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Infection and Immunity, December 2000, p. 7010-7017, Vol. 68, No. 12
Gastrointestinal Unit, Massachusetts General
Hospital, and Harvard Medical School, Center for the Study of
Inflammatory Bowel Disease, Boston, Massachusetts 02114
Received 20 June 2000/Returned for modification 22 August
2000/Accepted 7 September 2000
Initiation and perpetuation of the inflammatory intestinal
responses in inflammatory bowel disease (IBD) may result from an exaggerated host defense reaction of the intestinal epithelium to
endogenous lumenal bacterial flora. Intestinal epithelial cell lines
constitutively express several functional Toll-like receptors (TLRs)
which appear to be key regulators of the innate response system. The
aim of this study was to characterize the expression pattern of TLR2,
TLR3, TLR4, and TLR5 in primary intestinal epithelial cells from
patients with IBD. Small intestinal and colonic biopsy specimens were
collected from patients with IBD (Crohn's disease [CD], ulcerative
colitis [UC]) and controls. Non-IBD specimens were assessed by
immunofluorescence histochemistry using polyclonal antibodies specific
for TLR2, TLR3, TLR4, and TLR5. Primary intestinal epithelial cells
(IEC) of normal mucosa constitutively expressed TLR3 and TLR5, while
TLR2 and TLR4 were only barely detectable. In active IBD, the
expression of TLR3 and TLR4 was differentially modulated in the
intestinal epithelium. TLR3 was significantly downregulated in IEC in
active CD but not in UC. In contrast, TLR4 was strongly upregulated in
both UC and CD. TLR2 and TLR5 expression remained unchanged in IBD.
These data suggest that IBD may be associated with distinctive changes
in selective TLR expression in the intestinal epithelium, implying that
alterations in the innate response system may contribute to the
pathogenesis of these disorders.
The two major forms of idiopathic
inflammatory bowel diseases (IBDs), ulcerative colitis (UC) and
Crohn's disease (CD), are distinguished by a complex chronic
inflammatory process. Although there is increasing evidence that IBD
results from the combined effects of environmental agents in the
genetically susceptible host, neither the specific genes nor the
environmental triggers have been definitively identified yet. A central
role for specific immune responses to discrete antigens has been
presumed, and circumstantial evidence in humans and direct studies of
mutant murine models implicate lumenal bacteria as necessary cofactors
for initiating and perpetuating inflammation.
Bacteria contain toxic compounds which are potent stimuli of innate
immune responses, as exemplified by the gram-negative bacterial cell
wall component lipopolysaccharide (LPS). However, the mechanistic basis
of the interaction between the lumenal flora and the intestinal mucosa
remains to be fully defined. It is possible that bacterial products
penetrate the epithelial barrier, either due to damage or via
paracellular pathways, to directly stimulate the underlying
constituents of the mucosal immune system. However, alternatively, it
is possible that products may interact at the apical surface and induce
responses in the intestinal epithelial cell which in turn produces
cytokines, chemokines, and other mediators inducing inflammatory
activation of the mucosal immune system (4, 9, 11, 30, 35,
36).
A variety of studies have provided increasing evidence that the surface
epithelium serves a critical function as the defensive front line of
the mucosal innate immune system in the gastrointestinal tract
(23). We and colleagues have previously demonstrated that various intestinal epithelial cell lines constitutively express several
members of a novel family of transmembrane receptors designated Toll-like receptors (TLRs) which may serve as a major link between innate and adaptive mucosal immune responses (5). LPS is
able to elicit several immediate stress responses in intestinal
epithelial cell lines in vitro which result in secretion of numerous
proinflammatory cytokines and chemokines via distinct signaling
pathways through TLRs (5, 19, 42).
The TLR family comprises at least eight human homologues of the
Drosophila Toll protein which appear to be key regulators in
differential cellular recognition of conserved molecular patterns associated with microbial pathogens (25, 33, 40). Recent studies have demonstrated that TLRs may act as transmembrane
coreceptors with CD14 in the cellular response to LPS, a glycolipid
derived from the outermost membrane of pathogenic gram-negative
bacteria (18). Among this family of receptors, TLR2 and TLR4
have been most extensively studied to date, and these studies have
variably suggested that both TLRs may serve as potential main mediators of LPS signaling (15, 16, 39, 41). Downstream, LPS-induced signaling through TLRs rapidly leads to NF- Recent studies reinforce earlier observations suggesting that the
overlying epithelial mucous surface may be severely impaired in
patients with IBD (37). This may increase direct exposure of
the intestinal epithelium to large amounts of lumenal bacteria. We
speculate that immune imbalance in IBD might result from an exaggerated
activation of the mucosal innate immune system in response to the
bacterial products of the lumen initiated through dysregulation of TLRs
in the intestinal epithelium. However, it remains unclear whether TLRs
are expressed in primary intestinal epithelial cells in vivo and how
expression may be altered in association gastrointestinal inflammation.
Thus, the aim of this study was to characterize expression of the
potential LPS-signaling receptors TLR2, -3, -4, and -5 in intestinal
mucosa of IBD patients compared with normal controls.
Population and tissue samples.
Tissue samples (n = 31) were obtained from 25 patients (Table
1) undergoing complete colonoscopy at the
Massachusetts General Hospital (MGH), Boston, Mass. Informed consent
was obtained from all patients prior to the procedure, and the protocol
was approved by the Human Studies Committee of the MGH. In each case,
the diagnosis was confirmed by standard endoscopic and histological
criteria (additional hematoxylin and eosin staining of each sample).
Specimens were taken from macroscopically "involved" and
"noninvolved" mucosa in patients with active IBD. Specimens were
taken from all areas of the colon, including the terminal ileum. All 31 tissue samples were processed to be stained with the anti-TLR antisera
or preimmune sera, respectively, and then evaluated. Thus, reported
findings show representative results of all samples examined from each subgroup (non-IBD, CD, and UC), if not otherwise specified in Results.
0019-9567/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.
Differential Alteration in Intestinal Epithelial
Cell Expression of Toll-Like Receptor 3 (TLR3) and TLR4 in Inflammatory
Bowel Disease
ABSTRACT
Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
INTRODUCTION
Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
B activation and cytokine expression in monocytes (7, 10). However, the functional roles of the other TLRs and the possible interactions between different
TLRs and other nonbacterial ligands, as well as the details of the
TLR-induced cellular signal transduction pathways, have not been fully
defined. Moreover, it remains unclear whether dysregulation of
TLR-mediated microbial recognition is present in infectious and
inflammatory diseases. However, two murine mutant models suggest that
TLR dysregulation may be associated with increased or decreased
susceptibility to infection: TLR4 point mutation renders C3H/HeJ mice
endotoxin hyporesponsive, whereas variant alleles of the TLR5 gene may
make MOLF/Ei mice susceptible to Salmonella enterica serovar
Typhimurium (32, 38).
MATERIALS AND METHODS
Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
TABLE 1.
Study population
80°C
until further processing, as described below.
Antibodies. Human TLR3 protein (GI no. 2459626) was plotted using the ExPASy Proteomics Tools website (www.expasy.ch) and the SeqWeb interface (helix.mgh.harvard.edu:8080/gcg-bin/seqweb.cgi) (predictions of secondary structure according to Garnier, Osguthorpe, and Robson, hydrophilicity according to Kyte and Doolittle, and antigenicity index according to Jameson and Wolf), and the area including amino acids 444 to 469 in the extracellular domain was subsequently chosen for peptide synthesis (GQELTGQEWRGLENIFEIYLSYNKYL). Peptides of the extracellular domains of human TLR2 (FRASDNDRVIDPGKVETLTIRRLHIPR) and human TLR4 (FKEIRLHKLTLRNNFDSLNVMKT) were selected, as previously described (43).
Possible homologies of all three peptide sequences with other known TLRs or similarities with other peptides were excluded by conducting BLASTP (2.0.10) alignments through the National Center for Biotechnology Information website (www.ncbi.nlm.nih.gov). Peptides were synthesized at the MGH Peptide Core Facility, Boston, Mass. Rabbits were immunized (Covance, Denver, Pa.) as follows. An initial single boost of 500 µg of peptide was administered (intradermal back, multiple sites), followed by individual 250-µg boosts of each peptide (subcutaneous nodal area, dorsal or neck at multiple sites), which were repeated every 10 to 14 days. After 10 weeks of injections, production bleeds (20 ml per rabbit) were pursued every 14 to 21 days. The antisera were affinity purified (NAb protein A spin chromatography kit; Pierce Chemical Co., Rockford, Ill.), tested, and stored in aliquots at20°C. Protein concentration was determined by the colorimetric (595 nm) Bradford protein assay (Bio-Rad, Hercules, Calif.). A specific goat
polyclonal antibody to the human TLR5 NH2-terminal domain
was obtained from Santa Cruz Biotechnology, Santa Cruz, Calif.
Testing of antisera: specificity by Western blotting.
Cross-reactivity of the antisera with each other was excluded, and the
specificity of the newly generated antibodies to TLR2, TLR3, and TLR4
antigens was confirmed by Western blotting (Fig. 1). The human colonic cancer cell line
T84 constitutively expresses TLR2, TLR3, and TLR4 mRNA, as previously
shown by this laboratory (5), and was therefore used as a
positive control for correct molecular weight sizing of the TLR
proteins.
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Immunohistochemistry.
In order to facilitate
permeabilization, all biopsy specimens were pretreated with freshly
made, ice-cold 2% paraformaldehyde (pH 7.0) containing 0.1% Triton
X-100 for 30 min at 4°C and then further fixed in 4% buffered
formalin, embedded in paraffin wax, sectioned, mounted on coated glass
slides, and baked for 15 min. Each sample was also stained with
hematoxylin and eosin and subsequently analyzed histologically for the
presence of inflammatory, neoplastic, and fibrotic changes in order to
confirm the macroscopic diagnosis. After deparaffinization (three
times, each 5 min; Hemo-De; Fisher Scientific, Pittsburgh, Pa.),
sections were rehydrated in graded ethanol (100% twice, 90% once,
80% once, and 70% once, each for 5 min), washed in distilled water
(twice, 5 min each), and then exposed to microwave pretreatment (in 10 mM sodium citrate, pH 6.0, at 900 W for two periods of 5 min) to
enhance antigenicity. After cooling to room temperature for 20 min and
subsequently washing with distilled water (three times, 2 min each),
sections were incubated for 10 min in ice-cold 3%
H2O2 (Sigma). After washing with PBS (two
times, 5 min each), nonspecific binding was blocked with normal goat or
rabbit serum (1:100 in PBS, Vector Laboratories) for 60 min at room
temperature. After removal of the blocking solution, sections were then
incubated in a moist chamber with anti-TLR2, anti-TLR3, anti-TLR4, or
anti-TLR5 serum (1:100 to 1:500 in PBS) or
as negative controlswith
normal rabbit or goat immunoglobulin G (IgG) (Santa Cruz) and preimmune
serum (equivalent dilutions) overnight at 4°C. Fluorescein-conjugated
goat anti-rabbit IgG or rabbit anti-goat IgG antibodies (Vector
Laboratories, Burlingame, Calif.) were used as secondary antibodies
(1:250, 60 min, room temperature). While protected from direct light
exposure, samples were washed three times in PBS and mounted
(Vectashield mounting media; Vector Laboratories). Control experiments
were performed omitting the primary antibody.
Image acquisition and analysis. Sections were viewed within 12 h on inverted and upright immunofluorescence microscopes (10× or 40× objective, model IX70 [TLR2, TLR4] or AX70 [TLR3, TLR5]; Olympus, New Hyde Park, N.Y.). Fluorescence images were viewed in a blinded fashion and obtained using standardized camera settings (Olympus PM-C35DX) between positive sample and negative control. Digitized images were then cropped into Adobe Photoshop 5.0.2 (Adobe Systems, Inc.). The pictures were imported to PowerPoint (Microsoft) for assembly and labeling in a standardized way.
All images shown are representatives of the common result in each disease subgroup. Each picture shown represents a different patient.Statistical analysis. The measurement of the automatic exposure time (full image area to a final standard) was taken as an indirect reflection of the staining intensity of TLR3 (P value; t test [heteroscedastic, two tailed]).
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RESULTS |
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Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
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TLR2.
TLR2 expression was barely detectable in primary
intestinal epithelial cells throughout the normal terminal ileum and
colon in all samples examined (Fig. 2A).
Isolated cells within the lamina propria, presumably monocytes and
macrophages, were only weakly positive for TLR2 in the normal mucosae
examined. The intensity of the staining for TLR2 was not significantly
increased in the ileal or colonic epithelium from either UC or CD
patients compared to normal tissue (Fig. 2B and C). Significant
upregulation of TLR2 protein expression in active IBD was observed
in scattered inflammatory cells of the lamina propria (Fig. 2D).
Similar results were obtained for all patients examined.
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TLR3.
In all normal small intestine and colon specimens,
intense staining for cytoplasmic TLR3 was consistently present on
intestinal epithelial cells (Fig. 3A and
B). Subepithelial blood vessels and
muscle cells of the submucosa also showed substantial TLR3 protein
expression (not shown). A similar pattern of TLR3 expression was
present in colonic specimens from all UC patients. There were no
apparent differences in expression level at different sites or between
noninflamed and inflamed mucosae in tissues from UC patients (Fig. 3C
and D). TLR3 expression was mostly present on basolateral surfaces of
intestinal epithelial cells in colonic specimens from UC patients.
Inflammatory cell infiltrates of the lamina propria also expressed
abundant TLR3 on cell surfaces in UC (not shown).
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TLR4.
While only minimally detectable in small intestinal and
colonic epithelial cells of normal, non-IBD mucosa (Fig. 5A and
B), TLR4 was abundantly expressed by
epithelial cells of all UC and CD patients (Fig. 5C to F). Both
microscopically inflamed and noninflamed mucosae throughout the colon
and terminal ileum showed intense intestinal epithelial cell expression
of TLR4 (Fig. 5C to F). This result was reproducible in all samples
examined. Of note, the subcellular distribution of TLR4 in the
epithelial compartment differed between CD and UC. Intense staining was
mostly present at basolateral surfaces in mucosal sections of UC
patients (Fig. 5C and D). In contrast, staining of TLR4 was intense at
the apical pole of intestinal epithelial cells in most CD samples (Fig.
5E and F). It is noteworthy that TLR4-positive intestinal epithelial cells were also found in inactive disease (Fig. 5C). Scattered inflammatory cells in the lamina propria were weakly positive for TLR4
in normal controls (Fig. 5A and B). Enhanced expression of TLR4 was not
limited to epithelial cells, and a significant increase of the
expression intensity was also present in the lamina propria of IBD
specimens (Fig. 5C to F).
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TLR5.
TLR5 was expressed on epithelial cells throughout the
normal lower gastrointestinal tract (Fig. 6A and
B). There was no evident difference in
expression between normal controls and IBD patients (Fig. 6A and B
versus C and D). Of note, TLR5 appeared to be selectively expressed by
the surface epithelium and was not present in either crypt epithelium
or cell populations within the underlying lamina propria and submucosa
(Fig. 6A and C). All samples showed similar results.
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DISCUSSION |
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Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
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The present study demonstrates that TLRs are expressed in normal human intestinal mucosa. This same study demonstrates that epithelial cells rather than macrophages and other lamina propria populations are the predominant cells expressing TLRs. Further, this pilot study suggests that there is differential expression of different members of this receptor family. Thus, primary intestinal epithelial cells (IECs) of normal, nondiseased mucosa constitutively express TLR3 and TLR5, whereas TLR2 and TLR4 are present in much lower amounts as assessed by immunohistochemistry.
The intestinal epithelium serves as an essential barrier between microbes of the lumen and inflammatory cells of the lamina propria. It also plays a critical role in regulating the host immune defense reaction by recognizing and subsequently responding to invading pathogens by secretion of proinflammatory cytokines and chemokines (19, 42). We have recently demonstrated that various intestinal epithelial cell lines constitutively express several TLRs in vitro (5). This expression is consistent with the emerging consensus that these receptors act as key mediators of host defense to bacterial challenges, linking innate and adaptive immune responses (9). Thus these receptors appeared to be deployed to the true site of interface with lumenal bacteria and their products, the surface epithelium. The detection of TLRs at the mucosal surface in vivo is consistent with the detection of the TLRs on the apical surface of intestinal epithelial cell lines in vitro (unpublished observation).
Although the various TLRs seem to differ in their recognition of
diverse bacterial products, TLRs' induced cell responses may be
mediated by a common signaling pathway which shares many features with
the IL1R pathway, including the involvement of MyD88, IRAK, TRAF6, and
NF-B. Stimulation of this pathway leads to production of
inflammatory cytokines and costimulatory molecules (43). It
is very likely that LPS-induced TLR signals via a similar pathway in
IECs, as intestinal epithelial activation of these proteins has
recently been shown in response to IL-1
stimulation (2).
In addition to the demonstration of TLR expression by normal intestinal epithelium, the present unicenter study suggests that expression of TLRs may be selectively altered in association with IBD and further that some of these alterations may be specific to the form of IBD, whether UC or CD. Thus, TLR3 and TLR4 are differentially modulated in the intestinal epithelium of patients with IBD. While TLR3 expression by IECs of UC patients is comparable to that of normal controls, TLR3 expression is significantly downregulated in CD. Of interest, reduced expression of TLR3 on IECs seems to be consistent in CD, irrespective of location or inflammatory activity. At a minimum, this implies that reduced TLR3 does not simply reflect the local effect of some inflammatory mediator. Inflammatory cells of the lamina propria remain positive for cell surface expression of TLR3, suggesting that the decrease of TLR3 may reflect a distinct intestinal epithelial cell-specific impairment in active CD but not UC. Thus, deficient TLR3 expression in the intestinal epithelium may be a distinctive feature of CD but not UC and could reflect a divergent dimension of pathophysiological mechanisms involved in these two disorders.
It is important to note that the functional role of TLR3 in mediating innate immune responses to specific microbes and their toxic constituents has not yet been definitively established. TLR3 mRNA may be significantly downregulated in response to LPS in mature dendritic cells (26). In contrast, preliminary studies from this laboratory reveal that TLR3 protein is significantly upregulated in IECs in response to LPS in vitro (unpublished observation). Others have also recently demonstrated that expression of TLR3 mRNA may be upregulated by LPS and also tumor necrosis factor alpha in mature Langerhans cells (12). Collectively, these divergent findings suggest that TLR3 can mediate cell-specific responses to LPS (26, 27). Further studies are needed to clarify the functional role of TLR3 as a specific pattern recognition receptor, its interaction with other receptor molecules, its regulation by cytokines in the intestinal epithelium as well as inflammatory cells, and finally, its causal relevance in the differential pathogenesis of inflammatory bowel diseases.
Interestingly, TLR3 is localized on chromosome 4 (q35) (33) at the border of a large linkage region of a recently described IBD susceptibility gene, suggesting a potential pathogenic association of IBD with the TLR3 gene (14). Thorough assessments of novel mutant polymorphisms in the TLR3 gene may provide insight into IEC-specific dysregulation of the receptor in CD.
In contrast to TLR3, TLR4 is significantly increased in IECs throughout the lower gastrointestinal tract regardless of whether assessed in active or inactive disease of both CD and UC patients. However, the subcellular distribution of TLR4 differed between CD and UC epithelia (apical versus basolateral). Recent findings from animal models and genetic complementation studies have suggested that TLR4 can serve as a major transducing subunit of the LPS receptor complex (31, 39). Lumenal LPS is usually well tolerated in large quantities within the healthy intestine. This tolerance could result from TLR4 downregulation minimizing LPS recognition, given that primary IECs in normal tissue appear to express very little, if any, TLR4 (28). However, in IBD, host tolerance towards lumenal bacterial toxins may be broken (8, 17, 21), which could reflect increased LPS recognition as a result of TLR4 upregulation. Acute injury of the intestinal mucosa may also lead to recruitment of TLR4-positive macrophages into the mucosa. These inflammatory cells highly express the TLR4 coreceptor CD14, which could play an important linking role in enhancing hyperresponsiveness of the intestinal mucosa to LPS in IBD (1, 13, 34).
Spontaneous mutations of TLR4 could prime individuals experiencing acute infections to develop especially severe disease (3). It has previously been shown that C3H/HeJ mice which have a single point mutation of TLR4 (16, 32) are highly susceptible to developing a more severe form of dextran sodium sulfate-induced colitis (9). Interestingly, the TLR4 gene is localized on chromosome 9 (q32-33) (33), another genomic region in which a CD susceptibility gene has been implicated (6). In active IBD, variant alleles in the TLR4 gene could induce functional dysregulation of the receptor to LPS. In this study, we also found that during long-standing, quiescent disease, IECs constitutively overexpress TLR4 compared to normal controls. This observation could result from a "gain-of-function" mutation in this receptor which could functionally exhibit proinflammatory effects in response to physiological concentrations of LPS. However, it remains to be shown whether upregulated TLR4 confers functional hyperresponsiveness of the intestinal epithelium to LPS or rather reflects a loss of response. Moreover, TLR4 upregulation could also result from the effects of ligands other than LPS (20, 29). The factors and mechanisms regulating TLR4 expression in IECs in IBD remain to be further elucidated.
Our study suggests that TLR2 and TLR5 expression in IECs remain unchanged in active IBD. Neither control nor IBD tissues exhibit significant TLR2 expression in IECs. Upregulation of TLR2 is restricted to scattered inflammatory cells of the lamina propria in active IBD. While TLR4 appears to be important for LPS signaling, recent in vitro studies suggest that TLR2 mainly transduces signals by gram-positive ligands such as lipoteichoic acid, peptidoglycan, and lipopeptides (22, 24). The lack of any significant alteration in intestinal epithelial expression of TLR2 in IBD suggests that such bacterial cell wall components of gram-positive microbes may not play a major role in modulation of innate immune responses in these disorders.
Similar to TLR2, TLR5 also appears not to be significantly regulated in acute intestinal inflammation in IBD. TLR5 is constitutively expressed on all surface IECs, regardless of whether derived from normal or IBD mucosae. However, the functional role of TLR5 in the gastrointestinal immune system needs to be further defined.
This is the first report suggesting that TLR expression may be altered in disease. However, the conclusiveness of this preliminary report is limited by the fact that it has been performed in a unicenter setting. It is evident that larger multicenter studies are needed to further specify differences in TLR expression between these entities of IBD and, more importantly, other inflammatory diseases of the gastrointestinal tract. So far only 10 members of the TLR superfamily have been identified. It is expected that more than 30 different TLRs are expressed in mammals; hence, at this point we cannot exclude the possibility that our newly generated antibodies might cross-react with any other, so far unknown TLR which might show homologies in the extracellular domains with TLR2, TLR3, or TLR4.
Based on the results of this initial study, we note that epithelial cells may be the predominant site of TLR expression in intestinal mucosa and postulate that IBD may be associated with distinctive changes in selective TLR expression in the intestinal epithelium. However, it remains unclear whether immune imbalance in IBD may either lead to or result from TLR dysregulation in IEC. Further studies are needed to focus on the direct pathogenetic relevance and immune consequences of TLR dysregulation in active IBD.
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ACKNOWLEDGMENTS |
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This work was supported by grants DK41557 and DK43351 from the National Institutes of Health (to D.K.P.) and Ca226/2-1 from the Deutsche Forschungsgemeinschaft (to E.C.).
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FOOTNOTES |
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* Corresponding author. Mailing address: Massachusetts General Hospital, Gastrointestinal Unit GRJ719, 32 Fruit Street, Boston, MA 02114. Phone: (617) 726-7411. Fax: (617) 726-3673. E-mail: podolsky.daniel{at}mgh.harvard.edu.
Editor: J. D. Clements
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Discussion
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