Disturbances of bile acid metabolism in intestinal disease.
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The possibility of using erythrocytic ganglioside diagnostic reagents (EGDR) for the detection of V. cholerae, E. coli and S. typhimurium enterotoxins in the passive hemagglutination (PHA) test has been shown. Museum strains and cultures isolated from patients with acute intestinal diseases were tested for the presence of enterotoxins. Cell-free extracts were studied by biological methods and by serological titration in the PHA test with the use of EGDR. The diagnostic reagent was found to interact only with those enterotoxins whose specific receptors were gangliosides GM1.
Intestinal smooth muscle cells (SMC) produce the fibrotic tissue, strictures, that characterize Crohn's disease. These SMC change their phenotype from a contractile muscle form to an inflammation-responsive form that migrates and synthesizes a collagen matrix. It is postulated that the inflammatory responsive SMC form associates differently with its surrounding collagen matrix compared to the normal SMC form. SMC derived from Crohn's diseased and uninvolved bowel were sustained in cell culture. Cultured SMC incorporated in collagen lattices have the capacity to reduce the size of that lattice, referred to as lattice contraction. At day 2, Crohn's SMC-populated collagen lattices were reduced to 21% of their initial area, while non-Crohn's SMC collagen lattices were reduced to 8%. Crohn's SMC demonstrate retarded lattice contraction compared to non-Crohn's SMC. When grown in monolayer culture, Crohn's-derived SMC cover 30% more area than non-Crohn's SMC. By Western blot analysis Crohn's SMC express more gelsolin, an actin-binding protein found elevated in cells exhibiting increased cell motility. Was the increased expression of gelsolin related to retarded collagen lattice contraction? Intracellular levels of gelsolin were elevated by the electroporation of plasma gelsolin protein into suspended non-Crohn's SMC. When incorporated in collagen lattices, gelsolin loaded cells showed retarded lattice contraction compared to SMC loaded with albumin. Crohn's SMC show increased expression of gelsolin, which may be associated with a diminished capacity to reorganize collagen fiber bundles. It is suggested that increased concentrations of gelsolin in Crohn's SMC is consistent with enhanced cell migration as a consequence of the inflammatory state of Crohn's diseased intestine.
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Campylobacter jejuni is an infrequent cause of self limiting acute diarrheal disease in adults in the Indian subcontinent. We report the occurrence of a life threatening diarrhea due to C jejuni infection in a patient with immunoproliferative small intestinal disease. We postulate that immunosuppression due to malignancy, malnutrition and cancer chemotherapy was responsible for the unusually severe diarrhea.
Intestinal strictures are frequent in Crohn's disease but not ulcerative colitis. We investigated the expression of transforming growth factor (TGF)-beta isoforms by isolated and cultured primary human intestinal myofibroblasts and the responsiveness of these cells and intestinal epithelial cells to TGF-beta isoforms. Normal intestinal myofibroblasts released predominantly TGF-beta(3) and ulcerative colitis myofibroblasts expressed both TGF-beta(1) and TGF-beta(3), whereas in myofibroblast cultures from fibrotic Crohn's disease tissue, there was significantly lower expression of TGF-beta(3) but enhanced release of TGF-beta(2). These distinctive patterns of TGF-beta isoform release were sustained through several myofibroblast passages. Proliferation of Crohn's disease myofibroblasts was significantly greater than that of myofibroblasts derived from normal and ulcerative colitis tissue. In contrast to cells from normal and ulcerative colitis tissue, neutralization of the three TGF-beta isoforms did not affect the proliferation of Crohn's disease intestinal myofibroblasts. Studies on the effect of recombinant TGF-beta isoforms on epithelial restitution and proliferation suggest that TGF-beta(2) may be the least effective of the three isoforms in intestinal wound repair. In conclusion, the enhanced release of TGF-beta(2) but reduced expression of TGF-beta(3) by Crohn's disease intestinal myofibroblasts, together with their enhanced proliferative capacity, may lead to the development of intestinal strictures.
We performed a detailed histological and immunohistological study on both fresh-frozen and paraffin-embedded tissue from full-thickness jejunal biopsy specimens taken from three patients with immunoproliferative small-intestinal disease (IPSID). In all three patients, the mucosal infiltrate consisted of "centrocyte-like" (CCL) cells forming lymphoepithelial lesions and plasma cells. In one patient, the mucosal infiltrate was strikingly follicular. Immunohistochemistry showed alpha 1 heavy chain, but no light chain, in the perinuclear space and cytoplasm of the CCL cells and in the plasma cells. In two patients, the plasma cells (but not the CCL cells) also contained alpha 2 heavy chain. In the case showing a follicular pattern, the extrafollicular CCL cells and most of the cells within the mucosal follicles expressed alpha 1 heavy chain, but a minor and variable population of cells expressed polytypic IgM. The dendritic reticulum cells stained for alpha 1 (but not alpha 2) heavy chain, mu chain, and both light chains. In all cases, the CCL cells did not stain for common acute lymphoblastic leukaemia antigen (CALLA); in the follicles, CALLA negative cells displaced a residual CALLA-positive population to the periphery and merged with the CALLA negative cells outside the follicles. These findings confirm the homology between IPSID and low-grade B-cell "Western" lymphomas arising in mucosa-associated lymphoid tissue; they suggest that the follicular pattern sometimes seen in these lymphomas is caused by selective colonization of reactive follicles by CCL tumor cells.
UNLABELLED: Congenital disorders of glycosylation type I (GDG-I) is a class of genetic multisystem disorders characterised by defective glycosylation of glycoproteins. The characteristics and mechanisms of failure to thrive and intestinal diseases present in CDG-I are anectodal. PATIENTS AND METHODS: The aim of this study was to analyse 7 CDG-I (4 CDG-Ia, 2 CDG-Ib and 1 CDG-Ix) with important digestive symptoms and failure to thrive in order to characterise the mechanisms implied. RESULTS: Four children had no skin abnormality or dysmorphia (1 CDG-Ia, 2 CDG-Ib, 1 CDG-Ix). An encephalopathy with cerebellar hypoplasia was present only in the 4 CDG-Ia. Failure to thrive and diarrhea were present during the first month of life in 6 and appeared at 5 years in one CDG-Ia associated to mild or severe hepatopathy in all patients. One CDG-Ia, 1 CDG-Ib, 1 CDG-Ix had an exsudative enteropathy. A positive steatorrhea was present in 3 patients. Five patients had an abnormal small bowel biopsy. Abnormalities were variable: moderate inflammation of the chorion without villous atrophy in 2, intra-enterocyte fat accumulation without villous atrophy in 2, and partial villous atrophy with lymphangectasia in 1. In 2 CDG-Ia the intestinal biopsy was normal. Enteral nutrition in 4 and parenteral nutrition in 2 were effective in 4 patients and 1 patient with an exsudative enteropathy respond to a free fat diet (CDG-Ix). CONCLUSION: The digestive symptoms with failure to thrive is a common feature of CDG-I and could be the first symptoms. The diagnostic should be suspected if no other cause is found. Mechanisms of the intestinal symptoms appear to be multiple such as inflammation, abnormal enterocyte lipid transport or intestinal permeability related to the abnormal glycosylation of intestinal mucosa glycoproteins.
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Gastrointestinal lymphoma, uncommon in the West, is far more prevalent in developing countries where it falls into two groups: 'Western'-type lymphomas, similar to those seen in developed countries, and the so-called Mediterranean-type lymphoma. It is now accepted that Mediterranean lymphoma represents, in the majority if not in all cases, the late stage of alpha heavy chain disease (alpha-HCD). This disease is characterized by abnormal secretion of an immunoglobulin fragment; alpha-HCD and Mediterranean lymphoma constitute two ends of a spectrum of pathology now classified as immunoproliferative small intestinal disease (IPSID). IPSID is associated predominantly with poor socioeconomic conditions; patients present with progressive malabsorption in the second and third decades of life. Diagnosis is established by small bowel biopsy, with or without high serum levels of the alpha heavy chain protein. Treatment consists of an initial staging laparotomy, with debulking of lymphomatous deposits if appropriate, followed by chemotherapy or radiotherapy. Overall prognosis is poor but the recent use of doxorubicin-based chemotherapy offers some hope for the future.
Eikosanoids (prostaglandins, thromboxanes, prostacyclins, hydroxyfatty acids, leucotriens) are metabolites of arachidonic acid and are of importance for many functions of the gastro-intestinal tract. They increase the enteral secretion of water, sodium and chloride ions, stimulate inflammatory and immune reactions, inhibit the proliferation of the colon epithelium and regulate by means of cytoprotection the peristalsis and the intestinal blood supply. Though in chronic inflammatory intestinal diseases the concentrations of metabolites of arachidonic acid are increased up to now there are no conclusive proofs for their causal pathogenetic role.
As revealed in this study, 56.8 +/- 4.3% of children under 1 year, suffering from acute intestinal diseases of unknown (i.e. not determined by common bacteriological methods) etiology, show the presence of enterobacteria capable of the combined synthesis of enterotoxins and adhesion antigens. No such cultures are isolated from healthy children. In cases of diarrhea of domestic animals (piglets and calves), frequent isolation of enterobacteria characterized by both, toxigenicity and capacity for producing adhesion antigens (50.6 +/- 4.8% and 42.9 +/- 4.8% respectively), is noted.
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This investigation is a follow up study of our previous study (Sborn. lék., 90, 1988, 140-146). In the same group of 119 patients with inflammatory intestinal diseases (Crohn's disease - 37, ulcerative colitis - 50, celiac sprue - 32) we followed further affection of locomotor system, peripheral arthritides. Inflammatory manifestations in peripheral articulations were manifest in 11 (9.2%) patients. Among common features of enteropathic arthritides belong: asymmetrical mono-oligoarthritis, in 67% of cases in lower extremities, without X-ray structural manifestations - erosive changes in the whole course, without functional deficit, inflammatory nature of the exudate, absence of rheumatoid nodes, RF negativity, episodic course. On the contrary in 3 (27%) patients the course was chronic. Incidence, relapse, activation of arthritis depends in 18% on activity and in 17% on intestinal complications of the underlying disease. Surgical treatment of small and/or large intestines lead in 60% of cases to remission of peripheral arthritis. In 1 patient (with celiac sprue) synoviorthesis with radioactive coloid 90Y was performed.