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Harvard Medical School, Boston, MA and Pediatric Gastroenterology and Nutrition, Massachusetts General Hospital and Children’s Hospital, Boston, MA
2To whom correspondence should be addressed.
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONToxin interaction with the...Clinical consequences of toxin...REFERENCES |
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KEY WORDS: • bacterial toxin • enterocyte • developmental regulation
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONToxin interaction with the...Clinical consequences of toxin...REFERENCES |
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, Chu and Walker 1991
,
Cohen et al. 1986
, Field et al. 1989
).
The role of human milk, host defenses and luminal factors in the
prevention of diseases such as necrotizing enterocolitis
(NEC)3
have been the focus of research in recent years. The
purpose of this review will be to provide a brief insight into the
significance of intracellular events that follow toxin-receptor
interactions in the developing gut.
The mucosa forms the first barrier to antigens presented at the
epithelial surface. The mucosal barrier comprises several components,
including factors such as gastric pH, gastric and pancreatic enzymes, a
glycoprotein-rich mucin layer and an intact microvillous enterocyte
surface under growth factor control. Surface immunoglobulin (Ig)A and
Ig M also provide surface protection at the epithelial surface
(Table 1
).
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-interferon, tumor necrosis factor (TNF)
and IL-8, whereas anti-inflammatory cytokines include IL-1 Ra,
transforming growth factor-ß, IL-4 and IL-10. Apart from the actions
of cytokines, there are a variety of other events that occur at the
epithelial surface on exposure to bacterial colonization or adherence;
these include the release of prostaglandins (PG), up-regulation of
molecules such as class II antigens, poly A receptor, cytokine
receptors and the release of growth factors and growth factor–binding
proteins. |
Toxin interaction with the intestine |
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TOPABSTRACTINTRODUCTIONToxin interaction with the...Clinical consequences of toxin...REFERENCES |
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Much of our understanding of bacterial epithelial interaction comes
from studies on cholera toxin and the mucosa. Cholera toxin (CT) is an
84-kDa protein secreted by Vibrio cholera that colonizes the
upper small intestine. The binding component consists of five identical
B- (binding) subunits that bind specifically to apical ganglioside GM1
receptors activating adenylate cyclase to induce a massive secretory
response. The A- (activation) subunit is comprised of two peptides
linked by noncovalent interactions and a disulfide bond. CT activation
of adenylate cyclase involves several steps. Binding of the
B-subunits to the ganglioside GM1 on the cell surface is followed
by translocation of the A-subunit across the membrane. The
disulfide bond is then reduced to form the enzymatically active
A-subunit that catalyzes ADP-ribosylation of the regulatory
GTPase Gs-
and in turn activates adenylate cyclase. GM1 receptors
with which CT makes contact lie on the apical surface of polarized
cells, whereas the activation of adenylate cyclase occurs at the
basolateral membrane. The intracellular route that CT takes to achieve
these effects was previously unclear. One of the possibilities was that
the A-subunit penetrates the plasma or possibly the endosomal
membrane. The hypothesis that endocytosis and vesicular transport are
required for the action of CT on polarized intestinal epithelial cells
was tested using a T84 human intestinal epithelial cell line that forms
confluent monolayers of polarized columnar cells displaying features of
crypt cells. When applied to apical or basolateral surfaces, CT induced
a cAMP-dependent chloride secretory response. Lencer et al. (1995)
showed that the toxin requires endocytosis and
processing in intracellular compartments to elicit its effect. They
then proceeded to show that cholera toxin in fact entered basolaterally
directed transport vesicles and both B- and A-subunits were hence
delivered intact to the basolateral membrane, identifying a possible
explanation for the surface receptor and basolateral effects seen with
cholera toxin. Toxin-induced signal transduction depended on the
specificity of the ganglioside receptor and on the coupling of cholera
toxin with caveolae or caveolae-related membrane domains
(Wolf et al. 1998
). CT may also stimulate intestinal
secretions by an activation of the enteric nervous system and a
secondary activation of arachidonic acid metabolites, causing an
increase in the production of PG. Cholera toxin and heat labile
Escherichia coli toxin have been considered previously to be
identical in their mode of action by increasing intracellular adenosine
3–5 cyclic monophosphate concentration. As recently shown by
Turvill et al. (1998)
, the secretagogue
5-hydroxytryptamine (5-HT) is involved in CT secretion but not in
labile toxin (LT) secretions. CT-mediated secretions were reduced
by 5-HT depletion and inhibited by 5-HT antagonists.
Endotoxin interaction.
Endotoxin or lipolpolysaccharide (LPS) is the outer membrane glycolipid
of gram-negative bacteria. On release from bacteria, it stimulates
mediators from host cells and may lead to septic shock.
LPS-responsive cell types include monocytes/macrophages,
polymorphonuclear leukocytes (PMN), and endothelial and epithelial
cells. Endotoxin may compromise basal colonic water and electrolyte
transport as well as increase intestinal permeability (Detch et al. 1987
, Odwyer et al. 1988
). Increased release
of cytokines, TNF, IL-1, platelet-activating factor (PAF) and
oxygen-derived free radicals from the gastrointestinal tract has
been shown to occur with endotoxins (Ciancio et al. 1992
). Recognition of LPS triggers gene induction by myeloid
and nonmyeloid cells; these genes encode proteins that include
cytokines, adhesive proteins and enzymes that produce
low-molecular-weight inflammatory mediators. Thus they up-regulate
host defense mechanisms that work toward elimination of the bacteria
(Ulevitch and Tobias 1995
). CD 14 is a protein that
plays a key role in LPS-induced cell activation. Sheifele et al. (1987)
have shown an association between
endotoxemia and thrombocytopenia in NEC.
Other bacterial products that may play an important role in the
intestinal epithelium include butyrate, a short-chain fatty acid
that is a product of bacterial fermentation of carbohydrates. Butyrate
may not only be an energy source for colonocytes (Roediger 1982
) but may also stimulate epithelial cell proliferation and
cytokine release (Kripke et al. 1989
). Sodium butyrate
may increase significantly the release of IL-8 from intestinal
epithelial cells, and this effect is particularly marked when the cells
are also stimulated with IL-1 ß or LPS. Butyrate also enhanced IL-8
mRNA in Caco2 cells, suggesting that the intestinal epithelial cell may
regulate intestinal inflammation in response to changes in the
intestinal luminal contents (Fusunyan et al. 1998
).
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Clinical consequences of toxin interaction |
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TOPABSTRACTINTRODUCTIONToxin interaction with the...Clinical consequences of toxin...REFERENCES |
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NEC is a disease of the immature bowel. It is a clinicopathologic
syndrome defined as idiopathic coagulation necrosis and inflammation of
the intestine in a neonatal patient (Kleinhaus et al. 1992
). Its pathogenesis is multifactorial, with several major
factors implicated; these include enteral feeding, intestinal ischemia,
bacterial adherence, invasion and proliferation (Kleigman et al. 1993
), along with host factors such as gut immaturity.
Manifestations vary from a benign feeding intolerance to abdominal
distension, diarrhea, intestinal perforation, sepsis and shock.
Pathologic changes include mucosal edema, hemorrhage, ischemia,
necrosis and bacterial overgrowth (Santulli et al. 1975
)
NEC is a leading cause of morbidity and mortality in newborns; some
reports estimate a >10% incidence among infants weighing <1500 g
(Lencer et al. 1995
) (Fig. 1
). Extensive research done to understand the pathophysiology of NEC
suggests that newborn infants may have systemic as well as
gastrointestinal mucosal impairments that may predispose them to
aberrant gut bacterial overgrowth and subsequent mucosal inflammation
and injury (Spencer et al. 1990
). In addition to reduced
numbers of B cells, decreased IgA-producing plasma cells and
decreased T cells in the intestinal mucosa, there may also be an
increased intestinal permeability to macromolecules and bacteria that
would contribute further to inflammation and fulminant NEC
(Spencer et al. 1990
). Animal studies done have helped
in increasing the understanding of NEC. Neonatal rats fed under hypoxic
conditions developed features of NEC. Intravenously infused cytokines
such as PAF, TNF- and LPS have led to pathologic changes in the
bowel consistent with NEC (Kleigman and Walsh 1987
,
Sun and Hsueh 1988
, Tracey et al. 1986
).
Intestinal colonization with cytotoxin-producing organisms can also
induce different degrees of enterocolitis (Schiefele 1990
).
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, Goman et al. 1979
, Kleigman and Walsh 1987
, Schiefele 1990
). It was found that neonates requiring intensive care
showed abnormal bowel flora development, suggesting that initial
colonization was with bacteria whose by-products were toxic to
intestinal epithelial cells. Organisms associated with these findings
included, Clostridium difficile, E. coli,
Klebsiella pneumoniae, Staphylococcus aureus and
S. epidermidis (Bennet et al. 1986
,
Goman et al. 1979
, Han et al. 1983
,
Schiefele et al. 1987
, Schiefele 1990
, ).
In germ-free animals, strains of these organisms were associated
with bowel injury (Lawrence et al. 1982
).
Bacterial infections in the neonate and infant are responsible for
significant morbidity and sometimes even death. Bacteria vary in their
mode of action or invasion at the epithelial surface. Important
virulence factors include fimbrial attachment factors that promote
attachment to the epithelial surface, the production of various
enterotoxins, expression of key outer membrane proteins that determine
internalization by the enterocyte and the release of cytotoxins that
promote mucosal cell death (Caplan and MacKendrick 1994
,
Isberg and Leong 1990
, Kantele and Makela 1991
, Levine et al. 1983
). Theoretically,
prevention of NEC would include elimination of risk factors that would
promote intestinal ischemia in the immature gut and the promotion of
the use of breast milk that may contain growth factors, hormones and
immunoglobulins that would promote intestinal maturity.
There has been a great deal of enthusiasm for the anti-infective
properties of breast milk. Apart from being a relatively uncontaminated
source of nutrition, it contains several factors that may enhance host
resistance to intestinal pathogens. It contains glycoconjugates, with
generalized and specific protective properties, and antioxidants that
alter the inflammatory response (Goldman et al. 1986
).
Breast milk also contains several nonimmune factors. It contains GM1
ganglioside, which binds cholera toxin and LT of E. coli
(Otnaess et al. 1983
), as well as globotriose that
functions similarly to bind Shiga toxin (Lingwood et al. 1987
, Newburg et al. 1992
). Milk
oligosaccharides such as the fucosylated trisaccharide block the
heat-stable toxin (ST) of E. coli (Newberg et al. 1990
); others block C. jejuni, S.
pneumoniae and Hemophilus influenzae binding
(Anderson et al. 1986
, Cravioto et al. 1991
, Jumawan et al. 1977
). In vitro and in vivo
animal studies have demonstrated a decrease in intestinal permeability
to orally fed protein on administration of growth factors. Similarly,
steroids and thyroid hormone may induce maturation of surface enzymes
(Chu and Walker 1986
, Jumawan et al. 1977
), membrane fluidity (Israel et al. 1987
),
surface glycoconjugates and receptors (Pang et al. 1987
).
Changes in intestinal permeability (Daniels et al. 1973
,
Israel et al. 1986
) and bacterial colonization have also
been demonstrated with the use of steroids. Prenatal and postnatal
steroid treatment (Bauer et al. 1984
, Halac et al. 1990
) have also been associated with a decrease in NEC. A
study that reported use of intravenous epidermal growth factor (EGF)
was also efficacious in a neonate with NEC (Sullivan et al. 1991
). Animal experiments in rat pups with prenatal steroid use
showed a decrease in NEC. The number of bacterial colonies was also
reduced in steroid-treated pups, suggesting that it may render the
pups less susceptible to bacterial organisms.
One of the first immune responses to enteric pathogens is the
development of an IgA response with the production of specific IgA
antibodies to the antigen. Passively administered antibodies through
breast milk concentrates confer a very high level of protection in
adults challenged with E. coli or Shigella.
Intracellular bacterial infections in the neonate may also elicit a
powerful MHC class I restricted cytotoxic lymphocyte response
(Brown et al. 1980
, Kaufmann 1988
). An Fc
recptor specific to IgG has been demonstrated in fetal intestine and
may play a role in protection against the development of NEC in
neonatal intestine.
Enterotoxin induced diarrhea.
Toxin intestinal interactions require the following three important steps: 1) toxin binding to the microvillous receptor, 2) signal transduction response, and 3) an enterocyte-effector response. Developmental differences may exist in the intestine at all three levels of this interaction.
Bacterial toxin receptors at the microvillous membrane.
Specific oligosaccharides on surface receptors may serve as important
factors in bacterial interaction at the enterocyte (Karlsson 1989
, Paulson 1989
, Radenmacher et al. 1988
). Binding sites at the surface of the cell may exist as
glycolipid or glycoprotein structures. Using a rat glial C6 cell line,
Fishman et al. (1980)
showed the importance of a
glycoprotein in CT binding. This binding also requires the presence of
three sugar moieties, galactose, N-acetylgalactosamine and
sialic acid. These cell surface carbohydrates are regulated
developmentally and are species and tissue specific; hence they may
affect age-specific susceptibility to intestinal infections.
Glycolipid receptors.
Although the core sequences of glycolipid receptors are structurally
similar, it is the terminal oligosacchariode sequence that determines
toxin binding specificity. Several such receptors have been identified
(Table 2
).
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E. coli produces both an LT and
an ST. Although LT binds principally to GM1 on the enterocyte, one of
the receptors for ST is a plasma membrane form of guanylate cyclase
(Schulz et al. 1990
). Recent evidence also indicates
that C. difficile toxin A binds a glycoprotein receptor in
hamsters and rabbits (Pothulakis et al. 1988
).
Tucker and Wilkins (1991)
demonstrated that three human
carbohydrate antigens with a similar conformation can serve as the
binding site to toxin A (Tucker and Wilkins 1991
). The
three antigens, I, X and Y, can be expressed as either surface
glycolipids or glycoproteins.
Developmental changes in membrane receptors and host response
Developmental differences in the number and affinity of surface receptors may play an important role in the development of toxigenic diarrhea. These age-related differences have been studied with the use of binding assays or glycoprotein analysis.
In animal experiments, it was demonstrated earlier that there was a
great difference in fluid secretion in the intestine of preweaned rats
exposed to CT compared with mature intestine (Chu et al. 1989
, Fig. 2
). On comparison of receptor numbers and affinity between mature
and immature intestine, a similar number of receptors but with a slight
increase in binding affinity were noted in the immature intestine. On
estimation of coupling efficiency for receptor binding and response, a
decrease was seen from 30% in the preweaned to 1% in the weaned rat,
suggesting that cellular maturation may account for the decreased
receptor effector coupling seen. Other factors that may influence this
response include luminal factors such as the presence of enzymes,
microflora and mucin at the intestinal cell surface.
|
) Postreceptor events may also contribute to the
developmental variations in host response to bacterial toxins. Although
ST acts via guanylate cyclase to increase cGMP, CT acts via activation
of cAMP, both producing a secretory response.
Receptor-dependent decrease in host responsiveness.
Animal studies have shown a direct correlation between receptor
expression and toxin effects with Shiga toxin and C.
difficile toxin A. Rabbit intestine shows an age-dependent
increase in receptor expression for Shiga toxin with the receptor Gb3
detectable in rat intestine only postweaning (Cohen et al. 1988
, Mobasseleh et al. 1988
and 1989
). This may
explain the relative resistance to Shigella infections in the neonate.
With C. difficile, however, receptor underdevelopment in
combination with mucosal factors may be important in protection against
the toxin. C. difficile receptors in human intestine differ
from those present in rabbit intestine, and the organism does not
produce disease in the infant even though it is frequently detected in
the stool (Eglow et al. 1992
, Van der Waaj 1989
).
Developmental control of receptor expression.
Because a specific oligosaccharide structure is important in receptor
binding by bacteria, regulation of specific sugar expression would
control effective bacterial binding to the enterocyte. Although
incompletely understood, one of the mechanisms is through the control
of glycosyltransferase expression. In the rat small intestine, there is
a shift from sialylation to fucosylation of the microvillous membrane
with weaning (Torres Pinedo and Mahmood 1984
). This
increased sialylation is reflected in an increased surface expression
of GM3 but not GM1 (Bouhors and Bouhors 1983
). An
increase in fucosyltransferase activity may also control an increased
expression of fucosyl lipids and proteins and therefore enhance
C. difficile receptor expression. The activities of
galactosyltransferase and N-acetyl
galactosamineyltransferase also increase with age but their importance
in receptor expression remains to be elucidated.
External factors.
External factors such as phorbol esters (Ozaki et al. 1989
), sodium butyrate (Simmons et al. 1975
),
nutrients in the diet and various deficiencies such as that of vitamin
A (Sato et al. 1984
), cortisone and thyroxine
(Chu et al. 1989
) as well as bacterial products may also
influence the expression of surface receptors. Cortisone, known to
promote enterocyte maturation when injected into suckling rats,
decreased host sensitivity to CT significantly (Chu et al. 1989
). These factors may exert control at the transcriptional
level by influencing gene expression of glycosyltransferases or by
phosphorylation-dephosphorylation.
Postreceptor events.
In comparison to secretory responses to CT/LT in mature enterocytes,
the immature intestine has an exaggerated response (Chu et al. 1989
). An increased response in adenylate cyclase activity may
be a possible explanation and suggests that postreceptor signal
transduction events may be important in the exaggerated secretory
response seen in neonates on exposure to toxin (Seo et al. 1989
). Gs- is the target protein for CT. A postweaning
decline in this protein has been demonstrated in the rat small
intestine. Developmental regulation of Gs- expression in rat
intestine may influence responsiveness to CT (Chu et al. 1991
and 1992
).
Additional factors that may influence toxin receptor interaction in the
developing gut may include factors such as membrane fluidity in
immature vs. mature enterocytes, allowing for greater uptake and
migration of the A1 component of CT (Pang et al. 1983
). Other factors such as immaturity of the
Na+/K+ ATPase, Na/Cl
cotransporters and the chloride channels may also influence fluid
secretion from the enterocyte (Zemelman et al. 1992
).
With the use of rat microvillous membranes, previous work showed that
developmental changes in membrane structure that influence binding
affinity but not receptor density may contribute to the increased
sensitivity of immature enterocytes to CT.
Prevention and treatment
Breast milk contains a variety of factors that have been
demonstrated to have anti-inflammatory properties and may protect
the neonate from the development of toxin-induced diarrheas. Such
cytoprotective factors include PGE2,
PGF2, EGF and lactoferrin. Maturational
factors such as steroids and thyroid hormones are also protective.
Enzymes that degrade inflammatory mediators such as
PAF-acetylhydrolase, inflammatory modulators such as lysozymes,
secretory IgA, antioxidants such as -tocopherol, ascorbate,
ß-carotene and uric acid may also play a role in protection.
Probiotics.
Probiotics such as lactobacilli stimulate mucosal barrier function, by
competing with pathogenic bacteria for mucosal colonization and by
metabolizing nutrients to promote host defense. These are live
microorganisms belonging to normal flora and have low or no
pathogenicity. It is becoming increasingly evident that probiotics may
be effective tools in controlling bacteria at the mucosal surface. They
can control various enteric pathogens such as Salmonella
typhimurium, Shigella, Campylobacter and
E. coli (Corthier et al. 1985
,
O’Sullivan et al. 1992
, Perdigon et al. 1990
). Lactobacillus rhamnosus strain GG (ATCC
53103) has proven to be effective in preventing and treating diarrhea
in premature infants, newborns, children and travelers (Isolauri et al. 1995
, Millar et al. 1993
, Sepp et al. 1993
). Lactobacillus planatarum prevents the
adherence of E. coli to the mucosa and hence interferes with
the delivery of endotoxin to the epithelium.
SUMMARY
The complex environment that exists within the intestinal lumen is tightly regulated by an interaction between the normal flora and ingested nutrients. Diet and environmental factors can influence this equilibrium. Modified enteric nutrients may serve to down-regulate the inflammatory response induced by bacteria not only by altering bacterial colonization but also by affecting directly enterocyte gene expression of inflammatory cytokines. Specific nutrients such as probiotics may act to enhance intestinal host defense. Further work is required to elucidate the role of nutrients in the mucosal inflammatory response and particularly the role of breast milk in the development of the mucosal immune response.
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FOOTNOTES |
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3 Abbreviations used: CT, cholera toxin; EGF, epidermal growth factor; 5-HT, 5-hydroxytriptamine; Ig, immunoglobulin; IL, interleukin; LPS, lipopolysaccharide; LT, labile toxin; NEC, necrotizing enterocolitis; PAF, platelet-activating factor; PG, prostaglandin; PMN, polymorphonuclear leukocyte; ST, heat-stable toxin; TNF, tumor necrosis factor.
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REFERENCES |
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TOPABSTRACTINTRODUCTIONToxin interaction with the...Clinical consequences of toxin...REFERENCES |
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