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Mechanisms of infectious diarrhea

Udayakumar Navaneethan and Ralph A Giannella*

S U M M ARY INTRODUCTION
Enteric infections that cause diarrhea are a major
Infectious diarrhea is an important public health problem worldwide.
cause of morbidity throughout the world. In
Research has provided new insights into the mechanisms of diarrhea
developing countries, infectious diarrhea is fre-
caused by various pathogens that are classified as noninflammatory,
quently disabling and contributes substantially
inflammatory or invasive. These three groups of organisms cause two
to malnutrition, resulting in high morbidity and
diarrheal syndromesnoninflammatory diarrhea and inflammatory
diarrhea. The noninflammatory diarrheas are caused by enterotoxin-
mortality, particularly in infants and children. It
producing organisms such as Vibrio cholerae and enterotoxigenic has been estimated that 2billion to 4billion epi-
Escherichia coli, or by viruses that adhere to the mucosa and disrupt the sodes of infectious diarrhea occur annually in
absorptive and/or secretory processes of the enterocyte without causing developing countries, with the highest rates of
acute inflammation or mucosal destruction. Inflammatory diarrhea is infection occurring in children below the age
caused by two groups of organismscytotoxin-producing, noninvasive of 5years.1 At present, the life-time risk of con-
bacteria (e.g. enteroaggregative Escherichia coli, enterohemorrhagic tracting diarrheal disease is increased fivefold in
Escherichia coli and Clostridium difficile), or by invasive organisms (e.g. sub-Saharan Africa compared with developed
Salmonella spp., Shigella spp., Campylobacter spp., Entamoeba histolytica). countries (39.1% versus 7.2%, respectively).2 In
The cytotoxin-producing organisms adhere to the mucosa, activate fact, in 2001 the WHO reported that diarrheal dis-
cytokines and stimulate the intestinal mucosa to release inflammatory eases were the second leading cause of disability-
mediators. Invasive organisms, which can also produce cytotoxins, adjusted life-years lost, and contributed to
invade the intestinal mucosa to induce an acute inflammatory reaction, 2.2million deaths, making diarrheal diseases the
involving the activation of cytokines and inflammatory mediators. third leading cause of death worldwide.3
Regardless of the underlying mechanism they use, these various types of Although the morbidity and mortality associ-
pathogen have all successfully evolved to evade and modulate the host ated with infectious diarrhea is considerably less
defense systems. The mechanisms by which the different pathogens invade in Western countries, this disease is neverthe-
the host and cause infectious diarrhea are the topic of this Review. less a major cause of morbidity, physician visits,
Keywords diarrhea, enteric infection, enteropathogens, enterotoxin,
hospitalizations and absence from work or
infectious diarrhea school. In fact, physicians in the US are consulted
annually for 8.2million diarrheal episodes,
REVIEW CRITERIA including infectious and noninfectious types.4 In
In January 2008 MEDLINE was searched from 1962 to the present using the medical addition, infectious diarrheal diseases constitute
subject headings (MeSH) terms diarrhea, infectious diarrhea pathogenesis, and
mechanism, alone, and in combination with each other. Abstracts and full papers the most common health problem in Western
were considered. No language restrictions were placed on the search. Important persons who travel to developing countries.5
developments in molecular and genomic research, experimental reports from Our knowledge of infectious diarrheal disease
centers of excellence, and our own research developments were used to form the has expanded enormously over the past decade,
basis of this review article. The reference list was last updated in August 2008.
particularly with regard to understanding
U Navaneethan is a Resident in the Department of Internal Medicine, the pathogenesis of infectious diarrhea and the
and RA Giannella is the Mark Brown Professor of Medicine in the Division addition of new organisms to the existing reper-
of Digestive Diseases, at the University of Cincinnati College of Medicine, toire of agents that cause diarrhea. This Review
Cincinnati, OH, USA. presents our current understanding of the
mechanisms of important underlying infectious
Correspondence
*Division of Digestive Diseases, ML 0595, University of Cincinnati College of Medicine,
diarrheas, including host defense mechanisms
Cincinnati, OH 45267-0595, USA that provide protection against ingested infec-
ralph.giannella@uc.edu tious pathogens. In addition, the epidemiology
and clinical syndromes of infectious diarrheas
Received 27 March 2008 Accepted 20 August 2008 Published online 23 September 2008
www.nature.com/clinicalpractice
are discussed. Owing to space limitations, the
doi:10.1038/ncpgasthep1264 management of infectious diarrheas is not

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considered; instead, the reader is referred to other
articles that review various aspects of infectious
diarrhea, including its management.69
EPIDEMIOLOGY OF INFECTIOUS
DIARRHEAS
Virus-induced diarrheas account for 3040%
of acute episodes of diarrhea in the US, with
norovirus (previously known as Norwalk
virus) and rotavirus being the most common of
the diarrhea-causing viruses.10 In children in the
US, rotavirus is responsible for 35% of hospi-
talized cases and 1030% of community-based
cases of diarrhea.11 Norovirus affects people of
all ages and is responsible for approximately
40% of nonbacterial outbreaks of diarrhea
in the US.12 By contrast, in developing coun-
tries where there is relatively poor sanitation,
enteric bacterial pathogens (e.g. Vibrio cholerae,
enterotoxigenic Escherichia coli [ETEC] and
enteropathogenic E.coli [EPEC]), protozoa
and intestinal parasites are the predominant
causes of infectious diarrhea.8
V. cholerae is one of the most common causes
of diarrhea worldwide. Diarrhea associated with
cholera is predominantly seen in the Indian
subcontinent, South East Asia, Africa and South
America.13 In the US, sporadic cases of V. cholerae-
induced diarrhea have been reported along
the Gulf coast.14 Vibrios are classified into O1
or non-O1 serogroups based on whether they
undergo agglutination by antisera against the
O1 antigen (cell wall polysaccharide). Diarrhea
caused by the non-O1 toxigenic strain Vibrio
0139 Bengal, which was described in 1992,
started in southern India and Bangladesh and
spread to other parts of Southeast Asia.15,16 At
present, Vibrio 0139 Bengal is present only in
Asia.15,16 Another Vibrio species, V. parahemo-
lyticus, is more common than V. cholerae in the
US, and V. parahemolyticus-induced diarrhea
occurs sporadically along the US coast.8
Pathogenic E. coli are another important
cause of diarrhea worldwide, and are classi-
fied according to their pathogenic mechanisms.
ETEC are among the most common causes of
diarrhea in children in developing countries
including Mexico, Central and South America,
India, Southeast Asia and Africa, and affect
1550% of travelers to these regions of the
tropics, making ETEC the most common cause
of travelers diarrhea.17 By contrast, ETEC
infections are not common in the US or other
developed countries.
638 nature clinical practice GASTROENTEROLOGY & HEPATOLOGYNavaneethan and Giannella november 2008 vol 5 no 11
Enteroinvasive E. coli (EIEC) infections are seen
predominantly in tropical countries including
Thailand,18 with occasional cases reported in the
US. Enterohemorrhagic E. coli (EHEC) are one
of the most common causes of bloody diarrhea
in the US19 and throughout the world, including
Canada and Europe. Infection occurs primarily
after ingestion of undercooked hamburgers and
meat patties. Enteroaggregative E.coli (EAEC)
affect children and adults of developing and
developed countries. EAEC have been shown to
cause acute and/or persistent diarrhea in 1044%
of patients with an HIV infection and are also a
major cause of travelers diarrhea.20,21
Among cases of infectious diarrhea caused by
invasive pathogens, shigellosis is common and
accounts for 1020% of cases of enteric infec-
tions throughout the world.22 Shigellosis is com-
monly seen in children younger than 5years of
age, although adults of all ages are susceptible.8
Non-typhoidal salmonellosis is also seen world-
wide and is one of the most common causes of
food poisoning and diarrhea in the US. In fact,
close to 1.4million cases of salmonella food poi-
soning occur annually in the US.8 Campylobacter
infection is also an important cause of diarrhea,
with C. jejuni being the most common cause of
acute bacterial diarrhea in the US.8 Similarly to
salmonella infections, most C. jejuni infections
are related to the consumption of improperly
cooked chicken.23
One of the most important causes of diar-
rhea in the US is Clostridium difficile infection.
The incidence of this infection has increased
dramatically and it is now recognized as the
most common cause of nosocomial infectious
diarrhea in developed countries.24,25
Intestinal protozoa are also important causes
of diarrhea in the developing world and are
an increasingly common cause of diarrhea in
Western countries. Entamoeba histolytica is
one of the most important causes of diarrhea
and dysentery throughout the world, with an
estimated 3450million symptomatic infec-
tions occurring worldwide annually.26 Giardia
lamblia is the intestinal parasite most com-
monly implicated as a cause of diarrhea in the
US, where it is most commonly found in chil-
dren in day-care facilities and in sexually active
homosexual men, but is also common in the
general population.27 Cryptosporidium infec-
tion is seen not only in HIV-infected indivi
duals but also in cases of self-limited diarrhea in
immunocompetent persons.28

HOST FACTORS
A complex set of defense mechanisms operating
in the host, from the stomach to the colon, help
protect against ingested infectious pathogens.
Gastric acidity
Gastric acidity forms an important first line of
defense against ingested bacteria, which must
survive the acidic environment of the stomach to
establish infection. For this reason, achlorhydric
patients are more susceptible to infection by
various bacterial enteropathogens.8 In a study of
gastric acid in patients with diarrhea, those with
diarrhea caused by V. cholera or ETEC had low
gastric acid levels, whereas gastric acid levels were
normal in patients with shigellosis, amebiasis and
strongyloidosis.29 Furthermore, in an experi-
mental setting, when V. cholera are administered
along with sodium bicarbonate, which neutral-
izes gastric acid, or instilled directly into the duo-
denum, fewer bacteria are necessary to produce
V. cholera-induced diarrhea, highlighting the
protection afforded by gastric acidity.9,30
Intestinal motility and mucus
In the small intestine, normal motility, with the
aid of secreted mucus that physically entraps
bacteria, sweeps ingested bacteria out of the
small bowel into the colon. Mucus also protects
the intestinal epithelium by covering glycolipid
and glycoprotein receptors on the surface of
the enterocytes, which prevents bacteria from
adhering to and invading the enterocytes.31 The
importance of mucus has been further demon
strated in an experimental model of Shigella spp.
infection.32 Some bacteria also secrete toxins that
impair intestinal motility, thereby facilitating
the ability of the bacteria to establish infection
within the host.33
Intestinal microflora
In the colon, the normal intestinal microflora
produces protective factors including short-
chain fatty acids (SCFAs) that are toxic to many
bacterial pathogens. SCFAs, in particular acetate
and formate, have antimicrobial properties
against enteric pathogens including Shigella
spp.34 Administration of an antibiotic that alters
the intestinal microflora increases susceptibility
to infection by multiple pathogens including
C. difficile and Salmonella spp.24,35 Finally, in a
mouse model of Shigella colitis, the administra-
tion of SCFAs demonstrated the protective role
that SCFAs have against bacterial infections.36
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Systemic and local immune responses
Both mucosal and systemic immune systems
provide protection against pathogenic organisms,
as illustrated by the heightened susceptibility of
immunodeficient patients to enteric pathogens.
The epithelium and M cells covering the Peyers
patch and the underlying lymphocytes are essential
for processing antigens for an immune response.37
The importance of secretory immunity is evident
from the development of recurrent infections in
patients with an IgA deficiency. Secretory antibodies
appear in the intestine before serum antibody
after infection by Shigella spp. or V. cholerae and
afford immune protection.38 Toll-like receptors,
in particular, have an important role in innate
immunity by recognizing microbes and activating
an immune response against them.39 In addition,
peptides called defensins, which are produced by
Paneth cells, have an important role in protec-
tive immunity as they are bactericidal for several
microbes.40 Intestinal defensins are also postu-
lated to coordinate host defense responses, and the
interaction between them and the immune cells
has a clear protective role against pathogens.41
Other factors
Breast milk contains multiple factors that protect
against enteric infection. These factors include
anti-infective IgA antibodies, lactoferrin, lyso-
zyme, and lactoperoxidase, and peptides that
inhibit bacterial adherence.42
Genetic factors and polymorphisms
The human genome contains approximately
1.42million single nucleotide polymorphisms
(SNPs). These polymorphisms can be regulatory
and have been investigated in many diseases.
Jiang et al. used fecal DNA to investigate five
SNPs in the IL8 gene that confer susceptibility
to EAEC-associated diarrhea.43 The presence
of an AA genotype at the 251 position in the
promoter region correlated with symptomatic
illness after exposure to EAEC.43 The same geno
type was also found to confer increased suscepti
bility to C. difficile infection.44 In 2007, the
same group demonstrated that a SNP in exon
15 of the lactoferrin gene was associated with
an increased risk of travelers diarrhea among
North American students visiting Mexico.45
SNPs have also been investigated with regard
to conferring susceptibility to viral causes of
diarrheaan association between SNPs in the
fucosyltransferase gene (FUT2) and norovirus
infections has been reported.46 Norovirus produces
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Table 1 Characteristics of inflammatory versus noninflammatory infectious Noninflammatory diarrhea

diarrheas. Noninflammatory diarrheas are usually caused
Characteristic Inflammatory diarrhea Noninflammatory diarrhea
by pathogens that affect the small intestine and
adhere to the mucosa, disrupting the absorp-
Fecal leukocytes Positive Negative
tive and/or secretory processes of the enterocyte
Clinical presentation Bloody, mucoid small- Large-volume, watery without causing considerable acute inflamma-
volume diarrhea; tenesmus diarrhea; no blood, pus
lower left quadrant or tenesmus. May have tion or mucosal destruction. Microbial causes
abdominal cramps: may be nausea, vomiting, cramps, of noninflammatory diarrhea include rotavirus,
febrile and toxic but no fever norovirus, ETEC, V. cholerae, Staphylococcus
Causes Shigella spp., Salmonella Norovirus, rotavirus, aureus, Clostridium perfringens, G. lamblia and
spp., amebic colitis, Vibrio cholerae, Giardia C.parvum.8 Many of these organisms (e.g.
Campylobacter spp., lamblia, ETEC, enterotoxin-
EAEC, EHEC, EIEC, producing bacteria, V.cholerae, ETEC and rotavirus) secrete entero-
Yersinia spp., Clostridium Staphylococcus aureus, toxins that stimulate intestinal secretion and
difficile Cryptosporidium parvum,
Clostridium perfringens
hence the production of watery diarrhea without
any blood or pus.8 Patients with noninflammatory
Site of involvement Colon Small intestine
diarrhea generally have few systemic signs or
Permission obtained from Elsevier Ltd Park SI and Giannella RA (1993) Approach to the symptoms such as abdominal cramping, nausea
adult patient with acute diarrhea. Gastroenterol Clin North Am 22: 34833497. Abbreviations:
EAEC, enteroaggregative Escherichia coli; EHEC, enterohemorrhagic Escherichia coli; EIEC, or vomiting, and fever is typically absent.
enteroinvasive Escherichia coli; ETEC, enterotoxigenic Escherichia coli.

infection by binding to the H type 1 oligo
saccharide on gastric and duodenal epithelial
cells, and the synthesis of H type 1 is contributed
to, in part, by FUT2.46 In fact, a homozygous
inactivating mutation in FUT2 imparts resistance
to infection by norovirus.46
HLA gene polymorphisms, which influence
the T-cell immune response, have been impli-
cated in susceptibility to infections caused by
E.histolytica and Cryptosporidium parvum.4749
Multiple susceptibility loci have also been identi
fied on chromosomes 8, 11 and 13 and in the
STAT6 gene that might determine susceptibility
to infection by Ascaris spp.50,51 In addition,
the presence of the ApoE4 allele might protect
against the cognitive impairment that can be
caused by diarrhea in children.52
Thus, host genetic factors confer susceptibility
to various infections. Future research could help
predict the populations who might benefit from,
or require, vaccination and/or prophylaxis to
prevent diarrheal infections.
CLINICAL SYNDROMES OF INFECTIOUS
DIARRHEA
Infectious diarrheas can be classified, based
on their clinical presentation, into two syn-
dromesnoninflammatory and inflammatory
diarrheas. The characteristics of these two syn-
dromes are compared in Table 1. The clinical
syndromes and mechanisms underlying these
two syndromes differ considerably and are,
therefore, discussed separately.
Inflammatory diarrhea
Organisms that cause inflammatory diarrhea
primarily target the lower bowel, particularly the
distal ileum and colon. These organisms cause
disease either by secreting noxious cytotoxins or
by invading the intestinal epithelium, resulting
in an acute inflammatory reaction.68
Cytotoxin-producing, noninvasive organisms
include EAEC, EHEC and C. difficile. Patients
infected with these noninvasive organisms
usually present with watery diarrhea with or
without passage of blood or mucus, abdominal
pain, and low grade fever.68
Invasive organisms including Shigella spp.,
Campylobacter spp., Salmonella spp., Yersinia
spp., EIEC and E. histolytica also cause an
inflammatory diarrheal syndrome that is
characterized by diarrhea (with or without dys-
entery), abdominal pain and fever.8 Microbial
invasion of the mucosa results in an acute
inflammatory reaction with disruption of the
epithelial barrier, resulting in the presence of
mucus, red blood cells and polymorphonuclear
leukocytes in the stool.7,8 Compared with non-
invasive organisms, invasive organisms can
cause more-severe abdominal pain, more blood
in stool, frank dysentery and a higher fever.8
MECHANISMS OF ENTERIC INFECTION
AND DIARRHEA
Noninflammatory diarrhea
As mentioned earlier, a number of organisms
cause diarrhea by producing and secreting
various proteins called enterotoxins. Most of
these enterotoxins induce intestinal secretion by

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increasing the intracellular concentration of one
of three mediatorscAMP, cGMP or intracellular
calcium.7,8 An overview of the pathogenesis of
these noninflammatory diarrheas is shown in
Figure 1 and is discussed further below.
Vibrio cholerae
V. cholerae causes disease by producing cholera
toxin. All Vibrio strains, including Vibrio 0139
Bengal, produce the same enterotoxin. The clini-
cal features resulting from infection with Vibrio
0139 Bengal resemble those produced by toxin-
producing V. cholerae 01 species (classical and
E1 Tor biotypes).53,54 A study from Bangladesh
comparing the clinical features of infection by
Vibrio 0139 versus V. cholerae 01 in two medical
centers found the clinical features to be largely
similar, but that the different species had differ-
ences in their antibiotic susceptibility.53 Vibrio
0139 was found to be susceptible to tetracycline
and furazolidone in more than 90% of infected
patients; by contrast, V. cholerae 01 was suscep-
tible to tetracycline and furazolidone in 2758%
of infected patients.55
Although cholera toxin can affect the whole
intestine, cholera is largely caused by toxin acti
vity in the proximal small intestine (e.g., the
duodenum and upper jejunum), which is typical
of noninflammatory diarrhea.56 The adherence of
the bacterium to the intestinal epithelium is criti-
cal for the survival of both enterotoxin-producing
and invasive bacteria.8 The attachment of
V.cholerae is mediated by a fimbrial colonization
factor, known as the toxin-coregulated pilus.55
Additional pilus structures, including the fucose-
binding and mannose-binding hemagglutinins,
also promote colonization by the classical and El
Tor biotypes of V. cholerae 01, respectively.57
After adhesion, V. cholerae secretes cholera
toxin.56 Cholera toxin consists of two subunits,
a single toxic active A subunit (CTA), and a
Bsubunit pentamer (CTB), which is responsible
for binding of the toxin to the intestinal epithelial
cell via a ganglioside (GM1) receptor present on
the brush border membrane.57 The bound toxin
is internalized into the intestinal epithelial cell,
through either caveolin-coated vesicles, clathrin-
coated vesicles or the so-called Arf6 endocytic
pathway.58 The A subunit is then cleaved into two
peptides; A1 and A2. The A1 peptide has enzy-
matic ADP-ribosylating activity, and stimulates
the ribosylation of Gs, the stimulatory subunit of
heterotrimeric G protein, leading to irreversible
activation of adenylate cyclase.55 The resultant
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Ingestion of toxin Ingestion of organisms
Bowel colonization
Toxin elaboration
Toxin binding to enterocyte receptors
Concentrations of intracellular mediators
( cAMP, cGMP, Ca2+)
Activation of targets of intracellular mediators
(protein kinases, etc.)
Alteration of transporter proteins and ion channels
Diarrhea
Figure 1 Schema illustrating mechanisms of
pathogenesis for enterotoxin-mediated bacterial
diarrheas. Bacterial enterotoxin (either ingested
in food or produced by ingested pathogens)
binds to receptors on the surface of enterocytes.
This receptor binding results in an increase in
concentrations of either cellular cAMP, cGMP,
or Ca2+, which causes the activation of various
protein kinases. This kinase activation leads to
altered electrolyte transport, resulting in the onset
of diarrhea.
increase in intracytoplasmic cAMP concen
tration leads to altered electrolyte transport by
enterocytes in the form of increased chloride
secretion by crypt cells and reduced absorption
of sodium and chloride ions by villous cells,
which results in diarrhea.55 In addition, cholera
toxin stimulates enterochromaffin cells to release
serotonin, which in turn stimulates the release of
vasointestinal peptide from local enteric neurons,
also producing diarrhea.59
Enterotoxigenic E. coli
ETEC infection causes a noninflammatory
toxin-mediated diarrhea that is similar to, but
less severe than, cholera. As with V. cholerae,
ncpgh_2007_261f1.eps
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ETEC initially adhere to the surface of small
intestinal enterocytes through ligandreceptor
interactions via protein antigens on the surface
of fimbriae, known as adherence antigens or
colonization factor antigens.60
After colonization, ETEC can secrete two
types of plasmid-encoded enterotoxinheat-
labile enterotoxin and heat-stable enterotoxin.
The heat-labile enterotoxin is closely related
to cholera toxin, both biologically and anti-
genically; it also acts on intestinal epithelia and
activates adenylate cyclase through ADP ribo-
sylation of Gs.61 Similarly to CTB, the B subunit
of heat-labile enterotoxin (LTB) is made up of
five identical subunits. However, in addition to
the high affinity of heat-labile enterotoxin for
GM1, this enterotoxin also has binding affinity
for various receptors in the human intestine,
including polylactosaminoglycan-containing
receptors or glycoproteins.62
In addition, the heat-stable enterotoxin pro-
duced by many ETEC strains causes diarrhea by
binding to guanylate cyclase C and triggering
an increase in the intracellular levels of cGMP.8
In fact, close to half of clinical isolates of ETEC
secrete heat-stable enterotoxin only.63 As men-
tioned above, ETEC diarrhea is usually rela-
tively mild, in contrast to the severe dehydration
characteristic of cholera.
Rotavirus
Rotavirus causes diarrhea by producing an
enterotoxin and by activation of the enteric
nervous system. Experimental studies in mice
have hypothesized that a nonstructural rotavirus
protein, NSP4, could be involved in altering epi-
thelial cell function and permeability.64 NSP4
has been shown to increase chloride secretory
currents through a calcium-dependent chloride
secretory mechanism, and activate the enteric
nervous system to produce diarrhea.64 NSP4
also impairs sodiumsolute symport activities
in the gut by blocking the intestinal sodium/
glucose cotransporter 1 (SC5A1), hence contrib-
uting to diarrhea.65 As SC5A1 supports water
reabsorption under physiological conditions, the
inhibition of sodiumsolute symport systems
could also be a cause of rotavirus-induced
malabsorptive diarrhea.65
Norovirus
The exact mechanisms by which norovirus causes
diarrhea are not known. Studies have, however,
shown that norovirus causes malabsorption by
642 nature clinical practice GASTROENTEROLOGY & HEPATOLOGYNavaneethan and Giannella november 2008 vol 5 no 11
damaging the small intestine. This malabsorption
can occur through the broadening and blunting
of villi, and by the diminished activity of intes-
tinal disaccharidases, similar to the mechanisms
used by rotavirus to cause diarrhea.8
Cryptosporidium parvum
C. parvum infection is traditionally classified as
causing noninflammatory diarrhea, but it has
also been known to cause inflammatory diar-
rhea in children. Indeed, diarrhea caused by
C.parvum infection in children has been associ-
ated with elevated concentrations of lactoferrin
in stool, a marker of inflammation.8 By con-
trast, normal levels of lactoferrin are observed
in healthy adults with C. parvum infection.8 Of
note, adults infected with C. parvum usually have
a milder and self-limited illness.
C. parvum attaches to a 85kDa surface
protein on intestinal epithelial cells via its apical
glycoprotein CSL complex.66 After adhesion,
C.parvum causes fluid secretion through mul-
tiple mechanisms involving increased local levels
of prostaglandins, and hence cAMP-mediated
chloride secretion, inhibition of electroneutral
sodium chloride and decreased water absorp-
tion by enterocytes.67,68 Although C. parvum
produces secretory diarrhea, villous atrophy and
inflammatory infiltrate in the lamina propria
have been observed, providing an explana-
tion for the inflammatory diarrhea occurring
in children.69
Giardia lamblia
G. lamblia trophozoites adhere to the epithelium
of the upper small intestine and damage the
mucosal brush border without invasion.70
Pathologic changes correlate with the severity
of diarrhea and range from normal-appearing
duodenal mucosa to severe villous atrophy with a
mononuclear cell infiltrate similar to that seen in
patients with celiac sprue.70,71 The mechanisms
by which G. lamblia causes diarrhea are unclear.
HIV-1
In addition to the opportunistic infections that
cause diarrhea, HIV-1 can cause severe watery
diarrhea. In vitro models of HIV infection
indicate that the transactivating Tat peptide of
HIV-1 might stimulate active fluid secretion in
human enterocytes, in a similar way to cholera
toxin, and could have a role in the pathogenesis
of diarrhea in patients with AIDS.72 In addition,
Tat protein inhibits sodium ion and glucose

symporter activity, contributing to the occurrence
of osmotic diarrhea.72
Other enterotoxin-producing organisms
In addition to the above-mentioned causes of
noninflammatory diarrhea, several enterotoxin-
producing organisms have preformed toxins
and can cause food poisoning without
requiring intestinal colonization.8 S. aureus,
C.perfringens, and Bacillus cereus infections
all produce diarrhea by altering the intesti-
nal flux of salt and water in a similar way to
enterotoxin-producing bacteria.8
Inflammatory diarrhea
The main histologic finding in patients infected
with pathogens causing inflammatory diarrhea
is an acute inflammatory reaction in the mucosa,
with various degrees of mucosal ulceration.
As mentioned earlier, whereas the toxigenic
organisms that cause noninflammatory diar-
rhea characteristically involve the upper small
intestine, the cytotoxin-producing and invasive
pathogens that cause inflammatory diarrhea
target the lower bowel.
There are important differences among the
invasive microbes that cause inflammatory
diarrhea; however, they all share the property
of mucosal invasion as the initiating event.
Although a great deal is known about the
mechanisms underlying intestinal invasion,
the mechanisms of intestinal secretion are less
well understood. In some cases, these organ-
isms secrete enterotoxins that stimulate intesti-
nal secretion. In addition, the products of the
inflammatory reaction and the local synthesis
of inflammatory mediators including cytokines
and prostaglandins contribute to both mucosal
damage and intestinal secretion. An overview of
the pathogenesis of diarrheas caused by invasive
organisms is shown in Figure 2.
Enterohemorrhagic E. coli
Infection with EHEC, including E. coli O157:
H7 and other serotypes, can cause various
syndromes, including an acute hemorrhagic
colitis, nonbloody diarrhea, hemolytic-uremic
syndrome and thrombotic thrombocytopenic
purpura.73
EHEC strains initially attach to the intestinal
mucosa via a plasmid-encoded pilus.73 After
adherence, activation of protein kinase, along
with the release of intracellular calcium, produces
ultrastructural changes (i.e. flattening and
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Ingestion of organisms
Intestinal colonization
Mucosal invasion Cytotoxin elaboration
Intramucosal
multiplication
Arachidonic
acid
metabolites,
cytokines
Acute inflammation
Diarrhea
Figure 2 Schema illustrating mechanisms of
pathogenesis for invasive and cytotoxin-mediated
bacterial inflammatory diarrheas. After ingestion,
organisms colonize the intestine and either invade
the ileal and colonic mucosa or secrete a noxious
cytotoxin intraluminally. Both these pathways
induce an acute inflammatory reaction of the
mucosa. The products of this reaction induce
intestinal secretion and diarrhea.
dissolution of villi), termed attachingeffacing
lesions.73 Attachment is strengthened further by
binding of the EHEC outer membrane protein
intimin to its receptor (Tir), which is secreted by
EHEC into the intestinal epithelial cells and then
inserted into the plasma membrane.
In addition, EHEC secrete two Shiga-like
toxins; STX cytotoxins I and II.74 Some EHEC
strains, including the recently identified O26:
H11 strain, produce only STX I, but in addition
secrete hemolysins, serine proteases (EspP),
lymphotoxins (Efal) and have high patho
genicity islands, similar to Yersinia spp.73 The
pathophysiologic role of these various proteins
is unclear.
Clostridium difficile
C. difficile infection produces toxin-mediated
inflammatory diarrhea. The genes encoding
the two toxins (A and B), are in the C. difficile
pathogenicity locus, which also contains two
additional regulatory genes: tcdC and tcdD.75
ncpgh_2007_261f2.eps
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The tcdD gene product upregulates toxin trans
cription, while tcdC probably encodes a toxin
gene repressor.75 Toxins A and B are UDP-
glucose hydrolases and glucosyltransferases
that contribute to the inflammatory diarrhea;
however, it is thought that toxin B might be the
major inflammatory toxin.76
Toxins A and B initially attach to non
proteinaceous disaccharide galactose-14-N- Several Shigella spp. virulence factors, both
acetylglucosamine residues on colonic epithelial
cells.77 After adhesion, the toxin enters the cell
through receptor-mediated endocytosis and cata-
lyzes the transfer of a glucose residue from UDP-
glucose to guanosine-triphosphate-binding rho
proteins,65 which are the intracellular signaling
molecules that regulate cytoskeletal organiza-
tion and gene expression. Glucosylation of rho
proteins in turn leads to disruption of protein
synthesis and cell death.75 NF-B and MAP
kinases are also activated, leading to the release
of interleukin (IL)-1, tumor necrosis factor,
and IL8,8 which contributes to the marked
intestinal inflammatory response and secretion
that is observed with C. difficile infection.
Enteroaggregative E. coli
EAEC infect the intestine and produce diarrhea
by adhering to the epithelial brush border and
altering cell function, as discussed in further
detail below. A similar group of organisms,
EPEC, cause disease through similar mech
anisms. EPEC produce localized adherence
whereas EAEC produce a diffuse adherence.78
Although adherence of EAEC can occur in
jejunal, ileal and colonic epithelium, the colonic
epithelium is the principal target. Adherence is
mediated by the aggregative adherence fimbriae,
particularly aggregative adherence fimbria II.79
Another protein, dispersin, facilitates the dis-
persal of the EAEC and promotes the develop-
ment of new foci of infection.80 Other factors
including membrane associated protein and
aggregative protein 58 might also contribute
to adherence.79,80
EAEC adherence stimulates mucus production
and the production of a mucus biofilm, which
might contribute to the development of mal-
nutrition and prolonged diarrhea.81 An acute
inflammatory response follows after adhesion
and is associated with enterocyte damage, cyto-
kine release and intestinal secretion. The entero-
cyte damage is mediated by several toxins.82
Plasma encoded toxin produces both enterotoxic
and cytotoxic effects.82 EAEC flagellin triggers
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the host inflammatory response through toll-
like receptor 5,39 and stimulates the release of
IL-8, which causes epithelial cell destruction
and fluid secretion.21 The role of heat-stable
enterotoxin (EAST1) is not clear but it might
stimulate secretion.82
Shigella spp.
chromosomal and plasmid-encoded, are
involved in the cellular invasion that leads to the
death of an intestinal epithelial cell.22 Shigella
spp. contain a large plasmid that encodes the
principal type III secretion system and other viru
lence factors that facilitate host invasion.22,83
The plasmid copy number is upregulated on
contact with host intestinal cells: IpaB and IpaC
proteins are released and alter the function
of actin filaments. Shigella spp. also synthesize
an actin-nucleating protein (IcsA) that helps the
bacteria move laterally through one cell mem-
brane into an adjacent cell, thereby facilitating
the spread of infection by cell-to-cell transfer
of bacilli.22 Shigella spp. rarely penetrate beyond
the intestinal mucosa, but multiply within the
epithelial cells.83
Apoptosis of infected enterocytes releases
infective bacteria along with inflammatory
mediators, such as IL-8, which cause epithelial
cell destruction.84 In addition to the mechanism
described above, S. dysenteriae 1 and certain
strains of S. flexneri and S. sonnei also secrete
an enterotoxin that inhibits protein synthesis
by irreversible inactivation of the 60S ribosomal
subunit, causing cytotoxicity and cell death.74
This toxin also stimulates intestinal secretion
via upregulation of luminal galanin-1 receptors,
which in turn increases chloride secretion.85
Salmonella spp.
The principal target of Salmonella spp. is the
ileum and, to a lesser extent, the colon.8 As with
Shigella infection, both plasmid-encoded and
chromosomal-encoded virulence factors are
important in the pathogenesis of salmonella.
The Salmonella spp. plasmid contains genes
that encode proteins vital for bacterial spread
and invasion, survival within macrophages after
phagocytosis, and transepithelial signaling to
neutrophils, which together trigger cell destruc-
tion.86 Enterotoxins and the outer-membrane
lipopolysaccharide containing the Vi antigen
contribute to the pathogenesis of Salmonella
enterocolitis. Increased intestinal secretion results

from an inflammatory reaction in addition
to the response to enterotoxin.8,86
Campylobacter jejuni
C. jejuni infection produces a spectrum of illness
ranging from watery, noninflammatory diar-
rhea to acute inflammatory enterocolitis.8 The
pathogenesis of C. jejuni-mediated inflamma
tory diarrhea is different from that of diarrhea
caused by Shigella spp. or EIEC. C. jejuni enter
the intestinal epithelium through the M cells
of the Peyers patch via a microtubule-based
entry system,87 and spread to adjacent cells baso
laterally through interaction with host invasion
receptors.88 Pathogenic C. jejuni strains also
produce cytolethal distending toxin (CDT), a
nuclease that results in arrest of the cell cycle
and DNA damage.89 In addition to the direct
effect of the toxin, C. jejuni mucosal invasion
and CDT also trigger IL-8 release from the
epithelium.89 The proinflammatory cytokine
IL8 is also chemotactic, triggering an influx of
polymorphonuclear leucocytes. Both the local
inflammatory response and CDT-induced cell
damage cause inflammatory diarrhea.
Entamoeba histolytica
Invasive amebiasis attributable to infection by
E. histolytica is more common in developing
countries than developed countries.8 Colonic
inflammation caused by E. histolytica infec-
tion is a consequence of both amebic virulence
factors and the host response.8,90 After pen-
etrating the protective mucus barrier of the
colon, the trophozoite attaches to the colonic
mucins and epithelial cells via its galactose
N-acetyl-[D]-galactosamine-inhibitable surface
lectin.90 The lectin might also participate in sig-
naling cytolysis, block the deposition of mem-
brane complement and anchor the ameba to
intestinal proteoglycans.
After adhesion of the pathogen to the cell,
channel-forming peptides called amebophores
are formed that cause cytolysis, resulting in swell-
ing and lysis of the target cell, leaving the para-
site unharmed.90 Cysteine proteinases secreted
by the trophozoites, encoded by six different
genes (EhCP1 to EhCP6), then promote tissue
invasion by burrowing through human colonic
mucus and matrix proteins.91 Further disruption
of the colonic epithelium occurs from the host
immune response to the pathogen in the form of
neutrophil recruitment and immune-mediated
tissue damage.90
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CONCLUSIONS
A great deal has been learned about the patho-
genesis of intestinal infections that cause diar-
rhea in the past decade. Nevertheless, our
understanding of the pathogenesis of a number
of organisms, including the common norovirus
and EAEC, is still suboptimal. The finding that
there is a genetic association with susceptibility
to intestinal infections is exciting and has opened
up new avenues of researchfor example, defin-
ing populations at risk who could benefit from
interventions and treating those populations
appropriately. Much work remains to be done to
further understand hostmicrobe interactions,
the complex signaling pathways activated fol-
lowing invasion of the host, and how the host
response can be modulated to control the
disease process.
KEY POINTS
Infectious diarrhea is a global health
problem and can be classified, based on the
pathogenesis and clinical presentation, as
noninflammatory diarrhea or inflammatory
diarrhea
Various host factors protect against enteric
infection, and enteropathogens must overcome
these to cause disease
Common microbial causes of noninflammatory
diarrhea are viruses, enterotoxin-
producing organisms, Giardia lamblia and
Cryptosporidium parvum
Enterotoxigenic Escherichia coli and Vibrio
cholerae infections cause ADP ribosylation of
Gs protein, whereas heat-stable enterotoxin-
producing E. coli stimulate cGMP production;
both E. coli and V. cholerae increase chloride
secretion by crypt cells to produce watery
diarrhea
Inflammatory diarrhea is caused by two
groups of organisms: cytotoxin-producing,
noninvasive bacteria (enteroaggregative E. coli,
enterohemorrhagic E. coli, and Clostridium
difficile); and invasive organisms (e.g.
Salmonella spp., Shigella spp., Campylobacter
jejuni)
Cytotoxin-producing organisms adhere
to the mucosa, activate cytokines and
stimulate the intestinal mucosa to release
inflammatory mediators; invasive organisms,
which can also secrete cytotoxins, invade
the intestinal mucosa to induce an acute
inflammatory reaction and activate cytokines
and inflammatory mediators
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review
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