases is a mechanism involved in acetaldehyde-induced disruption of the tight junctions in the Caco-2 cell monolayer. Immunofluorescence localization of occludin and ZO-1 showed disruption of the tight junctions in acetaldehyde-treated cell monolayer. Administration of genistein prevented acetaldehyde-induced permeability. Acetaldehyde increased tyrosine phosphorylation of three clusters of proteins with molecular masses of 30-50, 60-90, and 110-150 kDa; three of these proteins were ZO-1, E-cadherin, and beta-catenin. Acetaldehyde reduced PTPase activity in plasma membrane and soluble fractions, whereas tyrosine kinase activity remained unaffected. Treatment with acetaldehyde resulted in a 97% loss of protein tyrosine phosphatase (PTP)1B activity and a partial reduction of PTP1C and PTP1D activities. These results strongly suggest that acetaldehyde inhibits PTPases to increase protein tyrosine phosphorylation, which may result in disruption of the tight junctions.
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Affiliation(s)
- K J Atkinson
- Department of Pediatrics, Medical University of South Carolina, Charleston, SC 29425, USA
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Jokelainen K, Parkkila S, Salaspuro M, Niemelä O. Covalent adducts of proteins with acetaldehyde in the liver as a result of acetaldehyde administration in drinking water. J Hepatol 2000; 33:926-32. [PMID: 11131454 DOI: 10.1016/s0168-8278(00)80124-5] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/04/2022]
Abstract
BACKGROUND/AIMS Acetaldehyde, the first metabolic product of ethanol, has been suggested to be responsible for several adverse effects of ethanol through its ability to form covalent adducts with proteins and cellular constituents. It has recently been suggested that acetaldehyde derived from microbial ethanol oxidation in the gut could also contribute to the effects of ethanol in the liver. The present work aimed to examine whether modification of proteins by acetaldehyde occurs in rat liver as a result of acetaldehyde administration in drinking water. METHODS Rats were fed with either 0.7% acetaldehyde (n=10) or water (n=10) for 11 weeks. At the end of the feeding period, liver specimens were processed for immunohistochemistry for protein adducts with acetaldehyde and for hepatic cell type-specific protein markers. RESULTS Mild fatty change was found in the liver of the acetaldehyde-treated animals but not in the control animals. Immunohistochemical stainings for acetaldehyde adducts revealed intensive positive staining for acetaldehyde adducts in eight (80%) of the animals fed with acetaldehyde. The adducts were predominantly perivenular, although positive staining also occurred along the sinusoids and in the periportal area. Double immunofluorescence staining experiments revealed that hepatocytes were the primary targets of acetaldehyde adduct deposition, although stellate cells and Kupffer cells also showed weak positive reactions. CONCLUSIONS The present data indicate that acetaldehyde-protein adducts are formed in the liver of animals following acetaldehyde administration in drinking water, which may contribute to the hepatotoxicity of extrahepatic acetaldehyde. These findings should be implicated in studies on the extrahepatic pathways of ethanol oxidation.
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Affiliation(s)
- K Jokelainen
- Alcohol Research Unit, Helsinki University Hospital, Finland
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Viitala K, Makkonen K, Israel Y, Lehtimäki T, Jaakkola O, Koivula T, Blake JE, Niemelä O. Autoimmune responses against oxidant stress and acetaldehyde-derived epitopes in human alcohol consumers. Alcohol Clin Exp Res 2000. [PMID: 10924016 DOI: 10.1111/j.1530-0277.2000.tb04656.x] [Citation(s) in RCA: 38] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
BACKGROUND Studies in experimental animals have indicated that chronic ethanol ingestion triggers the formation of antibodies directed against proteins modified with reactive metabolites of ethanol and products of lipid peroxidation. However, the nature and prevalence of such antibodies have not been compared previously in alcoholic patients. METHODS Autoantibodies against adducts with acetaldehyde- (AA), malondialdehyde- (MDA), and oxidized epitopes (Ox) were examined from sera of 54 alcohol consumers with (n = 28) or without (n = 26) liver disease, and from 20 nondrinking controls. RESULTS Anti-AA-adduct IgA and IgG antibodies were elevated in 64% and 31% of patients with biopsy-proven alcoholic liver disease (ALD, n = 28), respectively. The IgA titers were significantly higher than those from nondrinking controls (p < 0.001), or heavy drinkers without significant liver disease (p < 0.001). Anti-MDA adduct titers (IgG) were elevated in 70% of the ALD patients. These titers were significantly higher (p < 0.001) than those from nondrinking controls, or heavy drinkers without liver disease. Antibodies (IgG) against Ox epitopes occurred in 43% of ALD patients, and the titers also were significantly higher (p < 0.05) than those from nondrinking controls. The anti-AA and anti-MDA adduct titers in ALD patients correlated significantly with the combined clinical and laboratory index (CCLI) of liver disease severity (r(s) = 0.449, p < 0.05; r(s) = 0.566, p < 0.01, respectively), the highest prevalences of anti-AA-adducts (73%) and anti-MDA-adducts (76%) occurring in ALD patients with cirrhosis. CONCLUSIONS The present results indicated that autoantibodies against several distinct types of protein modifications are generated in ALD patients showing an association with the severity of liver disease.
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Affiliation(s)
- K Viitala
- EP Central Hospital Laboratory, Seinäjoki, Finland
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Blasiak J, Trzeciak A, Malecka-Panas E, Drzewoski J, Wojewódzka M. In vitro genotoxicity of ethanol and acetaldehyde in human lymphocytes and the gastrointestinal tract mucosa cells. Toxicol In Vitro 2000; 14:287-95. [PMID: 10906435 DOI: 10.1016/s0887-2333(00)00022-9] [Citation(s) in RCA: 47] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
The influence of ethanol and acetaldehyde on DNA in human lymphocytes, gastric mucosa (GM) and colonic mucosa (CM) was investigated by using the comet assay. All kinds of cells were exposed to ethanol and acetaldehyde in two regimens: the cells were incubated with either chemical and analysed or they were exposed first to ethanol, washed and then exposed to acetaldehyde and analysed. Lymphocytes were exposed to ethanol at final concentrations of 30 mM and acetaldehyde at 3 mM. GM cells were incubated with ethanol at 1 M and acetaldehyde at 100 mM. CM cells were exposed to ethanol at 10 mM and acetaldehyde at 100 mM. In combined exposure, the cells were subsequently exposed to ethanol and acetaldehyde at all combination of the concentrations of the agents. Ethanol caused DNA strand breaks, which were repaired during 4 hr, except when this agent was applied in GM cells at a concentration of 1 M. A dose-dependent decrease in the tail moment of all types of acetaldehyde-treated cells was observed. Similar results were obtained when a recognized DNA crosslinking agent, formaldehyde, was used. These results suggest that acetaldehyde may form crosslinks with DNA. These crosslinks were poorly repaired. CM cells showed the highest sensitivity of all cell types to ethanol than lymphocytes and GM cells. There were no differences in the sensitivity to acetaldehyde of all the cell types. Our results clearly indicate that ethanol and acetaldehyde can contribute to cancers of the digestive tract.
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Affiliation(s)
- J Blasiak
- Department of Molecular Genetics, University of Lodz, 12/16, 90-237 Lodz, Banacha, Poland.
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Tillonen J, Väkeväinen S, Salaspuro V, Zhang Y, Rautio M, Jousimies-Somer H, Lindros K, Salaspuro M. Metronidazole increases intracolonic but not peripheral blood acetaldehyde in chronic ethanol-treated rats. Alcohol Clin Exp Res 2000. [PMID: 10798595 DOI: 10.1111/j.1530-0277.2000.tb02026.x] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Abstract
BACKGROUND Metronidazole leads to the overgrowth of aerobic flora in the large intestine by reducing the number of anaerobes. According to our previous studies, this shift may increase intracolonic bacterial acetaldehyde formation if ethanol is present. Metronidazole is also reported to cause disulfiram-like effects after alcohol intake, although the mechanism behind this is obscure. Therefore, the aim was to study the effect of long-term metronidazole and alcohol treatment on intracolonic acetaldehyde levels and to explore the possible role of intestinal bacteria in the metronidazole related disulfiram-like reaction. METHODS A total of 32 rats were divided into four groups: controls (n = 6), controls receiving metronidazole (n = 6), ethanol group (n = 10), and ethanol and metronidazole group (n = 10). All rats were pair-fed with the liquid diet for 6-weeks, whereafter blood and intracolonic acetaldehyde levels and liver and colonic mucosal alcohol (ADH) and aldehyde dehydrogenase (ALDH) activities were analyzed. RESULTS The rats receiving ethanol and metronidazole had five times higher intracolonic acetaldehyde levels than the rats receiving only ethanol (431.4 +/- 163.5 microM vs. 84.7 +/- 14.4 microM,p = 0.0035). In contrast, blood acetaldehyde levels were equal. Cecal cultures showed the increased growth of Enterobacteriaceae in the metronidazole groups. Metronidazole had no inhibitory effect on hepatic or colonic mucosal ADH and ALDH activities. CONCLUSIONS The increase in intracolonic acetaldehyde after metronidazole treatment is probably due to the replacement of intestinal anaerobes by ADH-containing aerobes. Unlike disulfiram, metronidazole neither inhibits liver ALDH nor increases blood acetaldehyde. Thus, our findings suggested that the mechanism behind metronidazole related disulfiram-like reaction might be located in the gut flora instead of the liver.
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Affiliation(s)
- J Tillonen
- Research Unit of Alcohol Diseases, Helsinki University Central Hospital, Finland
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Homann N, Tillonen J, Salaspuro M. Microbially produced acetaldehyde from ethanol may increase the risk of colon cancer via folate deficiency. Int J Cancer 2000. [DOI: 10.1002/(sici)1097-0215(20000415)86:2%3c169::aid-ijc4%3e3.0.co;2-3] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/24/2023]
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Homann N, Tillonen J, Salaspuro M. Microbially produced acetaldehyde from ethanol may increase the risk of colon cancer via folate deficiency. Int J Cancer 2000; 86:169-73. [PMID: 10738242 DOI: 10.1002/(sici)1097-0215(20000415)86:2<169::aid-ijc4>3.0.co;2-3] [Citation(s) in RCA: 91] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
High alcohol and low folate intake are independent risk factors for colorectal cancer. Acetaldehyde has been postulated to be a factor responsible for ethanol-associated carcinogenesis. High levels of acetaldehyde accumulate in the large intestine via the microbial oxidation of alcohol. Acetaldehyde degrades folate in vitro. Thus, it is possible that high intracolonic acetaldehyde levels break down folate in the colon. Our aim was to test the effect of high alcohol and acetaldehyde concentrations in the gut on systemic and local intestinal folate levels in rats. Twenty rats received 3 g/kg of ethanol twice a day for 2 weeks with or without concomitant ciprofloxacin administration. Twenty control rats received saline with or without ciprofloxacin. All rats were fed a diet with normal folate content. Alcohol treatment led to very high intracolonic acetaldehyde levels (387 +/- 185 microM), which were markedly decreased by concomitant ciprofloxacin treatment (21 +/- 4 microM). Erythrocyte, serum and small intestinal folate levels were unaffected by alcohol treatment. Alcohol administration decreased significantly colonic mucosal folate levels by 48%, and this effect was prevented by ciprofloxacin. We conclude that alcohol administration for 2 weeks leads to local folate deficiency of colonic mucosa in rats, most probably via the degradation of folate by the high levels of acetaldehyde microbially produced from ethanol. Our findings offer a unique explanation for the increased risk of colonic cancer associated with alcohol intake and folate deficiency.
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Affiliation(s)
- N Homann
- Research Unit of Alcohol Diseases, Helsinki University Central Hospital, Helsinki, Finland
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Abstract
Abstract Alcohol generates a large caloric yield without supplying any essential nutrients; alcoholics may thus maintain body weight while suffering from malnutrition. In addition, diarrhea is a common complaint of both acute and chronic alcoholics. Here, we review the effects of alcohol on gastrointestinal morphology, function, its nervous system and motility. Acute morphological changes such as erosions, inflammatory cell infiltrations and microvascular changes are seen in the stomach and small intestine in acute alcoholics. In addition, atrophic gastritis, reduced villous height and decreased mucosal surface area of the small intestine have been described in chronic alcoholics. Acute administration of alcohol inhibits absorption of nutrients and fluids, and can stimulate secretion of water and electrolytes. Bacterial overgrowth in the proximal small intestine and decreased pancreatic secretions have been also described in chronic alcoholics. The well-known deleterious effects of alcohol on the central nervous system raise the possibility of similar acute and chronic effects of the enteric nervous system. Such effects could alter motility and transit. Indeed, esophageal dysmotility and delayed gastric emptying have been observed with high concentrations of alcohol in experimental studies and in chronic alcoholics. Small bowel motility and transit may be abnormal in both acute and chronic alcoholics, and colonic propulsive motility is increased after acute administration of alcohol. Any, or all, of these changes in gastrointestinal functions may contribute to diarrhea in acute binge drinkers and chronic alcoholics. Unfortunately, there is a lack of systematic studies of the pathophysiology of alcohol abuse, and an integrating concept of the diarrhea of alcoholics is still not possible.
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Affiliation(s)
- T Chiba
- Division of Gastroenterology, Mayo Clinic and Mayo Foundation, Rochester, Minnesota, USA
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