Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0024523 (malabsorption)
 7,319 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Carbohydrates are hydrolyzed in the intestinal lumen by specific enzymes to monosaccharides before transport across the brush border membrane of epithelial cells into the cell interior. The enzymes implicated in the digestion of carbohydrates in the intestinal lumen are membrane-bound glycoproteins that are expressed at the apical domain of the enterocytes. Absent or reduced activity of one of these enzymes is the cause of disaccharide intolerance and malabsorption, the symptoms of which are abdominal pain, cramps or distention, flatulence, nausea and osmotic diarrhea. Lactose intolerance is the most common intestinal disorder that is associated with an absence or drastically reduced levels of an intestinal enzyme, in this case lactase-phlorizin hydrolase (LPH). The pattern of reduction of activity has been termed late onset of lactase deficiency or adult type hypolactasia. It was thought that the regulation of LPH was post-translational and was associated with altered structural features of the enzyme. Recent studies, however, suggest that the major mechanism of regulation of LPH is transcriptional. Other forms of lactose intolerance include the rare congenital lactase deficiency and secondary forms, such as those caused by mucosal injury, due to infectious gastroenteritis, celiac disease, parasitic infection, drug-induced enteritis and Crohn's disease. This review will shed light on important strucural and biosynthetic aspects of LPH, the role played by particular regions of the LPH protein in its transport, polarized sorting, and function, as well as on the gene expession and regulation of the activity of the enzyme.
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PMID:Molecular and cellular aspects and regulation of intestinal lactase-phlorizin hydrolase. 1133 11

To date, microvillus inclusion disease (MID) has been diagnosed in six Dutch patients. It is a rare autosomal recessive hereditary intestinal disorder mostly presenting with malabsorption and severe secretory diarrhoea from birth. The diagnosis is confirmed by electron microscopy of intestinal mucosal biopsies, which show characteristic intracytoplasmic vesicles containing clearly recognisable microvilli and irregularly distributed microvilli in the brush border. The two clinical forms of the disease that have been recognised internationally, a 'congenital' and a 'late-onset' form of MID, have also been observed in the Dutch patients. At the last follow-up five patients had died, the sixth was 17 years old and alive. The pathogenesis and genetics of MID are, as yet, unknown. Eventually, all patients die from complications of the disease, notably from the total parenteral nutrition. The only chance of survival is intestinal or combined liver-intestinal transplantation.
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PMID:[Microvillus inclusion disease, a rare cause of severe congenital diarrhea]. 1219 12

Azathioprine is commonly prescribed for autoimmune hepatitis and inflammatory bowel disease. An acute gastroenteritis-like syndrome has been ascribed to azathioprine use, but chronic diarrhea has not. We report a patient with autoimmune hepatitis who developed severe small-bowel villus atrophy and chronic diarrhea after azathioprine was initiated (50 mg/day). We present a case report of a patient followed up prospectively. Duodenal mucosal histology and expression of brush border enzyme dipeptidyl peptidase IV and peptide transporter PepT1 messenger RNA levels were determined before and after azathioprine discontinuation. Chronic diarrhea developed several weeks after the initiation of azathioprine and resulted in micronutrient depletion and severe protein-calorie malnutrition, which was unresponsive to oral pancreatic enzyme therapy or a gluten-free diet. Severe malabsorption required parenteral nutrition support for longer than 1.5 years; this was complicated by unstable blood glucose control, acute calculous cholecystitis, catheter sepsis, and severe venous thrombosis. When the temporal association between azathioprine and diarrhea was identified, the drug was tapered while the patient consumed an unrestricted diet. Within 2 weeks after azathioprine was discontinued, diarrhea had completely resolved, and parenteral nutrition was discontinued. Mucosal biopsies obtained before and 4 months after azathioprine discontinuation showed complete reversal of severe duodenal villus atrophy and marked up-regulation of mucosal dipeptidyl peptidase IV and PepT1 messenger RNA. The patient has subsequently maintained normal liver function tests on low-dose prednisone alone, with normal stools and stable nutritional status for longer than 4 years. Azathioprine can induce severe small-bowel villus atrophy, diarrhea, and malabsorption that is reversible with drug discontinuation.
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PMID:Severe villus atrophy and chronic malabsorption induced by azathioprine. 1280 28

Carbohydrates are mostly digested to glucose, fructose and galactose before absorption by the small intestine. Absorption across the brush border and basolateral membranes of enterocytes is mediated by sodium-dependent and -independent membrane proteins. Glucose and galactose transport across the brush border occurs by a Na(+)/glucose (galactose) co-transporter (SGLT1), whereas passive fructose transport is mediated by a uniporter (GLUT5). The passive exit of all three sugars out of the cell across the basolateral membrane occurs through two uniporters (GLUT2 and GLUT5). Mutations in SGLT1 cause a major defect in glucose and galactose absorption (glucose-galactose Malabsorption), but mutations in GLUT2 do not appear to disrupt glucose and galactose absorption. Studies on GLUT1 null mice and Fanconi-Bickel patients suggest that there is another exit pathway for glucose and galactose that may involve exocytosis. There are no known defects of fructose absorption.
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PMID:Intestinal absorption in health and disease--sugars. 1464 59

T-cell-mediated pathogenesis has been documented in various idiopathic and microbially induced intestinal disorders. Diffuse microvillous shortening seen in giardiasis is responsible for disaccharidase insufficiencies and malabsorption of electrolytes, nutrients, and water. Other mucosal changes include crypt hyperplasia and increased numbers of intraepithelial lymphocytes (IEL). A recent report using an athymic mouse model of infection showed that these epithelial injuries were dependent on T cells. The aim of the present study was to identify which subset of superior mesenteric lymph node (SMLN) T cells were responsible for mucosal alterations in giardiasis. CD4+ and CD8+ T cells, as well as whole lymphocyte populations, were isolated from SMLN of Giardia muris-infected mice for adoptive transfer. Jejunal segments of recipient mice were assessed for brush border ultrastructure, sucrase activity, crypt/villus ratio, and IEL numbers. Mice that received enriched CD8+ and whole SMLN lymphocytes, but not CD4+ T cells, from infected donors showed diffuse shortening of microvilli, loss of brush border surface area, impaired sucrase activity, and increased crypt/villus ratios compared to respective controls. Transfer of whole SMLN lymphocytes, as well as enriched CD4+ or CD8+ T cells, from infected donors led to increased IEL numbers in the recipient jejunum. The findings indicate that loss of intestinal brush border surface area, reduced disaccharidase activities, and increased crypt/villus ratios in giardiasis are mediated by CD8+ T cells, whereas both CD8+ and CD4+ SMLN T cells regulate the influx of IEL.
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PMID:Role of CD8+ and CD4+ T lymphocytes in jejunal mucosal injury during murine giardiasis. 1515 62

T lymphocyte-mediated pathogenesis is common to a variety of enteropathies, including giardiasis, cryptosporidiosis, bacterial enteritis, celiac's disease, food anaphylaxis, and Crohn's disease. In giardiasis as well as in these other disorders, a diffuse loss of microvillous brush border, combined or not with villus atrophy, is responsible for disaccharidase insufficiencies and malabsorption of electrolytes, nutrients, and water, which ultimately cause diarrheal symptoms. Other mucosal changes may include crypt hyperplasia and increased infiltration of intra-epithelial lymphocytes. Recent studies using models of giardiasis have shed new light on the immune regulation of these abnormalities. Indeed, experiments using an athymic mouse model of infection have found that these epithelial injuries were T cell-dependent. Findings from further research indicate that that the loss of brush border surface area, reduced disaccharidase activities, and increase crypt-villus ratios are mediated by CD8+ T cells, whereas both CD8+ and CD4+ small mesenteric lymph node T cells regulate the influx of intra-epithelial lymphocytes. Future investigations need to characterize the CD8+ T cell signaling cascades that ultimately lead to epithelial injury and malfunction in giardiasis and other malabsorptive disorders of the intestine.
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PMID:Immunopathology of giardiasis: the role of lymphocytes in intestinal epithelial injury and malfunction. 1596 21

Giardia lamblia is an intestinal protozoan parasite infecting humans and various other mammalian hosts. The most important clinical signs of giardiasis are diarrhoea and malabsorption. Giardia lamblia is able to undergo continuous antigenic variation of its major surface antigen, named VSP (variant surface protein). While intestinal antibodies, and more specifically anti-VSP IgA antibodies, were proven to be involved in modulating antigenic variation of the parasite the participation of the local antibody response in control of the parasite infection is still controversial. Conversely, previous studies based on experimental infections in mice showed that cellular immune mechanisms are essential for elimination of the parasite from its intestinal habitat. Furthermore, recent data indicated that inflammatory mast cells have a potential to directly, or indirectly, interfere in duodenal growth of G. lamblia trophozoites. However, this finding was challenged by other reports, which did not find a correlation between intestinal inflammation and resistance to infection. Since intestinal infiltration of inflammatory cells and/or CD8+T-cells were demonstrated to coincide with villus-shortening and crypt hyperplasia immunological reactions were considered to be a potential factor of pathogenesis in giardiasis. The contribution of physiological factors to pathogenesis was essentially assessed in vitro by co-cultivation of G. lamblia trophozoites with epithelial cell lines. By using this in vitro model, molecular (through surface lectins) and mechanical (through ventral disk) adhesion of trophozoites to the epithelium was shown to be crucial for increased epithelial permeability. This phenomenon as well as other Giardia-induced intestinal abnormalities such as loss of intestinal brush border surface area, villus flattening, inhibition of disaccharidase activities, and eventually also overgrowth of the enteric bacterial flora seem to be involved in the pathophysiology of giardiasis. However, it remains to be elucidated whether at least part of these pathological effects are causatively linked to the clinical manifestation of the disease.
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PMID:Recent insights into the mucosal reactions associated with Giardia lamblia infections. 1618 98

Absorption of labeled simple 3',5',9'-(3)H pteroylmonoglutamate, ([(3)H]PG-1) and conjugated pteroyl-mu[(14)C]glutamyl-gamma-hexaglutamate, ([(14)C]PG-7) folates was assessed in six patients with tropical sprue, before and after 6 mo of treatment, utilizing jejunal perfusion and urinary recovery techniques. Degradation products of [(14)C]PG-7 which were produced during perfusion were identified by DEAE-cellulose column chromatography. Jejunal mucosal activities of folate conjugase, lactase, sucrase, and maltase were measured in every patient. Malabsorption of both [(3)H]PG-1 and [(14)C]PG-7 was found in every untreated patient, with significant improvement after therapy. The urinary excretion of (3)H and (14)C paralleled the luminal disappearance of both isotopes. The chromatographic patterns of intraluminal degradation products of [(14)C]PG-7 obtained during perfusion did not differ from those previously found in normal subjects and were similar in studies performed before and after treatment. The activity of folate conjugase was increased in the mucosa of the untreated patients when compared to the post-treatment levels while the activities of mucosal lactase, sucrase, and maltase were originally low and increased significantly after therapy. These observations suggest that folate conjugase originates at a different mucosal locus than the brush border disaccharidases, and are consistent with previous evidence that folate conjugase is an intracellular enzyme. The present studies have demonstrated unequivocal malabsorption of both simple and conjugated folates in tropical sprue. In tropical sprue, folate malabsorption is the reflection of impaired folate transport and not of impaired hydrolysis.
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PMID:Jejunal perfusion of simple and conjugated folates in tropical sprue. 1669 65

Acute T cell-mediated diarrhea is associated with increased mucosal expression of proinflammatory cytokines, including the TNF superfamily members TNF and LIGHT. While we have previously shown that epithelial barrier dysfunction induced by myosin light chain kinase (MLCK) is required for the development of diarrhea, MLCK inhibition does not completely restore water absorption. In contrast, although TNF-neutralizing antibodies completely restore water absorption after systemic T cell activation, barrier function is only partially corrected. This suggests that, while barrier dysfunction is critical, other processes must be involved in T cell-mediated diarrhea. To define these processes in vivo, we asked whether individual cytokines might regulate different events in T cell-mediated diarrhea. Both TNF and LIGHT caused MLCK-dependent barrier dysfunction. However, while TNF caused diarrhea, LIGHT enhanced intestinal water absorption. Moreover, TNF, but not LIGHT, inhibited Na+ absorption due to TNF-induced internalization of the brush border Na+/H+ exchanger NHE3. LIGHT did not cause NHE3 internalization. PKCalpha activation by TNF was responsible for NHE3 internalization, and pharmacological or genetic PKCalpha inhibition prevented NHE3 internalization, Na+ malabsorption, and diarrhea despite continued barrier dysfunction. These data demonstrate the necessity of coordinated Na+ malabsorption and barrier dysfunction in TNF-induced diarrhea and provide insight into mechanisms of intestinal water transport.
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PMID:Coordinated epithelial NHE3 inhibition and barrier dysfunction are required for TNF-mediated diarrhea in vivo. 1701 51

Intestinal epithelial cell protrusions referred as microvilli or brush border membranes (BBMs) are specialized in the digestion, uptake, and transport of nutrients, trace elements and vitamins from intestinal lumen into the circulation. Disorders of intestinal absorption are common in human pathology and include serious defects such as malabsorption. A detailed description of native digestive protein complexes in BBMs is therefore essential for understanding the physiology and pathology of digestion and absorption. In this study, we employed blue native PAGE (BN-PAGE) technique to separate protein complexes from purified mouse intestinal BBMs. We found 23 distinct protein complexes, which were cut off from the gel, and their protein composition was determined by LC-MS/MS. A total of 55 individual proteins were identified including peptidases, enzymes of carbohydrate metabolism, membrane transporters, cytoskeletal proteins, chaperones, and regulatory enzymes. From the identified proteins, 50% represent molecules with at least one predicted transmembrane domain as predicted by SOSUI software. To the best of our knowledge, this work is the first attempt aimed to characterize the native membrane proteome of intestinal BBM. As demonstrated here, BN-PAGE is a powerful tool for the separation of not only mitochondrial, but also membrane hydrophobic proteins in general. In addition, BN-PAGE technique preserves metal-protein interactions, as shown by the presence of 65Zn in metalloprotein complexes, isolated from zinc-radiolabeled BBMs.
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PMID:Native proteomic analysis of protein complexes in murine intestinal brush border membranes. 1720 97


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