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Home , Drinking, Duodenum, Gastric mucosa, Gastrointestinal tract, Ileum, Nutcracker esophagus

’s Role in Disorders

CHRISTIANE BODE, PH.D., AND J. CHRISTIAN BODE, M.D.

When alcohol is consumed, the alcoholic beverages first pass through the various segments of the gastrointestinal (GI) tract. Accordingly, alcohol may interfere with the structure as well as the function of GI-tract segments. For example, alcohol can impair the function of the muscles separating the from the , thereby favoring the occurrence of heartburn. Alcohol-induced damage to the mucosal lining of the esophagus also increases the risk of esophageal . In the stomach, alcohol interferes with and with the activity of the muscles surrounding the stomach. Similarly, alcohol may impair the muscle movement in the small and large intestines, contributing to the frequently observed in alcoholics. Moreover, alcohol inhibits the absorption of nutrients in the and increases the transport of toxins across the intestinal walls, effects that may contribute to the development of alcohol-related damage to the and other organs. KEY WORDS: ethanol ; AODE (alcohol and other effects); ; esophagus; stomach; intestine; ; intestinal mucosa; gastric lesion; gastric acid; gastrointestinal function; gastrointestinal absorption; muscle; neoplastic disease; toxins; free radicals; etiology; literature review

mong the many systems intestinal (from lesions in the acute and chronic effects on GI-tract that mediate alcohol’s effects on stomach or small intestine) and diar- function and structure. A the body and its health, rhea. Third, functional changes and This article reviews some of these the gastrointestinal (GI) tract plays a mucosal damage in the disturb the findings, focusing primarily on insights particularly important part. Several of other nutrients as well as gained during the past 10 years. (For processes underlie this role. First, the their into the body, there- extensive reviews of the developments GI tract is the site of alcohol absorption by contributing to the malnutrition and into the bloodstream and, to a lesser weight loss frequently observed in CHRISTIANE BODE, PH.D., is professor extent, of alcohol breakdown and pro- and chief of the Section of Physiology alcoholics. Fourth, alcohol-induced duction. (For more information on of Nutrition (140), Hohenheim mucosal injuries—especially in the alcohol absorption, metabolism, and University, Stuttgart, Germany. upper small intestine—allow large production in the GI tract, see sidebar, pp. 82Ð83.) Second, the direct contact of molecules, such as endotoxin and other J. CHRISTIAN BODE, M.D., is professor alcoholic beverages with the mucosa1 bacterial toxins, to pass more easily of and chief of the Section that lines the upper GI tract can induce into the or . These toxic of , and numerous metabolic and functional substances can have deleterious effects in the Department of changes. These alterations may lead to on the liver and other organs. Internal Medicine, Robert-Bosch- Krankenhaus, Stuttgart, Germany. marked mucosal damage, which can Over the past three decades, re- result in a broad spectrum of acute and searchers have made major progress 1For a definition of this and other technical terms used chronic diseases, such as acute gastro- toward understanding alcohol’s many in this article, see the central glossary, pp. 93Ð96.

76 ALCOHOL HEALTH & RESEARCH WORLD Gastrointestinal Tract Disorders

in this field up to the early 1980’s, see (figure 2). As the food mass moves Beazell and Ivy 1940; Bode 1980). through the small intestine, digestive secreted by the intestinal Oral cavity THE GI TRACT—AN OVERVIEW cells complete the chemical degrad- ation of nutrients into simple mole- Parotid The GI tract’s functions are to physi- cules that can be absorbed through the cally and chemically break down intestinal wall into the bloodstream. ingested food, allow the absorption of What finally remains in the intestine nutrients into the bloodstream, and are primarily indigestible waste prod- Teeth excrete the waste products generated. ucts. These products progress into the The GI tract can be viewed as one , where the waste is Salivary continuous tube extending from the compacted and prepared for excretion mouth to the (figure 1), which is through the anus. Like the small in- Esophagus subdivided into different segments testine, the large intestine can be with specific functions. divided into three segments: the ce- Stomach In the mouth, or oral cavity, the teeth cum; the colon, which constitutes mechanically grind the food into small about 80 percent of the large intes- pieces. Moreover, excreted by tine; and the . The following the salivary glands initiates the food’s sections review alcohol’s effect on the chemical degradation. From the oral different regions of the GI tract. cavity, the food passes through the (i.e., pharynx) into the esophagus. The THE ORAL CAVITY coordinated contraction and relaxation AND THE ESOPHAGUS of the muscles surrounding the esopha- gus propels the food into the stomach. The oral cavity, pharynx, esophagus, In the stomach, the chemical degra- and stomach are exposed to alcohol dation of the food continues with the immediately after its . Thus, help of gastric acid and various diges- alcoholic beverages are almost undi- Large intestine tive enzymes. Excessive gastric acid luted when they come in contact with (colon) production can irritate the mucosa, the mucosa of these structures. It is Rectum causing gastric pain, and result in the therefore not surprising that mucosal development of gastric ulcers. Two injuries (i.e., lesions) occur quite bands of muscle fibers (i.e., sphinc- frequently in people who large Figure 1 Schematic representation of ters) close off the stomach to the eso- amounts of alcohol.2 the human gastrointestinal tract. The phagus and the intestine. Weakness of Chronic alcohol abuse damages the small intestine comprises the duo- denum, the ileum, and the jejunum. the separating the stomach salivary glands and thus interferes from the esophagus allows the stom- with saliva secretion. In alcoholics this ach content to flow back into the eso- damage commonly manifests itself as poor nutrition or reflect alcohol’s phagus. This process, which is called an enlargement (i.e., hypertrophy) of direct effect on the mucosa. Finally, gastroesophageal reflux, can lead to the , although the mecha- chronic alcohol abuse increases the heartburn as well as (i.e., nisms leading to this condition are incidence of decay, gum disease, reflux ) and even to the unknown. Moreover, alcoholics may and loss of teeth (Kranzler et al. 1990). development of ulcers in the lower suffer from inflammation of the tongue Alcohol consumption can affect the part of the esophagus. (i.e., ) and the mouth (i.e., esophagus in several ways. For exam- From the stomach, the food enters stomatitis). It is unclear, however, ple, alcohol distinctly impairs esophageal the small intestine, which is divided whether these changes result from , and even a single drinking into three segments: the duodenum, episode (i.e., acute alcohol consump- the jejunum, and the ileum. Like the 2The alcohol amount necessary to cause mucosal tion) significantly weakens the lower esophagus and stomach, the intestine injury varies significantly among individual drinkers esophageal sphincter. As a result, is surrounded by layers of muscles, and depends, for example, on whether alcohol consumption occurs on an empty stomach or is gastroesophageal reflux may occur, the rhythmic movements of which accompanied by a meal. Thus, no clear threshold and the esophagus’ ability to clear the help mix the food mass and push it exists above which alcohol exerts its adverse effects. refluxed gastric acid may be reduced. along the GI tract. The intestine’s However, the risk for adverse effects such as Both of these factors promote the inner mucosal surface is covered with damage generally increases following the consump- occurrence of heartburn. Moreover, tion of more than 2 ounces of alcohol, which corre- small projections called villi, which sponds to approximately four standard (i.e., some alcoholics exhibit an abnormali- increase the intestinal surface area “heavy” or “excessive” drinking). ty of esophageal motility known as a

VOL. 21, NO. 1, 1997 77 functioning in several ways. For ex- ample, alcohol—even in relatively Small Intestine small doses—can alter gastric acid secretion, induce acute gastric mucos- al injury, and interfere with gastric Intestinal wall and intestinal motility. Gastric Acid Secretion Analyses in several species found that acute alcohol administration by mouth or by direct infusion into the Villi stomach (i.e., intragastrically) or the blood (i.e., intravenously) can affect gastric acid secretion (Chari et al. 1993). The secretory response of the stomach Intestinal muscles varies considerably, however, depend- ing on the species studied and the alco- hol concentrations used. In healthy, nonalcoholic , intravenous alco- hol administration of 0.3 to 0.5 grams per kilogram (g/kg) body weight or Villi intragastric infusion of alcohol with concentrations of up to 5 percent Submucosa stimulate gastric acid secretion, whereas Intestinal muscles intragastric infusion of higher concen- trations has either no effect or a mildly inhibitory one (Chari et al. 1993). Accord- ingly, alcoholic beverages with a low Figure 2 Schematic illustration of the villi lining the small intestine. These villi serve alcohol content (e.g., beer and wine) to increase the internal surface area of the intestine and thus enhance the strongly increase gastric acid secretion absorption of nutrients. and the release of , the gastric that induces acid secretion. In “,” which mim- um) that lead to abnormal acid produc- contrast, beverages with a higher alco- ics symptoms of coronary dis- tion. A diagnosis of Barrett’s esopha- hol content (e.g., whisky and cognac) ease (Bode and Bode 1992).3 gus is an important indicator of an stimulate neither gastric acid secretion Chronic alcohol abuse leads to an increased risk of , nor gastrin release. increased incidence not only of heart- because in some patients the altered The mechanisms underlying the but also of esophageal mucosal epithelial cells become cancerous. effects of alcoholic beverages on gas- inflammation (i.e., esophagitis) and Another condition affecting alco- tric acid secretion have not yet been other injuries that may induce mucosal holics is Mallory-Weiss syndrome, identified. Alcohol may interact direct- defects (i.e., esophagitis with or with- which is characterized by massive ly with the gastric mucosa (i.e., topical out erosions). In addition, alcoholics bleeding caused by tears in the mucosa stimulation); or, it may act through a at the junction of the esophagus and the more general mechanism affecting the make up a significant proportion of stomach. The syndrome accounts for 5 release of and the regulation patients with Barrett’s esophagus. This to 15 percent of all cases of bleeding in of functions involved in acid condition, which occurs in 10 to 20 the upper GI tract. In 20 to 50 percent secretion (Chari et al. 1993). More- percent of patients with symptomatic of all patients, the disorder is caused by over, researchers have shown that after gastroesophageal reflux disease increased gastric pressure resulting beer consumption, gastric acid secre- (Wienbeck and Berges 1985), is char- from repeated retching and tion also is stimulated by by-products acterized by changes in the cell layer following excessive acute alcohol of the fermentation process other than lining the esophagus (i.e., the epitheli- consumption (Bode and Bode 1992). alcohol (Chari et al. 1993). Chronic alcohol abuse also affects 3The term “nutcracker esophagus” refers to the THE STOMACH gastric function. Thus, alcoholics have painful, spasmodic contractions of the esophagus that a significantly higher incidence of the patients who suffer the disorder describe as feeling as though the esophagus were being squeezed by a Both acute and chronic alcohol con- shrinkage (i.e., atrophy) of the gastric nutcracker. sumption can interfere with stomach mucosa and decreased gastric secretory

78 ALCOHOL HEALTH & RESEARCH WORLD Gastrointestinal Tract Disorders

capacity than do healthy control sub- inflammatory reactions—also might Therefore, alcohol’s effects on nutri- jects of comparable age and sex (Bode contribute to the development of alco- ent absorption may vary throughout and Bode 1992). The resulting decrease hol-induced mucosal injury (Bode and the small intestine, and tissue-culture in acid production reduces the stomach’s Bode 1992). experiments with constant alcohol ability to destroy the that enter concentrations may not always reflect with food and thus favors the coloniza- Gastric and Intestinal Motility the conditions in the body. tion of the upper small intestine with Studies in laboratory have Alcohol can interfere with the activity potentially harmful . demonstrated that acute alcohol con- of the muscles surrounding the stom- Abstinence, however, can at least partly sumption can inhibit the absorption of ach and the small intestine and thus reverse these changes. , sodium, glucose, and certain alter the transit time of food through amino acids and fatty acids in the small these organs. In humans, alcohol’s Acute Gastric Mucosal Injury intestine (Bode 1980; Mezey 1985). effect on gastric motility depends on Several studies in humans have ana- Researchers have known for more the alcohol concentration and accom- lyzed the effects of chronic alcohol than 100 years that alcohol abuse can panying meals. In general, beverages consumption with the following results: cause mucosal inflammation (for a with high alcohol concentrations (i.e., review, see Beazell and Ivy 1940). In above 15 percent) appear to inhibit ¥ Both in healthy people and in alco- addition, alcohol abuse is an important gastric motility and thus delay the holics, chronic alcohol consump- cause of bleeding (i.e., hemorrhagic) emptying of the stomach. As a result tion led to markedly reduced water gastric lesions that can destroy parts of of the increased gastric transit time, and sodium absorption in the je- the mucosa. Although low or moder- bacterial degradation of the food may junum and ileum (Bode and Bode ate alcohol doses do not cause such begin; the resulting gases may lead to 1992; Pfeiffer et al. 1992). damage in healthy subjects, even a feelings of fullness and abdominal ¥ Alcoholics exhibited a reduced single episode of heavy drinking can discomfort. absorption of , pro- induce mucosal inflammation and In the small intestine, alcohol de- teins, and fats in the duodenum, but hemorrhagic lesions. Nonsteroidal creases the muscle movements that not in the jejunum (Pfeiffer et al. anti-inflammatory (e.g., aspirin help retain the food for further diges- 1992) (see table). and ibuprofen) may aggravate the tion (i.e., the impeding wave motility). development of alcohol-induced acute In contrast, alcohol does not affect the ¥ Alcoholics without confounding gastric lesions. movements that propel food through disorders, such as or How alcohol damages the gastric the intestine (i.e., the propulsive wave impaired pancreatic function, ex- mucosa has not yet been determined. motility) in either alcoholics or hibited of fat and Studies in both animals and humans healthy subjects. These effects may (see table). have found that alcohol concentrations contribute to the increased sensitivity of 10 percent and more disrupt the to foods with a high sugar content ¥ Alcoholics showed malabsorption gastric mucosal barrier and increase the (e.g., candy and sweetened juices), of xylose, a sugar frequently used to mucosa’s permeability (Bode and Bode shortened transit time, and diarrhea study the function of the digestive 1992). The changes induced by short- frequently observed in alcoholics tract. The proportion of alcoholics term exposure to alcoholic beverages (Bode and Bode 1992). who experienced this malabsorption are rapidly reversible. Prolonged alco- ranged from 18 to 76 percent in hol exposure, however, disturbs the various studies (see table). This THE SMALL INTESTINE microcirculation and leads to progres- variation may reflect differences in the nutritional status, the mean sive structural mucosal damage. As described previously, the small daily alcohol intake, or the presence Several studies have suggested that intestine is the organ in which most of alcohol-related the decreased formation of hormone- nutrients are absorbed into the blood- among the studies’ subjects. like substances called stream. Studies in humans and animals might play a role in alcohol-induced as well as in tissue culture have ¥ After chronic alcohol consump- mucosal injury (Bode et al. 1996). demonstrated that alcohol can inter- tion, the absorption of thiamine Prostaglandins protect the gastric fere with the absorption of several ( B1), folic acid, and vita- mucosa from damage by agents such nutrients. Alcohol itself, however, also min B12 was either unchanged or as aspirin that break the gastric mu- is rapidly absorbed in the small intes- decreased (Mezey 1985; Bode and cosal barrier without inhibiting acid tine. In the human jejunum, for exam- Bode 1992). Folic acid deficiency, secretion. Other studies have indicated ple, the alcohol concentration can drop which frequently occurs in alco- that an alcohol-dependent increase in from 10 percent to just 1.45 percent holics, can result in various disor- the production of leukotrienes—com- over a distance of only 30 centimeters ders of the GI tract as well as in pounds produced by the immune sys- (12 inches, about a quarter of the total . However, this deficiency tem that cause allergic and length of the jejunum) (Bode 1980). is more likely to result from a diet

VOL. 21, NO. 1, 1997 79 molecules that normally cannot cross Summary of Studies on Malabsorption of Carbohydrates, Fat, and Protein in the intestinal wall intact (e.g., hemo- Alcoholics Without Cirrhosis or Obvious Pancreatic Insufficiency globin) to travel between the gut and the bloodstream (Bode 1980). A. Frequency of Abnormal Absorption Among Alcoholics Similarly, was % Subjects enhanced in nonintoxicated alcoholics Nutrient Studied Number of Studies With Abnormal Absorption (Bode and Bode 1992). The enhanced permeability induced by acute and D-Xylose 5 18Ð76 Fata 235Ð56 chronic alcohol ingestion could allow Proteinb 152toxic compounds, such as endotoxin and other bacterial toxins, to enter the B. Mean Decrease in Absorption Compared With Nonalcoholic Controlsc bloodstream and subsequently reach the liver. The presence of endotoxin in Nutrient Studied % Decrease the blood has been documented in Carbohydrates 45 patients with early stages of alcohol- Lipids 40 related liver damage and transiently, Protein 81 after excessive alcohol consumption, aFat absorption was determined by measuring fat excretion in the . in people with no evidence of liver bProtein absorption was determined by measuring nitrogen excretion in the feces. c The study measured the absorption of a nutrient in the duodenum. disease (Fukui et al. 1991). Endotoxins SOURCES: A: Bode and Bode 1992; B: Pfeiffer et al. 1992. can induce the release of cytokines (e.g., tumor necrosis factor) and inter- containing insufficient folic acid upper region of the duodenum. Even leukins from certain white blood cells than from poor folic acid absorp- in healthy people, a single episode of and from Kupffer cells in the liver. tion (Halstedt and Keen 1990). heavy drinking can result in duodenal These cytokines, in turn, may play a erosions and bleeding. Animal studies In summary, alcohol inhibits ab- role in the development of alcohol- have indicated that several mecha- sorption of a variety of nutrients. The related damage to the liver and other nisms contribute to the development importance of these absorption disor- organs (Khoruts et al. 1991; Schäfer et of these mucosal injuries (Ray et al. ders in the development of nutritional al. 1995) (figure 3). (For more infor- 1989) (for a review, see Bode and disturbances in alcoholics, however, is Bode 1992). First, alcohol can directly mation on the association of endotoxin unclear. In alcoholics with limited disturb the integrity of the mucosal and cytokines with liver damage, see pancreatic function or advanced liver . Second, alcohol induces the article by Maher, pp. 5Ð12.) disease, digestion of nutrients may be the release of noxious signaling mole- a more significant problem than im- cules, such as cytokines, , Intestinal Bacterial Microflora paired absorption disorders. and leukotrienes. These substances Certain bacteria that are a major Intestinal Enzymes can damage the small blood vessels, source of endotoxin may overgrow or , in the intestinal mucosa the normal bacterial flora in the je- Alcohol can interfere with the activity and induce blood clotting. Such clot- of many enzymes that are essential for junum of alcoholics (Bode and Bode ting may lead to an impaired transport 1992). Together with the altered per- intestinal functioning. One of these of fluids across the capillaries; fluid meability of the gut induced by alco- enzymes is lactase, which breaks down accumulation under the tips of the the sugar ; lactase defi- villi; and, eventually, destruction of hol, this process may allow an increased ciency results in . the tips of the villi. The resulting escape of endotoxin from the intestine Alcohol also interferes with some of lesions allow large molecules, such as into the blood vessels leading to the the enzymes involved in transporting endotoxins and other bacterial toxins, liver, thus increasing the liver’s expo- nutrients from the intestine into the to enter the bloodstream and the lymph. sure to these toxins and, consequent- bloodstream and inhibits important Third, as in the stomach, decreased ly, the risk of (figure 3). enzymes that participate in the metab- synthesis may contribute The hypothesis that bacterial over- olism of drugs and other foreign or- to changes in the capillaries and to the growth may be responsible for the ganic substances in the gut (for development of mucosal injury. development of alcohol-related organ reviews, see Mezey 1985; Bode 1980). damage has been supported by the Intestinal Permeability observation that sterilization of the Intestinal Mucosal Injury In animal studies, alcohol administra- intestine prevents alcohol-induced Excessive alcohol consumption fre- tion increased the permeability of the liver injury in animal experiments quently causes mucosal damage in the intestinal mucosa, allowing large (Adachi et al. 1995).

80 ALCOHOL HEALTH & RESEARCH WORLD Gastrointestinal Tract Disorders

The Large Intestine Until recently, alcohol’s effects on Small intestine the large intestine had received only minor attention. Studies in found that acute alcohol administra- Disturbed motility tion depressed the colon’s impeding Alcohol Bacterial overgrowth Disturbed absorption motility but enhanced its propulsive motility (Mezey 1985). In healthy Decreased Increased formation of prostaglandin synthesis endotoxins and other toxins humans, alcohol administration also significantly reduced the frequency Mucosal lesions and and strength (i.e., amplitude) of the increased permeability muscle contractions in a segment of the rectum (Mezey 1985). These effects could reduce the transit time— and thus the compaction—of the Increased release of cytokines Increased uptake of endotoxins intestinal contents and thereby con- and other mediators from certain and other toxins into the tribute to the diarrhea frequently white blood cells and Kupffer cells bloodstream and lymph observed in alcoholics.

Damage to the blood vessels Liver cell injury and MEDICAL CONSEQUENCES and disturbed microcirculation other organ injury

Alcohol-induced digestive disorders and Figure 3 Schematic presentation of the possible causes and consequences of mucosal damage in the GI tract can mucosal injury, increased permeability of the intestinal mucosa to macro- cause a variety of medical problems. molecules, and bacterial overgrowth in the small intestine of chronic These include a loss of appetite and a alcohol abusers. Thickness of arrows indicates strength of association multitude of abdominal complaints, such between phenomena. (For definitions, see glossary, pp. 93Ð96.) as , vomiting, feelings of fullness, , and . Diseases of the liver and may contribute Epidemiological studies also strongly heavy beer consumption, whereas to and aggravate these complaints. Thus, indicate that chronic alcohol consump- distilled spirits appear to have no effect. about 50 percent of alcoholics with an tion, especially of distilled spirits, initial stage of liver damage (i.e., fatty markedly contributes to the develop- SUMMARY liver) and 30 to 80 percent of patients ment of esophageal cancer (Bode 1980; with an advanced stage of alcohol-in- Wienbeck and Berges 1985). Thus, Alcohol consumption can interfere with duced liver injury (i.e., alcoholic hepati- after adjusting for habits, the function of all parts of the gastroin- tis) report some symptoms of abdominal heavy beer drinkers have a 10 times testinal tract. Acute alcohol ingestion discomfort (Bode and Bode 1992). These greater risk and heavy whisky drinkers induces changes in the motility of the abdominal complaints can lead to re- a 25 times greater risk of developing esophagus and stomach that favor gas- duced food intake, thereby causing the esophageal cancer, compared with troesophageal reflux and, probably, the weight loss and malnutrition commonly people who consume less than 30 g of development of reflux esophagitis. observed in alcoholics. alcohol (i.e., about 2 standard drinks) Alcohol abuse may lead to damage of In addition to causing abdominal daily. The differences between beer and complaints, alcohol plays a role in the the gastric mucosa, including hemor- whisky drinkers remain even if they development of of the GI tract. rhagic lesions. Beverages with a low It is likely, however, that alcohol does consume the same amount of pure alcohol content stimulate gastric acid not cause GI-tract cancers by itself but alcohol. In drinkers who also smoke 20 secretion, whereas beverages with a acts in concert with other cancer-induc- cigarettes or more daily, the risk of high alcohol content do not. ing agents (i.e., as a cocarcinogen) (for esophageal cancer increases about 45- In the small intestine, alcohol in- reviews, see Seitz and Simanowski fold (Seitz and Simanowski 1988). hibits the absorption of numerous 1988; Garro and Lieber 1990). Alcohol Heavy alcohol consumption also is nutrients. The importance of these abuse, like smoking, is associated with associated with the development of absorption disorders for the develop- the development of cancers of the tongue, tumors in the colon and rectum. How- ment of nutritional disturbances in (i.e., the organ of voice), and ever, the relative risk of cancer is higher alcoholics, however, is unclear. In pharynx; both alcohol consumption and for rectal cancer than for colon cancer. alcoholics with other digestive disor- smoking independently increase the Moreover, the increased risk of rectal ders (e.g., advanced liver disease or risk for these tumors (Bode 1980). cancer appears to result mainly from impaired pancreatic function), impaired

VOL. 21, NO. 1, 1997 81 digestion likely is more significant. blood cells and Kupffer cells. These alcohol consumption and the develop- Acute alcohol consumption also dam- cytokines, in turn, exert multiple inju- ment of . ages the mucosa in the upper region of rious effects on membranes and the the small intestine and may even lead microcirculation. The result is possi- REFERENCES to the destruction of the tips of the ble cell damage and even cell death in villi. The findings of human and ani- the liver and other organs. ADACHI, Y.; MOORE, L.E.; BRADFORD, B.U.; GAO, W.; mal studies suggest that these mucosal AND THURMAN, R.G. prevent liver injury in Motility disorders, maldigestion, rats following long-term exposure to ethanol. Gastroen- defects favor the following sequence and malabsorption in alcoholics can terology 108(1):218Ð224, 1995. of events: Alcohol-induced mucosal result in digestive problems, such as BEAZELL, J.M., AND IVY, A.C. The influence of damage in the small intestine increas- alcohol on the digestive tract. Quarterly Journal of es the mucosa’s permeability, facili- anorexia, nausea, and abdominal pain. Studies on Alcohol 1:45Ð73, 1940. tating the transport of large molecules, Alcohol abuse also promotes the de- BODE, J.C. Alcohol and the gastrointestinal tract. Advances such as bacterial endotoxin and/or velopment of cancers of the tongue, in Internal Medicine and Pediatrics 45:1Ð75, 1980. other toxins, into the blood or lymph. larynx, pharynx, and esophagus. Finally, BODE, J.C., AND BODE, C. Alcohol malnutrition and the gastrointestinal tract. In: Watson, R.R., and Watzl, This results in the release of potential- the results of recent epidemiological B., eds. Nutrition and Alcohol. Boca Raton, FL: CRC ly toxic cytokines by certain white studies indicate an association between Press, 1992. pp. 403Ð428.

ALCOHOL ABSORPTION, METABOLISM, AND PRODUCTION IN THE GASTROINTESTINAL TRACT

The excessive consumption of alcoholic beverages interferes with NAD+ NAD+ the normal function and structure of the gastrointestinal (GI) tract. The relationship between alcohol Alcohol Acetate and the GI tract is a two-way street, however, and the GI tract plays a ADH ALDH role in the absorption, metabolism, The pathway of alcohol metabolism. Once in the liver, alcohol is converted into and production of alcohol. acetaldehyde, and the acetaldehyde is converted into acetate. The alco- hol dehydrogenase (ADH) assists the chemical reaction in (i.e., catalyzes) the Absorption first half of alcohol metabolism, and the enzyme aldehyde dehydrogenase (ALDH) catalyzes the second half. NAD+ is a coenzyme that plays an accessory role in Throughout the GI tract, alcohol enzyme catalysis. absorption into the bloodstream occurs through a process called temperature, the presence of certain metabolism) occurs not only in the simple diffusion. The rate at which in the body, and the liver, as with most other nutrients, this process occurs depends on types of spices in the food (Bode but also in the stomach and the small several factors, primarily the dif- 1980). For example, alcohol absorp- intestine (Mezey 1985). The enzyme ference between the alcohol con- tion occurs more slowly after the (ADH), centrations in the GI organs and in ingestion of beer than after the inges- which mediates the first step of alco- the adjacent small blood vessels, tion of an equal amount of alcohol in hol degradation (see figure), is pre- the regional blood flow, and the the form of whisky or brandy. Most sent in the mucosa of the stomach permeability of the GI tract lining of these factors probably inhibit or and the small intestine. In fact, sever- (i.e., the mucosa) in question. For enhance alcohol absorption by affect- al ADH variants (i.e., isoenzymes) example, the higher the concentra- ing the movement of the stomach with different kinetic properties exist tion of the ingested alcohol, the muscles (i.e., gastric motility) and in the mucosa of the GI tract; these more alcohol the mucosa absorbs. small intestinal blood flow. isoenzymes permit alcohol metab- In contrast, the presence of food in olism over a wide range of concen- trations. The ADH isoenzyme pattern the stomach decreases the rate of Metabolism alcohol absorption. Other factors in the GI tract differs from that found that may affect alcohol absorption More than two decades ago, in the liver. include the type of alcoholic bever- research-ers found that the initial Some researchers have postulated age, the drinker’s gender and body breakdown of alcohol (i.e., first-pass that first-pass metabolism in humans

82 ALCOHOL HEALTH & RESEARCH WORLD Gastrointestinal Tract Disorders

BODE, C.; MAUTE, G.; AND BODE, J.C. Prostaglandin KHORUTS, A.; STAHNKE, L.; MCCLAIN, C.J.; LOGAN, G.; RAY, M.; DINDA, P.K.; AND BECK, I.T. Mechanism of α E2 and prostaglandin F2 biosynthesis in human AND ALLEN, J.I. Circulating tumor necrosis factor, ethanol-induced jejunal microvascular and morpho- gastric mucosa: Effect of chronic alcohol misuse. Gut interleukin-1 and interleukin-6 concentrations in chronic logic changes in the . Gastroenterology 96(2):345Ð 39(3):348Ð352, 1996. alcoholic patients. Hepatology 13(2):267Ð276, 1991. 354, 1989. CHARI, S.; TEYSSEN, S.; AND SINGER, M.V. Alcohol and KRANZLER, H.R.; BABOR, T.F.; GOLDSTEIN, L.; AND gastric acid secretion in humans. Gut 34(6):843Ð847, 1993. SCHÄFER, C.; SCHIPS, I.; LANDIG, J.; BODE, J.C.; AND GOLD, J. Dental and alcohol-related indica- BODE, C. Tumor-necrosis-factor and interleukin-6 FUKUI, H.; BRAUNER, B.; BODE, J.C.; AND BODE, C. tors in an outpatient clinic sample. 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Absorption of a nutrient solution in chronic micronutrient metabolism and deficiencies. European alcoholics without nutrient deficiencies and liver lesions in the alcoholic. In: Seitz, H.K., and Kommerell, Journal of Gastroenterology and Hepatology cirrhosis. Scandinavian Journal of Gastroenterology B., eds. Alcohol-Related Diseases in Gastroenterology. 2:399Ð405, 1990. 27(12):1023Ð1030, 1992. New York: Springer-Verlag, 1985. pp. 361Ð375. occurs primarily in the stomach cosa or the colonic bacteria. nutrients and thus an increase in (Gentry et al. 1994) and correlates Alternatively, the acetaldehyde can be alcohol production. significantly with gastric ADH activi- absorbed into the bloodstream and —Christiane Bode and ty. However, other investigators have transported to the liver for further J. Christian Bode questioned the stomach’s role in first- degradation. Because ALDH activity pass alcohol metabolism (Levitt in the colonic mucosa is low, 1994). The proportion of alcohol acetaldehyde accumulates in the colon References eliminated by gastric first-pass and may even exceed the concentra- BODE, J.C. Alcohol and the gastrointestinal metabolism also remains controver- tion found in the liver (Salaspuro tract. Advances in Internal Medicine and sial (Sato and Kitamura 1996); com- 1996). These high acetaldehyde levels Pediatrics 45:1Ð75, 1980. pared with hepatic alcohol degradation, in the colon may contribute to the gastric first-pass metabolism seems to development of alcohol-induced diar- BODE, J.C., AND BODE, C. Alcohol malnutri- tion and the gastrointestinal tract. In: be quantitatively important only at rhea and—after absorption into the Watson, R.R., and Watzl, B., eds. Nutrition low alcohol concentrations. In wom- blood—liver injury. and Alcohol. Boca Raton, FL: CRC Press, en, first-pass metabolism is less effi- 1992. pp. 403Ð428. cient than in men. Consequently, Production women achieve higher blood alcohol GENTRY, R.T.; BARAONA, E.; AND LIEBER, concentrations than men with the In many animal species, including C.S. Agonist: Gastric first pass metabolism same low gastric alcohol concentra- humans, alcohol is not only degraded of alcohol. Journal of Laboratory and tion because more alcohol passes but also produced in the GI tract. This Clinical Medicine 123:21Ð26, 1994. from a woman’s stomach into the alcohol production is a by-product of LEVITT, M.D. Antagonist: The case against small intestine, where it is absorbed the bacterial breakdown of ingested first-pass metabolism of ethanol in the into the bloodstream. Furthermore, carbohydrates. Alcohol also is formed stomach. Journal of Laboratory and gastric first-pass metabolism decreas- in the human stomach, and in patients Clinical Medicine 123:28Ð31, 1994. es with long-term alcohol consump- with disturbed gastric emptying, the MEZEY, E. Effect of ethanol on intestinal tion, partly because of diminished concentrations can be as high as 0.35 morphology, metabolism, and function. In: ADH activity (Gentry et al. 1994). percent (i.e., about four times as high Seitz, H.K., and Kommerell, B., eds. A recent study suggests that alcohol as the blood alcohol levels for intoxi- Alcohol Related Diseases in Gastroenter- also can be metabolized by bacteria cation) (Bode and Bode 1992). Two ology. Berlin: Springer-Verlag, 1985. pp. residing in the large intestine (Sala- factors favor gastric alcohol production 342Ð360. spuro 1996). In this pathway, alcohol in these patients. First, they produce is transported to the colon via the less gastric acid and thus allow the SALASPURO, M. Bacteriocolonic pathway bloodstream and converted to acetalde- proliferation of bacteria in the stom- for ethanol oxidation: Characteristics and hyde by bacterial ADH (see figure). ach. Second, the patients retain their implications. Annals of Medicine 28:195Ð 200, 1996. The acetaldehyde subsequently can be food in the stomach for an extended metabolized further by the enzyme period of time. Both factors lead to an SATO, N., AND KITAMURA, T. First-pass aldehyde dehydrogenase (ALDH), increase in the bacterial degradation of metabolism of ethanol: An overview. which is localized in the colonic mu- Gastroenterology 111:1143Ð1150, 1996.

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