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Results for “Intestinal Barrier Function”

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At least 649 records · Page 36Linked to original sources

PubMed2002

Shed human enterocytes as a tool for the study of expression and function of intestinal drug-metabolizing enzymes and transporters.

OBJECTIVES: Intestinal metabolism and transport are now recognized as protective barriers against orally ingested xenobiotics, including drugs. However, in vitro studies of the expression and function of intestinal proteins are hampered by the limited availability of human intestinal tissues. Because enterocytes are constantly shed in large numbers into the gut lumen, this study investigated whether these cells could be collected with a multilumen perfusion catheter and whether they are functionally active. METHODS: In healthy volunteers, a 20-cm isolated jejunal segment was generated with the perfusion catheter by inflating 2 balloons with air. Shed cells were characterized by fluorescence-activated cell sorting analysis for leukocyte-specific CD45 and enterocyte-specific villin, as well as for apoptosis. Homogenates of the cells were used for reverse transcriptase polymerase chain reaction and Western blotting. Cytochrome P450 enzyme activity was determined with the calcium channel blocker verapamil as a substrate. RESULTS: On average, 4.83 mg protein and 56.23 million cells were collected from a 20-cm segment during 2 hours. A total of 84.2% of the cells were positive for enterocyte-specific villin, and only 1.6% of the collected cells were positive for CD45. The majority of cells (65.3%) were not in early or late apoptosis or necrosis. In all volunteers, drug-metabolizing enzymes (such as members of the cytochrome P450 family) could be detected as both messenger ribonucleic acid and proteins. Consistent with expression data, formation of verapamil metabolites catalyzed by CYP3A4 and CYP2C was shown. CONCLUSIONS: The majority of shed human enterocytes collected with a multilumen perfusion catheter were still functionally active and not apoptotic. Harvesting of spontaneously shed enterocytes provides a new tool for studies on expression and function of intestinal proteins.

Adult↗

PubMed2001

Glucagon-like peptide 2.

Glucagon-like peptide 2 (GLP-2) is a 33 amino acid peptide-encoded carboxyterminal to the sequence of GLP-1 in the proglucagon gene. Both GLP-1 and GLP-2 are secreted from gut endocrine cells and promote nutrient absorption through distinct mechanisms of action. GLP-2 regulates gastric motility, gastric acid secretion, intestinal hexose transport, and increases the barrier function of the gut epithelium. GLP-2 significantly enhances the surface area of the mucosal epithelium via stimulation of crypt cell proliferation and inhibition of apoptosis in the enterocyte and crypt compartments. The cytoprotective and reparative effects of GLP-2 are evident in rodent models of experimental intestinal injury. GLP-2 reduces mortality and decreases mucosal injury, cytokine expression, and bacterial septicemia in the setting of small and large bowel inflammation. GLP-2 also enhances nutrient absorption and gut adaptation in rodents or humans with short bowel syndrome. The actions of GLP-2 are transduced by the GLP-2 receptor, a G protein-coupled receptor expressed in gut endocrine cells of the stomach, small bowel, and colon. Activation of GLP-2 receptor signaling in heterologous cells promotes resistance to apoptotic injury in vitro. The cytoprotective, reparative, and energy-retentive properties of GLP-2 suggests that GLP-2 may potentially be useful for the treatment of human disorders characterized by injury and/or dysfunction of the intestinal mucosal epithelium.

Amino Acid Sequence↗

PubMed2002

The influence of apoptosis of mucosal epithelial cells on intestinal barrier integrity after scald in rats.

OBJECTIVE: To study the influence of apoptosis of intestinal epithelial cells occurring as a result of reperfusion after burn shock on the intestinal barrier. METHODS: Fifty Wistar rats were subjected to a 30% TBSA full thickness burn, and normal saline (40 ml/kg) was given intraperitoneally immediately after the injury (group A). Ten rats served as a sham control group. The experimental group B consisted of 50 rats with identical injuries, but the normal saline was not given until 6h after the injury. Apoptosis of intestinal epithelial cells was verified by DNA fragmentation, DNA agarose gel electrophoresis, TUNEL and electron microscope (EM), and DNA fragmentation rate was expressed as ap%. The D-lactic acid in portal vein blood and intestinal diamine oxidase (DAO) were determined to evaluate the permeability and integrity of intestinal mucosal epithelium. RESULTS: The ap% of intestinal epithelium group B was higher than in that of group A (P<0.05 or 0.01), and its amplitude peaked at 12h for both groups. Typical DNA ladder pattern was seen in electrophoresis in both groups. Apoptotic cells were discerned on the tips of the ileal villi at 3h postscald by TUNEL and EM in the group B, and they appeared earlier than in the group A. There was a significant positive correlation between the ap% and the level of D-lactic acid (group A: r=0.817, P<0.05; group B: r=0.727, P<0.05). On the other hand, a significant negative correlation was found between the ap% and the DAO values (group A: r=-0.937, P<0.01; group B: r=-0.836, P<0.05). CONCLUSION: Apoptosis occurred in enterocytes after scald injury this pathological change might contribute to a breach of integrity of intestinal epithelium, leading to a compromise in its barrier function. Delayed fluid resuscitation might lead to an earlier and higher degree of apoptosis of the intestinal epithelial cells.

Amine Oxidase (Copper-Containing)↗

PubMed1997

Cell adhesion and migration. I. Neutrophil adhesive interactions with intestinal epithelium.

In many inflammatory conditions of the gastrointestinal tract, disease activity and patient symptoms correlate with the histological finding of neutrophil (PMN) migration across the epithelium. PMN interactions with intestinal epithelium can influence epithelial functions ranging from barrier maintenance to electrolyte secretion. Additionally, PMN recruitment to the epithelium can be modulated by epithelial interactions with luminal enteric pathogens. Adhesive interactions between PMN and intestinal epithelial cells have been shown to be distinct from interactions of PMN with endothelia. In particular, PMN transepithelial migration is modulated by a distinct array of cytokines including interferon-gamma and interleukin-4 and requires the PMN beta2-integrin CD11b/CD18 but is independent of CD11a/CD18, selectins, and intercellular adhesion molecule 1. Additionally, an integral membrane protein termed CD47 has recently been shown to play an important role in PMN transepithelial migration at point(s) subsequent to initial adhesive interactions. This article provides a brief overview of PMN interactions with epithelia and their functional consequences in relation to inflammatory disease.

Animals↗

PubMed2026

Multi-omics analysis reveals stage-associated differences in gut immunity and microbiota between juvenile and adult common carp (Cyprinus carpio).

In vertebrates, the development of intestinal immunity is closely associated with dynamic changes in the gut microbiota. However, stage-associated differences in intestinal immunity and gut microbial communities remain poorly characterized in teleost fish. In this study, transcriptomic analysis combined with 16S rRNA gene sequencing was employed to characterize intestinal immunity and gut microbial communities in juvenile and adult common carp (Cyprinus carpio). Transcriptomic profiling revealed marked developmental differences in intestinal immune function. Juvenile carp exhibited a predominantly innate immune phenotype, characterized by elevated expression of pro-inflammatory cytokines, antimicrobial peptides, and lysozyme-related genes. This immune profile was accompanied by enhanced mucosal barrier function and a relatively pro-inflammatory intestinal environment. In contrast, adult carp displayed increased expression of genes associated with adaptive immunity, suggesting that adult common carp exhibit relatively stronger adaptive immune characteristics than juvenile fish. Gut microbiota analysis demonstrated significant stage-dependent differences in microbial diversity and community composition. Juvenile fish were enriched with bacterial taxa potentially associated with innate immune activation, whereas adult fish harbored distinct microbial communities linked to intestinal homeostasis and barrier maintenance. Furthermore, correlation analyses identified significant associations between specific microbial taxa and innate immune-related gene expression, suggesting a close association between gut microbiota composition and intestinal immune characteristics in juvenile and adult common carp. Collectively, these findings reveal stage-associated differences in intestinal immunity and gut microbial communities between juvenile and adult common carp, thereby providing insights into intestinal immune characteristics at different developmental stages in teleost fish.

Animals↗

PubMed2001

Enteropathogenic Escherichia coli activates ezrin, which participates in disruption of tight junction barrier function.

Enteropathogenic Escherichia coli (EPEC) is an important human intestinal pathogen, especially in infants. EPEC adherence to intestinal epithelial cells induces the accumulation of a number of cytoskeletal proteins beneath the bacteria, including the membrane-cytoskeleton linker ezrin. Evidence suggests that ezrin can participate in signal transduction. The aim of this study was to determine whether ezrin is activated following EPEC infection and if it is involved in the cross talk with host intestinal epithelial cells. We show here that following EPEC attachment to intestinal epithelial cells there was significant phosphorylation of ezrin, first on threonine and later on tyrosine residues. A significant increase in cytoskeleton-associated ezrin occurred following phosphorylation, suggesting activation of this molecule. Nonpathogenic E. coli and EPEC strains harboring mutations in type III secretion failed to elicit this response. Expression of dominant-negative ezrin significantly decreased the EPEC-elicited association of ezrin with the cytoskeleton and attenuated the disruption of intestinal epithelial tight junctions. These results suggest that ezrin is involved in transducing EPEC-initiated signals that ultimately affect host physiological functions.

Animals↗

PubMed2003

Human ENS regulates the intestinal epithelial barrier permeability and a tight junction-associated protein ZO-1 via VIPergic pathways.

Although the enteric nervous system (ENS) has been shown to regulate various mucosal functions, its role in the physiological control of the human intestinal epithelial barrier is unknown. The aim of this study was to investigate whether the ENS is able to modulate epithelial barrier permeability and a key tight junction-associated protein, zonula occludens-1 (ZO-1). Therefore, we developed a co-culture model, consisting of human submucosa containing the submucosal neuronal network and human polarized colonic epithelial monolayers (HT29-Cl.16E or Caco-2). Submucosal neurons were activated by electrical field stimulation (EFS). Permeability was assessed by measuring the flux of paracellular permeability markers (FITC-dextran or FITC-inulin) across epithelial monolayers. Expression of ZO-1 was determined by immunofluorescence, quantitative immunoblot analysis, and real time RT-PCR. Using the coculture model, we showed that EFS of submucosal neurons resulted in a reduction in FITC-dextran or FITC-inulin fluxes, which was blocked by TTX. In HT29-Cl.16E, the effect of submucosal neuron activation was blocked by a VIP receptor antagonist (VIPra) and reproduced by VIP. Furthermore, ZO-1 expression (mRNA, protein) assessed in HT29-Cl.16E, was significantly increased after submucosal neuron activation by EFS. These effects on ZO-1 expression were blocked by TTX and VIPra and reproduced by VIP. In conclusion, our results strongly suggest a modulatory role of VIPergic submucosal neuronal pathways on intestinal epithelial barrier permeability and ZO-1 expression.

Adult↗

PubMed2003

Role of the gut in the course of severe acute pancreatitis.

INTRODUCTION: The pathogenesis of acute pancreatitis remains elusive. Sepsis and multiple organ failure continue to cause death (overall mortality rate, approximately 10%) despite immense improvements in supportive, radiologic, and surgical therapy. The gut appears to play a key role in the development of these complications. AIM: To critically review the evidence implicating the gut in the pathogenesis of acute pancreatitis. METHODS: Relevant English-language literature or abstracts cited in the MEDLINE database were reviewed. RESULTS AND CONCLUSION: Gram-negative enteric organisms account for most infections of pancreatic necrosis and subsequent sepsis, which suggests the gut as a source. Intestinal permeability is increased early in patients with severe acute pancreatitis and correlates with endotoxemia, which suggests translocation as a possible mechanism. The pathogenesis of the deranged function of the gut mucosal barrier and the possible sites of increase in intestinal permeability are discussed. The gut also plays a role in priming neutrophils and the release of inflammatory cytokines, which initiate and propagate nearly all the detrimental consequences of severe inflammation and sepsis. Future research avenues and potential therapeutic measures that may restore and preserve gut barrier function are explored.

Animals↗

PubMed2000

Intestinal manipulation during elective aortic aneurysm surgery leads to portal endotoxaemia and mucosal barrier dysfunction.

OBJECTIVES: to investigate the effect of intestinal manipulation on intestinal permeability and endotoxaemia during elective abdominal aortic aneurysm (AAA) surgery. DESIGN: prospective randomised controlled study. PATIENTS AND METHODS: fourteen patients undergoing elective infrarenal AAA repair were randomised into either the transperitoneal (n=7) or extraperitoneal approach (n=7). Intestinal permeability was measured preoperatively (PO), and at day 1 (D1) and day 3 (D3) after surgery using the lactulose/mannitol absorption test. Portal and systemic blood samples were taken before clamping, at completion of proximal and distal anastomoses and immediately before abdominal wound closure, for endotoxin measurement using the chromogenic limulus amoebocyte lysate assay. RESULTS: intestinal permeability was significantly increased at D1 (0.107+/-0.04 (mean+/-S.E.M.)) in the transperitoneal group compared to the PO level (0.020+/-0.004, p<0.05) and to the extraperitoneal group at D1 (0.020+/-0.004, p<0.05) which showed no change in comparison with the PO level. No correlation was seen between increased intestinal permeability and aortic clamp time, operation time, amount of blood lost or transfused. However, a significantly higher concentration of portal endotoxin was detected intraoperatively in the transperitoneal group of patients in comparison to the extraperitoneal group (p<0.05). There was a significant positive correlation between portal endotoxaemia and intestinal permeability (r(s)=0.955 p=0.001). CONCLUSION: an increase in intestinal permeability and a greater degree of portal endotoxaemia are observed during transperitoneal approach to the aorta. This suggests that intestinal manipulation may impair gut mucosal barrier function and contribute to the systemic inflammatory response seen in AAA surgery.

Aged↗

PubMed1997

Lazaroid improves intestinal blood flow in the rat during hyperdynamic bacteraemia.

BACKGROUND: Intestinal mucosal hypoperfusion and loss of barrier function during sepsis may contribute to maintaining the septic state. Free radicals are produced during sepsis and antioxidants improve survival from experimental sepsis. It is unclear whether endothelial cell injury from free radicals results in altered microvascular reactivity. Lazaroids are antioxidants which scavenge radicals and block lipid radical chain reactions. The authors sought to determine whether lazaroids altered the intestinal microvascular responses to sepsis. METHODS: In vivo video microscopy was used to study the ileal microcirculation of the rat. A1 (inflow) arteriolar diameter and flow, A3 (premucosal) arteriolar diameters, and cardiac output were measured. Lazaroid or vehicle was infused before a bolus injection of live Escherichia coli or saline. RESULTS: Lazaroid alone had no effect on the intestinal vessels or haemodynamics. E. coli caused vasoconstriction (A1, -21 per cent, A3, -19 per cent of baseline) and hypoperfusion (-36 per cent) despite increased cardiac output (+31 per cent). Lazaroid significantly attenuated both constriction (A1, -11 per cent; A3, 10 to -1 per cent) and hypoperfusion (-15 per cent), but did not increase cardiac output (30 per cent). CONCLUSION: E. coli bacteraemia led to intestinal vasoconstriction and hypoperfusion. Lazaroid reduced this effect without altering central haemodynamic responses, suggesting that free radicals have a deleterious effect on the intestinal microcirculation during bacteraemia.

Animals↗

PubMed2001

Intestinal and hemodynamic impairment following mesenteric ischemia/reperfusion.

BACKGROUND: Clinical intestinal ischemia/reperfusion (I/R) injury results in local and systemic dysfunction. A rat model of transient mesenteric occlusion has been used to study this phenomenon. However, a systematic analysis of the rat model with respect to intestinal permeability and hemodynamics has not been carried out. MATERIALS AND METHODS: In anesthetized rats, the superior mesenteric artery was occluded for 60 min, followed by reperfusion for 4 h. Intestinal impairment was evaluated via histological examination and by measuring ex vivo apparent permeability coefficients (Papp) of mannitol (0.18 kDa), inulin (5 kDa), and dextran (70 kDa). Hemodynamic effects of intestinal I/R were determined by monitoring mean arterial pressure (MAP) and heart rate (HR) via a catheter placed in the femoral artery. RESULTS: The animal model was associated with increased ex vivo Papp for mannitol and inulin. Although I/R injury was accompanied by significant histological disruption, there was no observable alteration in dextran permeability, suggesting that the loss in normal barrier function was limited to low-molecular-weight compounds. Hemodynamic measurements indicated that reperfusion induced a precipitous and sustained fall in MAP. HR values fell sharply following reperfusion but gradually increased and eventually "overshot" to values greater than baseline. CONCLUSIONS: Our findings demonstrate the selective loss of barrier function of the small bowel following intestinal I/R. Furthermore, these results also illustrate the importance of selecting appropriate permeability markers for the evaluation of intestinal damage. In light of the significant hemodynamic disruption accompanying the animal model, our investigation also points toward the need for developing therapeutic strategies that mitigate the local and systemic effects of intestinal I/R injury.

Animals↗

PubMed1998

[An experimental study on curative effect of Chinese medicine qing yi tang in acute necrotizing pancreatitis].

OBJECTIVE: To observe the curative effect of the traditional Chinese medicine (TCM) Qing Yi Tang (QYT) in acute necrotizing pancreatitis (ANP). METHODS: Twenty three dogs were randomly divided into 3 groups. In control group (n = 7), animals underwent laparotomy only. In ANP group (n = 8), acute necrotizing pancreatitis was induced by injection of 0.5 ml/kg 5% sodium taurocholate with 300 u/kg trypsin into the pancreatic duct. While in TCM group (n = 8) were fed everyday with QYT after onset of ANP. All animals were sacrified 7 days later and organs were gathered and cultured. Mucosal and luminal floras of the intestine were analysed. Pancreas and ileal mucosa were examined histologically and ultra-microscopically, the levels of lipopolysaccharide (LPS) and amylase in blood were determined. RESULTS: In TCM groups, histologic and ultra-structural damages in pancreas and ileal mucosa were much milder as compared with those of ANP group. In ANP group, there was a significant increase of E. coli and bacterocoids, and a significant decrease of bifidobacteria, lactobacilli and enterococci in the intestinal mucosa, while in TCM groups, these changes were alleviated significantly (P < 0.05 or P < 0.01). As compared with ANP group, the bacterial translocation (BT) rate was reduced from 100% to 50%, and the counts of translocated bacteria were decreased 10-40 times, the levels of LPS and amylase reduced 2 to 3 times. CONCLUSION: TCM recipe QYT showed their protective effects on gut barrier function by alleviating the damage of intestinal mucosa and microecologic disturbance following acute pancreatitis. As a result, the chances of BT and enterogenic infection declined. These preparation might be promising in the prophylaxis and treatment of infection complicating ANP.

Animals↗

PubMed1999

Modulation of intestinal functions by food substances.

The small intestinal epithelium plays a crucial role in the digestion/modification of food components, absorption of nutrients and recognition of food-derived signals. It also acts as a barrier against unfavourable materials in food. These intestinal functions may be influenced by food substances. In this paper, the effects of various food substances on the intestinal functions, particularly the absorption functions, are discussed. A new assay method, using a monolayer culture system of human intestinal epithelial cells, is applied to examine food-derived substances which could modulate the tight junction (TJ). Capsianoside, a diterpene glycoside from sweet pepper, was isolated and identified as one of the TJ-modulating substances. Those substances can be expected to facilitate the paracellular absorption of small molecular functional substances such as bioactive oligopeptides. The use of a human intestinal cell culture system also enabled us to make a simple screen test for food substances which affect the intestinal transporter functions. Substances which could suppress the activity of intestinal glucose transporters, for example, can be expected to reduce the dietary glucose uptake in the intestinal epithelium and control the blood glucose level. Polyphenolic compounds from plants, including green tea, were found to have such activity. Modulation of the brush border enzymes by food substances is also discussed.

Animals↗

PubMed2003

CARD15/NOD2 functions as an antibacterial factor in human intestinal epithelial cells.

BACKGROUND & AIMS: Mutations in the CARD15/NOD2 gene, a putative intracellular pattern recognition receptor, have been linked to the risk for Crohn's disease. Because intestinal epithelial cells play a role as the barrier to luminal microorganisms, we investigated the expression and function of CARD15/NOD2 in intestinal epithelial cells. METHODS: Expression of CARD15/NOD2 messenger RNA (mRNA) in intestinal epithelial cell lines and primary intestinal epithelial cells was assessed by reverse-transcription polymerase chain reaction (RT-PCR). Regulation of expression of CARD15/NOD2 by cytokines was determined by Northern blot using the SW480 cell line. Active CARD15/NOD2 protein in SW480 cells was assessed by the combination of immunoprecipitation and immunoblotting using anti-CARD15/NOD2 antisera. To identify the functional role of CARD15/NOD2 in intestinal epithelial cells, gentamicin protection assays of Salmonella typhimurium were performed using Caco2 cells stably transfected with either wild-type CARD15/NOD2 or the 3020insC mutant associated with Crohn's disease. RESULTS: CARD15/NOD2 mRNA was expressed in both intestinal epithelial cell lines and primary intestinal epithelial cells. CARD15/NOD2 mRNA and protein were up-regulated by tumor necrosis factor alpha (TNFalpha) in SW480 cells. The number of viable internalized S. typhimurium in Caco2 cells stably transfected with CARD15/NOD2 expression plasmid was lower than untransfected Caco2 cells or MOCK transfectant. In contrast, expression of a variant associated with Crohn's disease was unable to constrain bacterial survival. CONCLUSIONS: CARD15/NOD2 is expressed in intestinal epithelial cells and may serve as a key component of innate mucosal responses to luminal bacteria as an antibacterial factor. Failure in this activity may contribute to the development of Crohn's disease.

Caco-2 Cells↗

PubMed2003

Bacterial colonization leads to the colonic secretion of RELMbeta/FIZZ2, a novel goblet cell-specific protein.

BACKGROUND & AIMS: Goblet cells are highly polarized exocrine cells found throughout the small and large intestine that have a characteristic morphology due to the accumulation of apical secretory granules. These granules contain proteins that play important physiologic roles in cellular protection, barrier function, and proliferation. A limited number of intestinal goblet cell-specific proteins have been identified. In this study, we investigate the expression and regulation of RELMbeta, a novel colon-specific gene. METHODS: The regulation of RELMbeta messenger RNA expression was determined in LS174T, Caco-2, and HT-29 cell lines in response to stimulation with interleukin 13 and lipopolysaccharide. Quantitative reverse-transcription polymerase chain reaction, immunoblots, and immunohistochemistry were used to examine the expression of RELMbeta in BALB/c and C.B17.SCID mice housed in conventional, germ-free, and gnotobiotic environments. RESULTS: Messenger RNA for RELMbeta is restricted to the undifferentiated, proliferating colonic epithelium. Immunohistochemistry shows that this protein is expressed in goblet cells located primarily in the distal half of the colon and cecum with lower levels detectable in the proximal colon. High levels of RELMbeta can be detected in the stool of mice and humans, where it exists as a homodimer under nonreducing conditions. Interestingly, the secretion of RELMbeta is dramatically reduced in germ-free mice. Furthermore, introduction of germ-free mice into a conventional environment results in enhanced expression and robust secretion of RELMbeta within 48 hours. CONCLUSIONS: These studies define a new goblet cell-specific protein and provide the first evidence that colon-specific gene expression can be regulated by colonization with normal enteric bacteria.

Animals↗

PubMed2004

Modulation of human enteric epithelial barrier and ion transport function by Peyer's patch lymphocytes.

AIM: To investigate the role of Peyer's patch lymphocytes in the regulation of enteric epithelial barrier and ion transport function in homeostasis and host defense. METHODS: Mouse Peyer's patch lymphocytes were co-cultured with human intestinal epithelial cell line Caco-2 either in the mixed or separated (isolated but permeable compartments) culture configuration. Barrier and transport functions of the Caco-2 epithelial monolayers were measured with short-circuit current (Isc) technique. Release of cytokines was measured by enzyme-linked immunosorbent assay (ELISA) and cytokine mRNA expression was analyzed by semi-quantitative RT-PCR. Barrier and iontransport functions of both culture conditions following exposure to Shigella lipopolysaccharide (LPS) were also examined. RESULTS: The transepithelial resistance (TER) of the epithelial monolayers co-cultured with Peyer's patch lymphocytes was maintained whereas that of the Caco-2 monolayers alone significantly decreased after eight days in culture. The forskolin-induced anion secretion, in either absence or presence of LPS, was significantly suppressed in the both co-cultures as compared with the Caco-2 cells alone. Furthermore, only the mixed co-culture condition induced the expression and release of mIL-6 from Peyer's patch lymphocytes, which could be further enhanced by LPS. However, both co-culture conditions suppressed expression and release of epithelial hIL-8 under the unstimulated conditions, while the treatment with LPS stimulated their hIL-8 expression and release. CONCLUSION: Peyer's patch lymphocytes may modulate intestinal epithelial barrier and ion transport function in homeostasis and host defense via cell-cell contact and cytokine signaling.

Animals↗

PubMed2003

Role of the polymeric Ig receptor in mucosal B cell homeostasis.

Secretory IgA (SIgA) is the most characteristic component of the mucosal immune system and has long been considered the major protective factor that prevents pathogens from invading hosts through the mucosae. Recent studies, however, have suggested that complete immunity against a range of mucosal bacterial and viral pathogens can be achieved in the absence of IgA. Therefore, to further dissect the role of SIgA, we generated mice deficient in the polymeric Ig receptor (pIgR(-/-) mice). As a result of an inability to transport dimeric IgA to the secretions, pIgR(-/-) mice are deficient in SIgA and accumulate circulating dimeric IgA, with serum levels 100-fold greater than those observed in normal mice. Examination of lamina propria mononuclear cells showed that pIgR(-/-) mice had approximately 3 times as many IgA-secreting cells as C57BL/6 mice. Further analysis showed that these cells displayed the differentiated IgA(+) B220(-) phenotype and accounted for a 2-fold increase in the number of lamina propria blast cells in the pIgR(-/-) mice. Subsequent experiments showed that OVA-specific CD4(+) T cell expansion following OVA feeding was not elevated in pIgR(-/-) mice. Furthermore, no differences in CD8(+) T cell tolerance or induction of influenza virus-specific CD8(+) T cells were detected in pIgR(-/-) mice compared with controls. Therefore, while SIgA is clearly involved in maintaining some parameters of mucosal homeostasis in the intestine, the mechanisms associated with its barrier function and the clinical consequences of its deficiency are yet to be identified.

Administration, Oral↗

PubMed2005

Dietary threonine restriction specifically reduces intestinal mucin synthesis in rats.

We determined whether the steady-state levels of intestinal mucins are more sensitive than total proteins to dietary threonine intake. For 14 d, male Sprague-Dawley rats (158 +/- 1 g, n = 32) were fed isonitrogenous diets (12.5% protein) containing 30% (group 30), 60% (group 60), 100% (control group), or 150% (group 150) of the theoretical threonine requirement for growth. All groups were pair-fed to the mean intake of group 30. The mucin and mucosal protein fractional synthesis rates (FSR) did not differ from controls in group 60. By contrast, the mucin FSR was significantly lower in the duodenum, ileum, and colon of group 30 compared with group 100, whereas the corresponding mucosal protein FSR did not differ. Because mucin mRNA levels did not differ between these 2 groups, mucin production in group 30 likely was impaired at the translational level. Our results clearly indicate that restriction of dietary threonine significantly and specifically impairs intestinal mucin synthesis. In clinical situations associated with increased threonine utilization, threonine availability may limit intestinal mucin synthesis and consequently reduce gut barrier function.

Amino Acids↗