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Clin Exp Immunol. Dec 2002; 130(3): 526–531.
PMCID: PMC1906543

Selective reduction of intestinal trefoil factor in untreated coeliac disease

Abstract

The trefoil factor family (TFF) encompasses small peptides of which intestinal trefoil factor (ITF) is expressed specifically in goblet cells of the small and large intestine. Previous studies have shown that ITF plays an important role in mucosal protection and repair. Coeliac disease represents a model of immune-mediated small intestinal inflammation and damage, with recovery on gluten-free diet. The aim of this study was to investigate the expression of ITF in the distal duodenal mucosa of subjects with coeliac disease, before and after treatment with a gluten-free diet. Expression of ITF and mucin in the distal duodenal biopsies from treated (n = 11) and untreated (n = 9) coeliac subjects and controls (n = 8) was investigated by immunohistochemistry and semiquantitative PCR. In untreated coeliac disease, there was reduction of ITF immunoreactivity in goblet cells but mucin expression was preserved. Mucosal recovery on gluten-free diet was associated with increased ITF immunoreactivity in goblet cells. There was also reduction in the expression of ITF transcripts, relative to MUC2 mRNA, in untreated coeliac duodenal samples, with recovery on gluten-free diet. Our study suggests that there is a selective reduction in the expression of the ITF gene in untreated coeliac disease. Recovery of ITF expression on a gluten-free diet suggests that the mucosal immune system regulates goblet cell differentiation and ITF expression in the human intestinal mucosa.

Keywords: goblet cells, trefoil peptides, gluten-sensitive enteropathy

Introduction

The trefoil factor family (TFF) encompasses small peptides sharing a distinctive motif of six cysteine residues, which form intrachain disulphide bonds to create a characteristic three – loop structure that gives the peptide family its name [13]. The TFF proteins are expressed in salivary glands [4], lymphoid tissue [5], normal and neoplastic breast epithelium [6] and respiratory tract [7,8]. The TFF members are also selectively expressed in specific regions of the gastrointestinal tract [9]. Thus, pS2 (TFF1) is predominantly expressed in the proximal stomach [10], while human spasmolytic polypeptide (hSP; TFF2) is expressed in the distal stomach and biliary tract [11,12], and intestinal trefoil factor (ITF; TFF3) in the small and large intestine [1,13]. Studies in rodents and humans have shown that ITF is expressed specifically by goblet cells [14,15]. Expression of members of the trefoil family is up-regulated immediately adjacent to the site of mucosal ulceration and in vivo studies have demonstrated that it protects against mucosal injury [1621]. ITF [22] and hSP [23] enhance restitution, the essential initial phase of mucosal healing in which intestinal epithelial cells rapidly migrate across an ulcerated surface to effect closure and re–establish barrier function. The trefoil peptides appear to enhance defence in the viscoelastic mucus layer, at least in part, via their ability to stabilize the mucus gel by binding the long mucin molecules together, either by the oligosaccharide side chains or the core protein at exposed sites [2427]. The latter may contribute to mucosal protection in vivo by impeding penetration of injurious luminal agents to the epithelial surface. More recently, ITF has also been shown to protect intestinal epithelial cells against programmed cell death (apoptosis) [28].

Alterations in the expression of trefoil peptides have been observed in inflammatory bowel disease, but their expression has not been investigated in coeliac disease. The proximal small intestinal mucosa of untreated coeliac disease is characterized histologically by loss of the normal villous architecture and crypt hyperplasia. In contrast to the normal tall columnar shape of normal small intestinal surface epithelial cells, these cells in coeliac disease are pseudostratified with a reduction in enterocyte height [29]. Crypt hyperplasia is associated with increased turnover of epithelial cells, accelerating migration of cells from the crypt base to the villus tip. In addition to infiltration by T cells in the lamina propria, there is also an increase in the number of intraepithelial lymphocytes (IEL).

Following withdrawal of gluten from the diet of subjects with coeliac disease, there is usually complete restoration of normal small intestinal mucosal architecture. Thus, the villus structure and the surface epithelial cells return to normal, with a concomitant reduction in the number of lymphocytes in the mucosa. Coeliac disease therefore is a model of immune-mediated small intestinal inflammation and damage, with recovery following removal of gluten from the diet. In this study, we investigated the expression of ITF in the distal duodenal mucosa of subjects with coeliac disease, before and after treatment with a gluten-free diet. We show that there is a decrease in the expression of ITF in the intestinal mucosa of untreated coeliac disease, with recovery of protein expression following institution of gluten-free diet.

Materials and methods

Distal duodenal biopsies from treated (n = 11) and untreated (n = 9) subjects with coeliac disease and controls (n = 8; undergoing endoscopy for investigation of peptic ulcer disease) were obtained following informed consent. The untreated and treated coeliac disease groups included three patients from whom duodenal biopsies were obtained both before and after exclusion of gluten from the diet. These studies were approved by the Ethics Committee of the Federico II University of Naples.

The diagnosis of coeliac disease was based on the presence of serum antibodies to endomysium, histological changes in small intestinal biopsy and other criteria as previously described [30]. Distal duodenal biopsies were fixed in 0·9% NaCl containing 10% formalin and paraffin embedded serial sections were used for morphological studies [29,31] and immunohistochemistry using rabbit anti-human ITF antibody [15], polyclonal antibody to human colonic mucin [32,33], or pre-immune serum. Xylene-dewaxed and alcohol rehydrated paraffin sections were heated in a microwave with 0·01 m trisodium citrate solution. After washing in Tris buffered saline (pH 7·4), the sections were incubated with specific antibody. Immunodetection was performed as previously reported [34] using biotinylated secondary antibody, followed by application of avidin-biotinylated horseradish peroxidase complex (VectaStain ABC kit; Vector Laboratories, Burlingham, CA). Peroxidase activity was developed with diaminobenzidine tetrahydrocholoride and counterstained with haematoxylin. Sequential sections were also stained with haematoxylin and eosin and with alcian blue and periodic acid-Schiff reagent (PAS). Haematoxylin and eosin – stained sections were used for morphometric studies to grade the severity of small intestinal damage [2931] and goblet cells were identified and counted in PAS-stained sections.

An additional distal duodenal biopsy was collected at endoscopy for determination of mRNA expression. The biopsy was stored (at −70°C) in lysis buffer containing guanidium isothiocyanate (from Quiagen Ltd, Crawley, UK). Total RNA was ex-tracted from homogenized samples using a Quiagen Rneasy kit. The homogenate was applied to spin columns which selectivly bind RNA. The columns were washed to remove DNA and protein and bound total RNA was eluted from the column and used for reverse transcriptase-polymerase chain reaction (RT-PCR).

Rt-pcr

Total RNA was reverse transcribed in buffer containing murine Moloney reverse transcriptase and random hexamer primers. For PCR, 1 µl cDNA was used in a 50-µl reaction containing 5 mm dNTPs, 10 µmol each of the relevant primers and 2·5 U of Taq polymerase (from Promega). The following primer pairs were used; 5′CTG GTC CTG GCC TTG CTG TC3′ and 5′TTG CAC TCC TTG GGG GTC AC3′, to amplify 128 base pair ITF product; 5′CCA CGC TCT GCC CCA AGA 3′ and 5′ CAC TGT CCC CGA TGT CGT CAT A 3′ to amplify 168 base pair MUC2 product; 5′GGT GAA GGT CGG AGT CAA CGG A3′ and 5′GAG GGA TCT CGC TCC TGG AAG A3′ to amplify 240 base pair GAPDH product.

MUC2 was chosen as it is the predominant secreted mucin in the small intestine [35]. Amplification of cDNA was performed in 30 cycles, denaturation 45 s at 95°C, annealing 30 s at 54°C, extension 30 s at 72°C, followed by final annealing 2 min at 54°C and extension 7 min at 70°C.

Following electrophoresis, ITF, MUC2 and GAPDH PCR products were transferred to a nylon membrane and the amount of PCR product quantified using digoxigenin-labelled oligonucleotide probes specific for each PCR product (5′ACC AGT GTG CCG TGC3′ for ITF, 5′GCC TTG ACG GTG CCA T3′ for GAPDH, 5′ GGC TCG CCC TGC AT 3′ for MUC2), using a method modified from one described previously [36,37]. Following hybridization and incubation with alkaline phosphatase-conjugated rabbit anti-digoxigenin antibody (Boehringer Mannheim, Lews, UK), the membranes were incubated with chemiluminescent substrate (CPS-Star Boehringer Mannheim) and the photons emitted were captured on X-ray films. The intensity of individual bands was assessed by densitometry using a software package for evaluation of 1-D films and gels (RFL PrintTM, Poli, New York) and expressed as OD × mm2. For each specimen, each type of transcript was also expressed relative to one of the other two in the form of a ratio.

Statistical analysis

Differences between groups were studied by analysis of variance and unpaired Student's t-test.

Results

Subjects, tissue morphology and morphometry

Table 1 shows details of the subjects studied. Body mass index and serum cholesterol values were significantly lower in untreated coeliac subjects compared to controls and treated coeliac subjects (P = 0·05 for both).

Table 1
Details of subjects studied

Distal duodenal biopsies of untreated coeliac subjects were either partially or severely atrophic (Grade II or III a, b, c; as described by Oberhuber et al. [31]). Biopsies from coeliac subjects on a gluten-free diet showed normal morphology in all except two subjects in whom partial atrophy (Grade II) was seen.

The biopsies from three subjects in whom duodenal samples were obtained before and after (one year) of gluten-free diet, showed recovery of mucosal damage on gluten-free diet. In one subject an increased number of intraepithelial lymphocytes was noted (60 IEL/100 enterocytes).

Immunohistochemistry

Immunohistochemical studies were performed on serial sections of intestinal biopsies. The total number of goblet cells (per mm2) was determined in PAS-stained sections and the number of ITF positive and mucin positive goblet cells were counted from the same region in sequential sections, permitting determination of the proportion of ITF- and mucin-positive goblet cells. In controls, most of the goblet cells were immunoreactive for ITF (95·1 ± 2·8%) and mucin (98·2 ± 0·7%) (Table 2). In sections of distal duodenal biopsies from untreated patients with coeliac disease, there was a reduction in the total number of goblet cells (as identified by PAS) and although most of them expressed mucin (97.2 ± 3.1%), only 60·8 (±19·6)% were immunoreactive for ITF (P < 0·001 versus control). It was also noted that many of the goblet cells in untreated coeliac specimens were less immunoreactive for ITF than goblet cells in the control sections (Fig. 1). In distal duodenal biopsies from patients with coeliac disease that were treated with a gluten-free diet (and which, as outlined above, showed morphological recovery), there was an increase in the total number of PAS-stained goblet cells. Moreover, the majority of these goblet cells were immunoreactive for ITF (90·4 ± 15·3%; P < 0·001 versus untreated coeliac samples). There were no significant differences between untreated coeliac patients, treated coeliac patients and controls in the proportion of goblet cells immunoreactive for mucin in the distal duodenal mucosa.

Fig. 1
Representative photomicrographs of distal duodenal sections of an untreated coelic patient (a,b) and normal control (c,d) immunostained for intestinal trefoil factor (ITF; a,c) and mucin (b,d). Examples of ITF- or mucin-immunoreactive goblet are indicated ...
Table 2
Immunostaining for intestinal trefoil factor (ITF) and mucin in goblet cells of distal duodenal mucosa of control and coeliac subjects (untreated and treated)

ITF and MUC2 mRNA expression

Changes in the expression of ITF and MUC2 mRNA transcripts in distal duodenal biopsies from untreated and treated coeliac patients and controls were studied by semiquantitative RT-PCR (Table 3). When expressed relative to the constitutive marker GAPDH, there was reduced expression of ITF and MUC2 transcripts in biopsies from untreated and treated patients with coeliac disease, when compared to controls. However, the differences were statistically significant only for the ITF:GAPDH ratios and not for MUC2:GAPDH ratios. Compared to normal controls and treated coeliac samples, the ITF:MUC2 ratios were significantly lower in distal duodenal biopsies of untreated coeliac patients (Table 3). Findings comparable to those shown in Table 3 where found in RT-PCR analysis of RNA extracted from distal duodenal biopsies of three patients with coeliac disease studied before and after gluten-free diet.

Table 3
Analysis of ITF, MUC2 and GAPDH transcripts (by semiquantitative RT-PCR) in distal duodenal biopsies obtained from control subjects and patients with coeliac disease, before after gluten-free diet. Optical densities (OD) and their ratios are expressed ...

Discussion

In the gastrointestinal tract, mucin glycoproteins and members of the TFF family of peptides are coexpressed by goblet cells [16,24,38,39]. Expression of mucin glycoproteins and trefoil peptides vary in different anatomical sites (stomach, intestine, colon) and can be altered in association with pathologic processes (inflammation, metaplasia, tumours) [13,18,20,34]. These goblet cell products are essential for effective intestinal mucosal defence, possibly by stabilizing the mucus gel [24]. In the normal small intestine, MUC2 and ITF gene expression are closely associated exhibiting the same localization and pattern of expression in goblet cells [16,24,26].

Our study shows a reduction in the expression of ITF mRNA transcripts and protein in the distal duodenal mucosa of untreated patients with coeliac disease. Immunohistochemical studies showed that there was also a reduction in the total number of goblet cells in the duodenal mucosa of untreated coeliac patients but the expression of mucin in these cells was preserved. By contrast, a significant proportion of goblet cells in these samples did not express ITF protein. In many of the goblet cells that were positive for ITF in the untreated coeliac samples, expression of the protein per cell was reduced, as illustrated by weak immunoreactivity. In duodenal mucosal samples of coeliac patients on gluten-free diet there was recovery in the expression of ITF as shown by a significant increase in the proportion goblet cells immunoreactive for this protein. Studies of mRNA transcripts by semiquantitative RT-PCR suggested that the reduction in the expression of ITF protein in untreated coeliac duodenal samples results from a reduction in the steady state expression of the ITF gene. When compared with the expression of the constitutive transcript GAPDH, there was reduced expression of ITF and MUC2 (the latter was not statistically significant) transcripts in untreated duodenal samples. Since GAPDH transcripts would also be derived from other cell populations in the mucosal biopsies, the reduction in ITF and MUC2 transcripts reflects a reduction in the total number of goblet cells, as shown in our immunohistochemical studies. The ratio of ITF:MUC2 transcripts was lower in untreated coeliac duodenal biopsies than in normal controls, implying reduced expression of ITF gene in goblet cells of these samples. These findings, together with an increase in ITF:MUC2 ratio in duodenal biopsies of treated coeliac patients, mirror the findings obtained by immunohistochemistry.

Taken together, our studies imply markedly reduced ITF gene activation in the goblet cells of the distal duodenal mucosa of untreated patients with coeliac disease. This may be due to the altered differentiation pattern of epithelial cells as a consequence of the increased turnover and/or secreted products derived from activated T cells/macrophages. Other changes in goblet cell secretory products may also occur in coeliac small intestinal mucosa. Thus, in studies using lectin histochemistry, alterations in goblet cell secretory glycoconjugates in the jejunal mucosa of patients with gluten sensitive enteropathy have been reported [40]. Studies in parasite-infected mice have also demonstrated the capacity of T cells to influence intestinal epithelial differentiation and function [41,42].

Our data are consistent with the view that ITF may have a role in the preservation of the mucosal integrity against injurious agents and in the process of repair after damage [21,27], in cooperation with mucin glycoproteins [24,39,40]. Coeliac disease offers an in vivo human model of chronic small intestinal injury that can be completely reversed by gluten withdrawal from the diet. It is of interest that reduction of ITF expression in the atrophic mucosa of untreated coeliac disease contrasts with enhanced expression of trefoil proteins in other models of damage in proximal and distal gastrointestinal tract. In a model of ulceration, it has been reported that pS2, another member of trefoil family, is overexpressed in Crohn's disease [13]. Thus, in human intestinal diseases, the expression of trefoil proteins may be vary depending on the trefoil protein in question, the type of intestinal damage or the nature of the mucosal immune response. It is possible that, in the presence of mucosal ulceration, induced expression of trefoil peptides is a protective phenomenon. In coeliac disease, ITF protein expression paralleled changes in the duodenal mucosa. Thus, its expression was low in association with chronic inflammation and villus atrophy (but not epithelial ulceration) in untreated coeliac disease, with recovery following treatment with a gluten-free diet.

Acknowledgments

These studies were supported by the Medical Research Council and Dr Schär GmbH/Srl (part support for Dr Di Vizio).

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