Best Practice & Research Clinical Gastroenterology

Vol. 17, No. 4, pp. 575 –592, 2003

doi:10.1053/ybega.2003.392, www.elsevier.com/locate/jnlabr/ybega

Effect of alcohol consumption on the gut

Christiane Bode* PhD

Professor and Chair

Division of Physiology of Nutrition, Department of Biological Chemistry and Nutrition, Hohenheim University,
Garbenstr. 28, D-70599 Stuttgart, Germany

J. Christian Bode MD

Em. Chief
Department of Internal Medicine, Section Gastroenterology and Hepatology,
Robert–Bosch Hospital, stuttgart, Germany

APL Professor of Medicine

University of Tübingen, Honoldweg 18, D-70193 Stuttgart, Germany

Consumption of large quantities of alcoholic beverages leads to disturbances in the intestinal

absorption of nutrients including several vitamins. The inhibition of the absorption of sodium and
water caused by alcohol contributes to the tendency in alcoholics to develop diarrhoea. Excessive
alcohol consumption (even a single episode) can result in duodenal erosions and bleeding and
mucosal injury in the upper jejunum. An increased prevalence for bacterial overgrowth in the
small intestine may contribute to functional and/or morphological abnormalities of this part of the
gut and also to non-specific abdominal complaints in alcoholics. The mucosal damage caused by
alcohol increases the permeability of the gut to macromolecules. This facilitates the translocation
of endotoxin and other bacterial toxins from the gut lumen to the portal blood, thereby
increasing the liver’s exposure to these toxins and, consequently, the risk of liver injury. The
results of recent experimental studies support the assumption that alcohol significantly
modulates the mucosal immune system of the gut.

Key words: alcohol; alcoholic liver disease; alcohol metabolism; bacterial overgrowth (small
intestine); cytokines; endotoxin; ethanol; gut-associated immune system; intestinal absorption;
intestinal mucosa; intestinal permeability; mucosal injury.

Alcohol has been known for a long time to interfere with the absorption of several
nutrients, including vitamins, and to lead to mucosal damage of the upper small
intestine, thereby contributing to the qualitative and quantitative malnutrition
frequently observed in alcoholics.1,2 The findings of more recent studies have
suggested that the gut flora plays an important role in the initiation and progression of
alcoholic liver injury and in the pathogenesis of other alcohol-related diseases.3,4
Furthermore, there is increasing evidence that the effects of alcohol consumption on

* Corresponding author. Tel.: þ49-711-459-2295; Fax: þ49-711-459-3947.

E-mail address: bodech@uni-hohenheim.de (C. Bode).

1521-6918/03/$ - see front matter Q 2003 Elsevier Science Ltd. All rights reserved.
576 C. Bode and J. C. Bode

the mucosal immune system of the gut contribute to the immune deficiency associated
with chronic alcohol abuse, which results in an increased incidence of infections.5
The effects of acute and chronic ingestion of alcohol vary considerably and depend on
the concentration and dose of the alcoholic beverage together with various other
factors, such as nutritional status, gender and ethnicity, rendering generally accepted
statements difficult. This difficulty is intensified by the attempt to extrapolate from
findings obtained in animal experiments or from in vitro studies to the effect of alcohol
on humans. Furthermore, because of the high regenerative capacity of the gut mucosa,
injurious effects of alcohol may easily be missed after a few days of abstinence. In this
review the effects of alcohol ingestion on the gut that have been included are those that
have clearly been shown to occur, or at least are likely to occur, in humans. Most effects
reported in this chapter are only to be expected in subjects drinking alcoholic beverages
in amounts generally accepted to be associated with health risks (mean daily alcohol
intake in males . 40 g and in females . 20 g.6 The plethora of studies using high
concentrations of ethanol p (. 60% v/v) or pure ethanol as a model of acute injury will
not be discussed.
In this chapter the cited literature focuses primarily on papers published within the
past two decades. For the older literature, the reader is referred to earlier reviews.2,7

ABSORPTION AND METABOLISM OF ALCOHOL IN THE GUT

Absorption

Ethanol is absorbed through the mucosa of the entire gastrointestinal (GI) tract by
simple diffusion. The rate of diffusion of ethanol across the intestinal mucosa is
determined by the concentration gradient between the intestinal lumen and the sub-
epithelial capillaries, regional blood flow and the permeability of the mucosa in
question.7 The rate of ethanol absorption is decreased by delayed gastric emptying and
by the presence of food in the stomach. These findings had already been described
about 50 years ago.7 One explanation for these findings is that of first-pass metabolism
of alcohol in the stomach, which has recently been demonstrated.8 First-pass
metabolism of ethanol is observed only following small doses of ethanol. Its quantitative
importance for the overall metabolism of alcohol, as reported by different authors,
varies from 10% or less9 up to 40 –70%.8 Whether first-pass metabolism of alcohol
occurs mainly or exclusively in the stomach or not is still a matter of debate.8 – 10 High
concentrations of ethanol, similar to those of the ingested alcoholic beverages, are
reached only in the upper small intestine, i.e. the duodenum and jejunum.2,7 Even after
the oral administration of a large single dose of alcohol, the concentration of ethanol
reached in the ileum is not significantly different to the levels in the blood, suggesting
that ethanol enters the ileum from the vascular space.2 The damaging effects of alcoholic
beverages on the mucosa as a result of high luminal ethanol concentrations are
therefore to be expected predominantly in the duodenum and upper jejunum.

Alcohol metabolism

Alcohol dehydrogenase (ADH), the main enzyme involved in the first step of ethanol
oxidation, has been found in all parts of the gut.11,12 Ethanol metabolism has been
p
Alcohol and ethanol are used interchangeably.
 Effect of alcohol consumption on the gut 577

Portal vein :
Mucosal capillaries : Acetaldehyde ↑
Ethanol (up to 3%) → Liver injury (?)
Blood vessels

Ethanol (up to 3%)

Mucosa
Acetaldehyde↑

Acetate

Epithelial damage (?)

Ethanol (up to 3%) Carcinogenic action (?)
Luminal side
(Bacteria)

Acetaldehyde ↑ Acetate

Figure 1. Metabolism of alcohol by bacteria in the large bowel and the mucosa of the colon (bacteriocolonic
metabolism of alcohol). Note: Due to a higher capacity to convert ethanol to acetaldehyde than to further
oxidize acetaldehyde to acetate, the toxic acetaldehyde accumulates. Reproduced, with permission, from
Salaspurno (2001).4

shown to occur in the small intestine2,7 but seems to be in small quantities compared
with that documented in the stomach.9
From the results of recent experimental research and of studies performed in
humans, there is increasing evidence that the gut flora forms an important organ for
ethanol metabolism in the large bowel.13 In this area, alcohol is transported to the
lumen of the colon via the bloodstream and converted to acetaldehyde by bacterial
ADH (Figure 1). Since the capacity of the huge number of bacteria in the colon for the
first step of alcohol oxidation by ADH is much higher than that for the second step
from acetaldehyde to acetate, the concentration of the former increases distinctly. The
enhanced concentrations of acetaldehyde, a toxic compound, may contribute to the
damage of the colonic mucosa and, after being absorbed into the portal blood, to liver
injury (Figure 1). Another clinical implication of the ‘bacteriocolonic’ pathway of alcohol
breakdown might be the local carcinogenic action of acetaldehyde.13

Practice points
† first-pass metabolism of ethanol in the stomach may significantly contribute to
overall metabolism of alcohol when small amounts of alcoholic beverages are
consumed
† the recently discovered ‘bacteriocolonic’ metabolism of ethanol leads to the
accumulation of toxic acetaldehyde in the colon (a causative factor for
colorectal malignancies ?)
578 C. Bode and J. C. Bode

EFFECTS OF ALCOHOL ON THE SMALL INTESTINE

Absorption of macro- and micronutrients

Effects of acute alcohol administration

Acute exposure of the mucosal side of the small intestine to alcohol inhibits the active
transport of numerous nutrients across the epithelial layer.1,2,7,14 An inhibition of
absorption has been reported for monosaccharides, several L -amino acid residues and
lipids (fatty acids, monoglycerides) as well as for some vitamins (Table 1).
The effect of acute alcohol exposure on the absorption of the various nutrients has
predominantly been studied in animal experiments using in vitro techniques1,2,7,14 – 16
and in the fasting state of either experimental animals or human volunteers, thereby
eliminating the modifying effect of a meal or certain nutrients.15 Most of the inhibitory
effects of acute ethanol exposure on the absorption of nutrients, summarized in Table
1, have been observed in experiments in which the absorption was calculated for a
relatively small segment of the small bowel or per unit of mucosal surface (mainly
1 cm2). Considering the marked functional reserve of the total small intestine, a partial
inhibition of the absorption of a certain nutrient in the proximal small intestine may
easily be compensated for by absorption of this nutrient in a more distal part of the
small intestine, resulting, overall, in complete absorption (see Figure 2).

Effects of chronic alcohol consumption

Monosaccharides
Decreased absorption of D -xylose has been reported in alcohol-abusing subjects
without clinically overt liver disease, but the prevalence of disturbed absorption of
7
D -xylose varies markedly. In five studies, figures of from 18– 76% have been quoted.

Table 1. Effects of alcohol exposure on intestinal absorption of various nutrients in animal experiments
and humans.

Substance Animal Humans

D -glucose # #
D -xylose nc or # nc or #
L -amino acid residues (e.g. L -alanine, L -glycine, L -methionine) # #
Oligopeptides # ns
Monoglycerides, fatty acids # nc or #
Vitamins
Thiamine # nc or #
Folic acid nc or # nc
Vitamin A ns nc or #
Trace elements
Zinc # nc
Manganese " ns
Iron nc or # nc or "

Source: Bode and Bode (1990)1, Mezey (1985)2, Bode (1980)7 and Beck and Dinda (1981)14, " ,
increased; # , decreased; nc, no change; ns, not studied.
 Effect of alcohol consumption on the gut 579

Duodenal segment Jejunal segment

Carbohydrates 265 Carbohydrates 138

(mg/min) 153 (mg/min) 197

Protein Protein
199 67
(mg nitrogen/min (mg nitrogen/min
133 320
x 50) x 50)

Lipids Lipids
189 (µmol fatty acids no data
(µmol fatty acids
/min) 105 /min)

0 50 100 150 200 250 300 0 100 200 300 400

Figure 2. Duodenal and jejunal absorption of a nutrient solution containing a mixture of carbohydrates,
proteins and lipids in alcoholics and non-alcoholic controls using an intestinal effusion technique.
alcoholics; controls. Data taken from Pfeiffer et al (1992).21

This variation may reflect differences in the mean daily alcohol intake of the subjects
studied and/or in their nutritional status.7 The absorption of glucose does not seem to
be affected by chronic alcohol administration.1,7,14

Amino acids
Chronic ethanol intake did not affect the absorption of L -leucine from the small
intestine of rats fed a nutritious diet.17,18 Thus, it seems that the inhibition of amino acid
absorption induced by acute alcohol administration7,14 is not maintained when alcohol
is consumed chronically.

Protein, fat and complex carbohydrates

Steatorrhoea and increased faecal nitrogen excretion are well known features of
alcohol-abusing patients with exocrine pancreatic insufficiency and/or advanced
alcoholic liver disease. However, increased faecal fat excretion has also been reported
in alcoholics without cirrhosis or chronic pancreatitis.1,7 Increased faecal nitrogen
excretion was also observed in about 50% of alcoholics who had neither advanced liver
disease nor chronic pancreatitis.19 The pathomechanisms of the disturbed digestion
and/or absorption of lipids and protein in alcoholics have not been clarified. The finding
that ethanol interferes with the intestinal hydrolysis of peptides20 might, at least
partially, explain the ‘malabsorption’ of protein.
An important contribution to this field came from a study on alcoholics without
confounding disorders such as cirrhosis or pancreatic insufficiency.21 When the
duodenal and jejunal absorption of a nutrient solution containing a mixture of proteins,
lipids and carbohydrates (90% dextrin maltose) was determined using an intestinal
perfusion technique, the duodenal absorption of all three nutrients was lower in the
alcoholics compared to age-matched controls, but jejunal absorption rates were not
decreased (Figure 2). When the data for the duodenal and the jejunal segments were
combined, no statistically significant differences between the two groups were
detectable for any of the nutrients.21 The authors explained the different absorption
rates in the duodenum versus the jejunum of the alcoholics as being due to the more
pronounced alcohol-induced mucosal damage in the duodenum.
580 C. Bode and J. C. Bode

Water and electrolytes

Both in healthy subjects and in alcoholics, chronic alcohol consumption leads to
markedly reduced water and sodium absorption in the jejunum and ileum.1,21 The
reduced water absorption may contribute to diarrhoea in alcoholics.

Vitamins

† Folic acid. Folate deficiency, documented by low serum levels, has been described in
about 60 – 70% of binge drinkers.22 Reduced absorption is one of the causative
factors.23 Pure nutrition with inadequate dietary folate intake appears to be of
greater importance.23 A more pronounced folate deficiency may further aggravate
jejunal uptake of nutrients.23
† Vitamin B12. Chronic alcohol abuse may cause malabsorption of vitamin B12.23
However, despite the fact that alcohol may interfere with vitamin B12 absorption,
few alcoholics have clinical evidence of vitamin B12 deficiency.22,23
† Thiamine. Conflicting results have been published regarding the effect of chronic
ethanol ingestion on the intestinal absorption of thiamine in humans. In one study, a
reduced absorption was observed, while in other studies no effect on thiamine
absorption was seen.1,24,25 From the results of studies performed in rats, it has been
suggested that alcohol administration inhibits only the active transport of thiamine at
low concentrations of the vitamin.26 Alcohol abuse in cirrhotics was found to be
associated with low plasma thiamine concentrations and reduced thiamine
phosphorylation.22,27 Inadequate dietary thiamine intake is assumed to be an
important cause for thiamine deficiency in alcohol-abusing subjects.22,25
† Vitamin B6. Vitamin B6 (pyridoxal-5-phosphate) deficiency is observed in a high
proportion of alcohol abusers.22 The deficiency of this vitamin appears to be caused
by factors other than malabsorption.7,22
† Vitamin C. Low blood levels of ascorbic acid are primarily found in impoverished
alcoholics.28 Leading causes of vitamin C deficiency in alcoholics are inadequate
intake and increased urinary excretion, but alcohol has also been reported to impair
absorption of this vitamin.28
† Vitamins A, D, E and K. Plasma concentrations of the fat soluble vitamins are partially
below normal levels in alcoholic individuals. The prevalence of low levels of these
vitamins varies markedly depending on the nutritional status and the presence of
more advanced stages of liver disease and chronic pancreatitis. Intestinal absorption
of these vitamins is impaired in the presence of pancreatic insufficiency or cholestasis
but they appear to be absorbed normally in alcoholics without these endstage organ
diseases.

Calcium and Magnesium

The absorption of both minerals is not significantly affected by acute or chronic alcohol
ingestion. Hypomagnesaemia is a frequent finding in alcoholics but it is caused mainly by
increased magnesium excretion in the urine or as a result of diarrhoea.7,29

Trace elements
† Zinc. Alcohol abuse is frequently associated with zinc deficiency.30 Major reasons for
the zinc deficiency noted in alcoholics with or without liver disease are inadequate
dietary zinc intake and increased urinary loss of zinc.7,30 Impaired zinc absorption is
 Effect of alcohol consumption on the gut 581

another likely cause of zinc deficiency in alcoholics30, although in some studies no

abnormalities of zinc absorption in alcoholics were found.1
† Iron. Increased iron stores are common in alcoholics.7,31,32 The effect of chronic
alcohol consumption on iron absorption in humans has, however, not been clearly
defined.1,32 From the results of a more recent study, it was concluded that
unregulated increased iron absorption via the non-carrier mediated paracellular
route contributes to the iron overload in chronic alcoholics.33
† Selenium. Diminished contents of selenium in serum and erythrocytes have
repeatedly been observed in alcoholics with and without liver disease.34,35 Whether
or not loss of this trace element due to malabsorption contributes to selenium
deficiency in alcoholics remains an unanswered question.

Mucosal enzymes and metabolism

Alcohol can interfere with the activity of many enzymes located in the brush border or
other compartments of the enterocytes.

Brush-border enzymes
Disaccharidases
In experiments performed in rodents for the activity of the disaccharidases (lactase,
sucrase, maltase and trehalase), both reduced and unchanged values have been
reported following acute or chronic alcohol administration.7,32 In humans, lactase
activity in jejunal biopsies was found to be below normal in only a small percentage
of white alcoholics but was a regular finding in American blacks, in whom lactase
deficiency is more frequently found than in whites.7,32,36 Conflicting data have been
reported concerning the effect of chronic alcohol abuse on the activity of
saccharase and maltase.7,36

Gamma-glutamyl transferase (GGT)

Chronic alcohol administration increases the activity of this enzyme in the intestinal
mucosa in animal experiments and in humans.32 It has been suggested that intestinal
GGT may contribute to the increased serum GGT values commonly seen after high
alcohol intake in humans.

Enzymes of other cell compartments

The activity of several enzymes linked to energy-producing metabolism is affected by
acute and chronic alcohol administration in both experimental animals and humans.7,36
For the changes in the activity of enzymes of these and other cell compartments, the
functional importance still has to be clarified.

Effects on mucosal morphology

Acute alcohol exposure
In experimental animals (rodents, dogs), acute administration of alcoholic solutions at
concentrations corresponding to those of commonly available alcoholic beverages
leads to mucosal damage in the small intestine that extends to loss of epithelium at
582 C. Bode and J. C. Bode

Practice points
† acute administration of alcoholic beverages (i.e. . 2% v/v) interferes with the
active absorption of glucose, L -amino acid residues and certain vitamins in the
small intestine
† in chronic alcoholics with cirrhosis and/or chronic pancreatitis, disturbed
digestion and malabsorption of carbohydrates, lipids, protein and several
vitamins is evident
† malabsorption of the aforementioned nutrients also occurs in alcohol-abusing
subjects without advanced liver disease or pancreatic insufficiency, but is
restricted to the duodenum and upper part of the jejunum
† chronic alcohol abuse inhibits water and sodium absorption in the small
intestine, an important cause of diarrhoea in alcoholics

the tips of the villi, haemorrhagic erosions and haemorrhage in the lamina propria.14
When alcohol is administered orally or intragastrically, the lesions observed are most
prominent in the duodenum.37 Similar lesions were observed in volunteers 3 hours
after the oral ingestion of 1 g/kg body weight of ethanol.38 In accordance with these
findings are the results obtained in a large, prospective case – control study that
provided evidence that consumption of alcoholic beverages significantly increases the
risk of major duodenal bleeding in non- predisposed individuals.39
The mechanisms causing these pronounced structural changes have not been
completely clarified. From the results of earlier studies it has been concluded that
ethanol has a direct toxic effect on the mucosal epithelium.7 On the basis of extensive,
elegant experimental studies, other authors have proposed an indirect effect of alcohol
on the mucosal microcirculation that leads to an enhanced transcapillary fluid filtration
and subsequent rupture of the epithelial lining.14 In additional studies, the same group
provided evidence that alcohol induces villus contraction, which leads to villus tip bleb
formation, lymphatic obstruction and, eventually, to exfoliation of the tips of the villi
when the blebs rupture.40 From the results of more recent experiments, these authors
have suggested that the initial event in response to alcohol is an increased influx of
leukocytes leading to an enhanced release of noxious mediators, such as reactive
oxygen species41, leukotrienes42 and histamine by mast cells.43

Effect of chronic alcohol ingestion

Whether or not chronic alcohol ingestion damages the mucosa of the small intestine
remains controversial. When biopsies taken at duodenoscopies in chronic alcohol
abusers were studied, some authors found normal histology by light-microscopy while
others demonstrated significant histological alterations.1,32 The conflicting results may
be explained by the fact that, in the majority of subjects studied, the endoscopy was
performed 3– 14 days after admission. Considering the high regeneration rate of the
intestinal epithelium, many lesions might have healed within the interval between
starting abstinence and the endoscopy. The close association between high alcohol
intake and the risk of acute bleeding in both the stomach and the duodenum, reported
recently above39, supports the assumption that the type of mucosal injury discussed in
acute alcohol exposure does also occur after heavy drinking in subjects chronically
abusing alcohol. Even in studies in which the mucosa appeared to be normal when using
light-microscopy, structural changes of the mucosa of the small intestine were observed
 Effect of alcohol consumption on the gut 583

when quantitative morphometric methods or electron-microscopical examinations

were used. These changes include reduced villus height and reduced mucosal surface
area of villi, increases in the number of intra-epithelial mononuclear cells, goblet cell
hyperplasia and gastric metaplasia.1,7,32 The results of a recent study suggest that
chronic alcohol abuse induces alterations of the matrix network and increases the
number of myofibroblast-like cells in the duodenal mucosa, findings compatible with the
development of fibrosis of the intestinal mucosa.44
Similar to the situation in humans, chronic alcohol administration to experimental
animals has led to conflicting results. Using light-microscopy, both normal histology and
significant histological alterations, including inflammatory infiltrates and blebs at the
apex of the villus, have been described.1,7,32,45 The variable results may be explained by
differences in the type and dose of alcohol feeding, the strain, sex and age of the animals
and other factors concerning the study design.

Bacterial overgrowth in the small intestine

In studies using a specially devised tube, marked qualitative and quantitative alterations
of the jejunal microflora have been documented in recently drinking alcoholics.46
Nearly 50% of the alcoholics had a marked increase in the total number of bacteria
(. 105 colony forming units/ml of jejunal juice) with a predominant increase in bacteria
from the faecal flora. These results were confirmed in a study in which samples of
duodenal juice obtained during gastroduodenoscopy in alcohol-abusing subjects were
investigated.47 In agreement with these data are the results of studies in which the
prevalence of bacterial overgrowth in alcoholics was determined using the H2-breath
test after ingestion of glucose or lactulose.47 Bacterial overgrowth in the upper small
intestine might contribute to mucosal damage and disturbed absorption in subjects
chronically abusing alcohol. Furthermore, it might increase the production of bacterial
toxins, especially endotoxins from Gram-negative bacteria which, in combination with
the mucosal injury induced by alcohol, might contribute to an enhanced endotoxin
translocation from the luminal side into the portal blood (Figure 3, and see below).

INCREASED GUT PERMEABILITY

Increased intestinal permeability to macromolecules following alcohol ingestion was

reported in earlier animal experiments for haemoglobin, horseradish peroxidase and
polyethyleneglycol (PEG) 1500 Mr.7 Evidence of an increased intestinal permeability
caused by alcohol consumption in human subjects was first reported when smaller
molecules (Mr , 500) were used as a permeability probe.48 More recently, significantly
increased intestinal permeability in actively drinking alcoholics has been confirmed for
macromolecules such as PEG 4.000 Mr and 10 000 Mr. (Table 2).49 Interestingly, the
enhanced intestinal permeability for these macromolecules had already been found in
alcoholics without advanced stages of liver disease, a finding that strongly supports
the assumption that the increased permeability of the gut mucosa is caused by ethanol
itself and is not a consequence of advanced alcoholic liver disease.
The hypothesis that the acute and chronic ingestion of large quantities of alcohol
enhances the translocation of macromolecules through the intestinal mucosa is
supported by the observation of a transient endotoxaemia following acute alcohol
consumption in healthy volunteers and in alcoholics with fatty liver.47,49,50 Direct
 584 C. Bode and J. C. Bode
Small intestine
Disturbed motility Bile acid deconjugation

Alcohol Bacterial over growth Disturbed absorption

Prostaglandin synthesis Formation of endotoxins
decreased and other toxins
Mucosal lesions
Increased permeability

Portal vein
lymphatics } Increased uptake of
endotoxins (and other toxins)

Endotoxaemia

Increased release of mediators: TNF α, IL 1,

IL 6, leukotrienes, free radicals } RES : Kupffer cells monocytes,
macrophages { Inhibition of
phagocytosis

Endothelial lesions

Blood vessels
Increased permeability Liver cell injury
Activation of complement
Intravasal clotting
Other organ injury
Disturbed microcirculation

Figure 3. Schematic representation of the changes induced by alcohol abuse in the small intestine and the consequences of the resulting endotoxaemia on Kupffer
cells/macrophages, which may contribute to the initiation and promotion of alcoholic liver disease and, potentially, other organ injury. RES, reticulo endothelial system; TNF-
a, tumour necrosis factor a; IL-1, interleukin-1; IL-6, interleukin-6. Modified with the permission of the publisher, from Bode et al (1998).47
 Effect of alcohol consumption on the gut 585

Table 2. Gut permeability to polyethyleneglycol (PEG, Mr 10 000) in patients at different stages of

alcoholic liver disease.

Patients n PEG in urine positive n (%)

Controls 34 0
Fatty liver 17 7 (41)*
Alcoholic hepatitis (no cirrhosis) 18 7 (39)**
Alcoholic cirrhosis 19 6 (31,5)*

Source: Parlesak et al (2000)49,

*P , 0:05 versus controls, **P , 0:001 versus controls.

evidence of enhanced translocation of endotoxin from the gut lumen into the portal
blood has been achieved in experiments using the Tsukamoto-French model in rats.51
The intermittent endotoxaemia stimulates Kupffer cells and other macrophages in the
liver, thereby enhancing the release of reactive oxygen species and proinflammatory
mediators such as tumour necrosis factor-a (TNF-a), interleukin-1 (IL-1) and IL-6.47,52
Chronic overproduction of such mediators may induce the influx and activation of
neutrophil leukocytes, endothelial lesions, increased permeability of sinusoids,
disturbed microcirculation and other injurious events that finally lead to severe
forms of liver injury and other organ damage (Figure 3).1,47,52
The pivotal role of gut-derived bacterial toxins in the development of progressive
alcoholic liver injury is emphasized by the results of two studies in which the bacterial
flora of the gut was suppressed. Oral administration of broad-spectrum antibiotics
(polymyxinB and neomycin)53 and changing the intestinal flora by Lactobacillus feeding54
reduced endotoxaemia and the severity of alcoholic liver injury in rats. A marked
decrease in plasma endotoxin concentration was also observed in a small group of
cirrhotics treated with a combination of polymyxinB and neomycin55 while another
broad spectrum antibiotic treatment, paromomycin sulphate, for 3 weeks, did not
significantly influence plasma endotoxin concentrations in a placebo-controlled trial in
patients with alcoholic liver disease.56 Whether alcohol-induced alterations of the
permeability are mainly or exclusively located in the upper parts of the GI tract or
whether alcohol reaching the large bowel via the blood (Figure 1)4 also affects the
mucosal barrier in the colon remains to be clarified.

EFFECTS OF ALCOHOL ON GUT MOTILITY

The acute and chronic effects of pure alcohol and alcoholic beverages on the motility of
the stomach are discussed in Chapter 5. Changes in the gastric motility, such as delayed

Practice points
† alcohol abuse leads to mucosal damage in the upper gastrointestinal tract
extending to erosive lesions and haemorrhages in the duodenum
† the mucosal injury produced by alcohol promotes an increase in gut
permeability for endotoxin and other bacterial toxins from the gut lumen to
the portal blood leading to endotoxaemia
586 C. Bode and J. C. Bode

† the intermittent increase in gut-derived endotoxin in the portal blood stimulates

Kupffer cells and other macrophages to release proinflammatory mediators (e.g.
cytokines, reactive oxygen species). Chronic overproduction of such mediators
may induce disturbed microcirculation and multiple other injurious events that
finally lead to necrosis or apoptosis of hepatocytes, inflammatory infiltrates and
fibrosis
† modulation of the gut flora by antibiotics or probiotics to reduce endotoxin
production was shown to prevent alcoholic liver injury in animal experiments.
Whether such treatment is of benefit in humans has to be clarified by controlled
clinical trials

emptying of solid food from the stomach as the result of the intake of diluted ethanol
or various alcoholic beverages7,57 may also influence the motility of the small intestine
and the colon. The same holds true for the effects of alcohol itself and of certain
ingredients in alcoholic beverages on gastric acid secretion and production of gastrin
(see Chapter 5).

Motility of the small intestine

Acute effects of alcohol

In the fasting state, oral or intravenous alcohol administration to healthy volunteers
increased the mean number of phasic contractions in pars II of the duodenum, while the
number of segmental phasic contractions in the jejunum decreased.7 In the ileum the
number of propulsive contractions increased. Following intravenous ethanol adminis-
tration to volunteers, a shortening of the interdigestive motor cycle was observed.57
Conflicting results have been published regarding the effect of alcohol on
the postprandial motor function of the small intestine. Oral ingestion of red wine did
not significantly affect the postprandial phasic contractions in the jejunum of healthy
volunteers but abolished the circadian variability of the length of the interdigestive
motility cycle.58 Other authors have observed an induction of clustered contractions in
the duodenum and jejunum following intraduodenal infusion of 4% v/v ethanol.59

Chronic effects
Orocaecal transit time (OCTT), as assessed by the lactulose H2-breath test was
significantly delayed in comparison with healthy teetotal subjects60 or social
drinkers.60,61 In alcoholics there was no significant correlation between the OCTT
and daily alcohol intake or years of alcohol abuse.60 A subgroup of alcoholics reporting
diarrhoea had an accelerated OCTT compared to those without diarrhoea.51 On the
basis of the results of OCTT measurements it was postulated that the transit
abnormalities might be related to toxic damage of the intestinal smooth muscle.60,61
This assumption is supported by the results of experiments using smooth muscle canine
small bowel.62 Disturbances of the synthesis of smooth muscle contractile proteins in
the small intestine, observed in rats receiving ethanol, might contribute to altered
motor function.63
 Effect of alcohol consumption on the gut 587

Effects of alcohol upon the colon and rectum

Few data have been published on the effect of alcohol and alcoholic beverages on the
motor function of the large bowel. When chronic alcoholics were studied at admission,
the colorectal transit time was found to be reduced.64 This alteration of the transit time
was reversible following 10 days of abstinence and was explained as being due to
enhanced transit in the rectosigmoidal segment.

EFFECTS OF ALCOHOL CONSUMPTION ON THE INTESTINAL

IMMUNE SYSTEM

Both the specific and unspecific immune system are affected by acute and, more
importantly, by chronic alcohol ingestion.65,66 The immune modulating effects of
alcohol may lead to inflammatory reactions that contribute to the development of
organ injury and also to insufficiency of certain parts of the immune system, leading
to the well-known susceptibility to infectious diseases associated with alcohol
abuse.48,65,67,68
The intestine represents one of the most important immune systems in mammals. It
is involved in innate and specific defence of the body’s largest surface area, a surface
exposed to the heaviest burden of environmental antigens.69 However, little is known
about the potential effects of alcohol on this mucosal immune system.

Effects on the non-specific immune system

Results obtained when segments of the jejunum were perfused with 6% ethanol
suggest that ethanol mediates the damaging effects to the mucosa primarily by
promoting leukocyte infiltration which then leads to the release of reactive oxygen
species and histamine from mast cells.14,41 The latter results were obtained using
indirect methods to measure the increased influx of leukocytes in the mucosa and/or
increased adhesion of leukocytes to the endothelium. In other animal experiments
acute alcohol administration leading to mucosal injury in the upper small intestine
resulted in inflammatory infiltration of the lamina propria but the type of cells were
not specified.2,7,14
Duodenal or jejunal biopsies of actively drinking alcoholics taken after a few days of
abstinence, have usually shown no mucosal infiltrates of leukocytes or macrophages on
routine histology2,32 or on quantitative analysis comparing jejunal70 or duodenal71
biopsies of recently drinking alcohol-abusing subjects with those of non-alcoholic
controls.

Effects on the specific mucosal immune system

Using quantitative morphometric analysis several qualitative and quantitative alterations

in the number of mononuclear cells were observed in biopsies of the duodenal mucosa
of alcoholics. In subjects abstaining from alcohol for less than 5 days, the number of
B-lymphocytes in the lamina propria was significantly increased, while the number of
mononuclear macrophages was decreased by about 50%.71 These changes were no
longer observed in a second group abstaining for 5 –10 days. The number of IgA-
positive plasma-cells in the duodenal mucosa remained unchanged in the alcoholics
588 C. Bode and J. C. Bode

compared to controls.71 There were also no differences in the content of IgA in the IgA-
producing plasma cells in the two groups of patients. From the latter result it was
assumed that the plasma cells of the small intestine do not contribute to the elevated
plasma levels of IgA frequently observed in alcoholics.72 The results are also in
accordance with the assumption that enhanced IgA secretion in the upper small
intestine of alcoholics is caused by increased synthesis in the liver and biliary tract.73
The number of intra-epithelial lymphocytes, which represent a major part of the
specific cellular defence mechanisms of the gut-associated lymphoid tissue74, was found
to be increased in jejunal biopsies of alcoholics in one study70 but this was not
confirmed in a more recent study of duodenal biopsies from alcoholics.71
In studies designed to test whether ethanol consumption affects resistance to
mucosal and systemic infections by Salmonella typhimurium in mice, the feeding of an
alcohol-containing liquid diet resulted in a profound loss of lymphoid cells.75 From the
results of this and other studies it has been suggested that alcohol consumption by
experimental animals results in a suppression of the Th1-type cellular immune response
leading to increased susceptibility to oral infections by pathogens.75 On the basis of
these findings it has to be questioned whether the results of some in vitro studies of the
effect of certain alcoholic beverages upon enteropathogenic bacteria29,76,77 are of any
relevance in the in vivo situation in humans. Considering the well-known bactericidal
effect of ethanol, an inhibition of the growth of enteropathogens in the presence of wine
containing 10– 12% ethanol under in vitro conditions76,77 can be anticipated. Since wine
ingested during social drinking is immediately diluted in the stomach and alcohol is
rapidly absorbed in the upper small intestine2,7,32 it seems unlikely that wine consumed
together with meals prevents infections with enteropathogenic bacteria. Whether
alcohol itself or congeners of alcoholic beverages really reduce the risk of
gastroenteritis due to enteropathogenic bacteria29,78 can only be answered by well-
designed controlled trials.

Practice point
† acute and chronic alcohol exposure leads to several alterations of the non-
specific and the specific immune system of the small intestine. The physiological
relevance of these alterations needs to be clarified

COLON AND RECTUM

In contrast to the organs of the upper GI tract, the mucosa of the large bowel is
exposed only to alcohol concentrations corresponding to those of the blood. With the
exception of the bacteriocolonic metabolism of alcohol and its potential local and
systemic implications (see Figure 1 and Alcohol metabolism, above)13 and the
association between alcohol consumption and colorectal neoplasias (see Chapter 13),
the effect of alcohol on the large bowel has received little attention.
In rats, chronic alcohol consumption stimulated proliferation of epithelial cells in the
rectum.79 This effect was more pronounced in older rats.80 A similar hyper-
proliferation was found in rectum biopsies from alcoholics.81 Since, in the animal
experiments, the acetaldehyde concentration in the mucosa correlated with the activity
of the proliferation it was speculated that this toxic metabolite might induce damaging
effects to the mucosa.81
 Effect of alcohol consumption on the gut 589

SUMMARY

Acute and chronic consumption of large quantities of alcoholic beverages can interfere
with many functions of the gut. In the small intestine, alcohol inhibits absorption of
many nutrients. In the absence of advanced organ disease these absorption
disturbances do not seem to be of major importance for the nutritional status of
alcohol abusers. In alcoholics with cirrhosis or chronic pancreatitis, the combination of
impaired digestion and malabsorption markedly contributes to malnutrition. Acute
alcohol abuse damages the mucosa in the upper part of the small intestine and may even
lead to erosions and haemorrhages in the duodenum. The results of human and animal
studies strongly suggest that the mucosal defects favour the following sequence of
events: increased permeability in the gut to macromolecules; enhanced translocation of
endotoxin and/or other bacterial toxins into the blood; endotoxaemia increases the
release of proinflammatory/toxic mediators (e.g. TNF-a, IL-1, reactive oxygen species)
by Kupffer cells; the intermittent/chronic overproduction of these mediators may exert
multiple injurious effects on cell membranes and the microcirculation resulting in cell
death and inflammatory infiltrates in the liver and possibly other organs. Alcohol
consumption affects the immune system of the gut but more information is needed to
understand the relevance of the alcohol-induced changes in the immunological network
in this area. In addition to the aforementioned disorders, disturbed motility of the gut
may be involved in the abdominal symptoms frequently observed in alcoholics, such as
anorexia, nausea and abdominal pain.

Research agenda
† the quantitative contribution of gastric first-pass metabolism of alcohol under
conditions of daily life (social drinking, heavy alcohol consumption, various
types of meals) needs to be defined
† detailed studies are necessary to clarify the relevance of bacteriocolonic
metabolism of alcohol for the development of alcohol-induced organ damage
† detailed studies are necessary to define the effect of alcohol abuse on the
overall absorption of nutrients in (especially active drinking) subjects without
overt alcoholic liver disease or chronic pancreatitis
† the effects of moderate alcohol consumption and of alcohol abuse on the gut-
associated immune system need to be defined in detail
† studies are needed to clarify whether the alcohol-induced changes in gut
permeability occur only in the small intestine or also in the colon
† studies in actively drinking alcoholics are necessary to clarify whether or not
chronic alcohol abuse leads to mucosal injury of the upper small intestine
† controlled clinical studies are necessary to define the efficacy of oral broad
spectrum antibiotics or probiotics on alcohol-induced endotoxaemia and the
course of alcoholic liver disease

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