Heavy exercise causes gut symptoms and, in extreme cases, "heat stroke" partially due to increased intestinal permeability of luminal toxins. We examined bovine colostrum, a natural source of growth factors, as a potential moderator of such effects. Twelve volunteers completed a double-blind, placebo-controlled, crossover protocol (14 days colostrum/placebo) prior to standardized exercise. Gut permeability utilized 5 h urinary lactulose-to-rhamnose ratios. In vitro studies (T84, HT29, NCM460 human colon cell lines) examined colostrum effects on temperature-induced apoptosis (active caspase-3 and 9, Bax␣, Bcl-2), heat shock protein 70 (HSP70) expression and epithelial electrical resistance. In both study arms, exercise increased blood lactate, heart rate, core temperature (mean 1.4°C rise) by similar amounts. Gut hormone profiles were similar in both arms although GLP-1 levels rose following exercise in the placebo but not the colostrum arm (P ϭ 0.026). Intestinal permeability in the placebo arm increased 2.5-fold following exercise (0.38 Ϯ 0.012 baseline, to 0.92 Ϯ 0.014, P Ͻ 0.01), whereas colostrum truncated rise by 80% (0.38 Ϯ 0.012 baseline to 0.49 Ϯ 0.017) following exercise. In vitro apoptosis increased by 47-65% in response to increasing temperature by 2°C. This effect was truncated by 60% if colostrum was present (all P Ͻ 0.01). Similar results were obtained examining epithelial resistance (colostrum truncated temperature-induced fall in resistance by 64%, P Ͻ 0.01). Colostrum increased HSP70 expression at both 37 and 39°C (P Ͻ 0.001) and was truncated by addition of an EGF receptor-neutralizing antibody. Temperature-induced increase in Bax␣ and reduction in Bcl-2 was partially reversed by presence of colostrum. Colostrum may have value in enhancing athletic performance and preventing heat stroke.repair; gut growth; injury; clinical trial SEVERAL STRESSES AFFECT the integrity of the intestinal barrier. These include prolonged strenuous exercise (10), heat stress (11), and drugs such as nonsteroidal anti-inflammatory agents. Loss of intestinal barrier integrity leading to increased intestinal permeability may result in passage of luminal endotoxins into the circulation. This, in turn, results in an inflammatory cascade, exacerbating the loss of barrier function and, in severe cases, resulting in severe systemic effects.Severe cases of decompensation can result in the lifethreatening condition of exertional heat stroke, associated with hyperthermia, multiorgan failure, and endotoxemia. In addition, it is increasingly recognized that similar processes have relevance for many athletes involved in heavy exercise such as long-distance running. Gastrointestinal symptoms including cramps, diarrhea, nausea, and bleeding are commonly reported by long-distance runners (16). These symptoms are likely to be due to a combination of reduced splanchnic blood flow, hormonal changes, altered gut permeability, and increased body temperature.Pharmacological options to reduce these problems are limited, particularly in compe...
Background-Non-steroidal anti-inflammatory drugs (NSAIDs) are eVective for arthritis but cause gastrointestinal injury. Bovine colostrum is a rich source of growth factors and is marketed as a health food supplement. Aims-To examine whether spray dried, defatted colostrum or milk preparations could reduce gastrointestinal injury caused by indomethacin. Methods-EVects of test solutions, administered orally, were examined using an indomethacin restraint rat model of gastric damage and an indomethacin mouse model of small intestinal injury. EVects on migration of the human colonic carcinoma cell line HT-29 and rat small intestinal cell line RIE-1 were assessed using a wounded monolayer assay system (used as an in vitro model of wound repair) and eVects on proliferation determined using [ H]thymidine incorporation.Results-Pretreatment with 0.5 or 1 ml colostral preparation reduced gastric injury by 30% and 60% respectively in rats. A milk preparation was much less eYcacious. Recombinant transforming growth factor added at a dose similar to that found in the colostrum preparation (12.5 ng/rat), reduced injury by about 60%. Addition of colostrum to drinking water (10% vol/vol) prevented villus shortening in the mouse model of small intestinal injury. Addition of milk preparation was ineVective. Colostrum increased proliferation and cell migration of RIE-1 and HT-29 cells. These eVects were mainly due to constituents of the colostrum with molecular weights greater than 30 kDa. Conclusions-Bovine colostrum could provide a novel, inexpensive approach for the prevention and treatment of the injurious eVects of NSAIDs on the gut and may also be of value for the treatment of other ulcerative conditions of the bowel. (Gut 1999;44:653-658)
ABSTRACTpS2 is a member of the trefoil peptide family, all of which are overexpressed at sites of gastrointestinal injury. We hypothesized that they are important in stimulating mucosal repair. To test this idea, we have produced a transgenic mice strain that expresses human pS2 (hpS2) specifically within the jejunum and examined the effect of this overexpression on proliferation and susceptibility to indomethacin-induced damage. A transgenic mouse was produced by microinjecting fertilized oocytes with a 1.7-kb construct consisting of rat intestinal fatty acid binding protein promoter (positions -1178 to +28) linked to full-length (490 bp) hpS2 cDNA. Screening for positive animals was by Southern blot analysis. Distribution of hpS2 expression was determined by using Northern and Western blot analyses and immunohistochemical staining. Proliferation of the intestinal mucosa was determined by assessing the crypt cell production rate. Differences in susceptibility to intestinal damage were analyzed in animals that had received indomethacin (85 mg/kg s.c.) 0-30 h previously. Expression of hpS2 was limited to the enterocytes of the villi within the jejunum. In the nondamaged intestine, villus height and crypt cell production rate were similar in transgenic and negative (control) litter mates. However, there was a marked difference in the amount of damage caused by indomethacin in control and transgenic animals in the jejunum (30% reduction in villus height in controls vs. 12% reduction in transgenic animals, P < 0.01) but the damage sustained in the non-hpS2-expressing ileal region was similar in control and transgenic animals. These studies support the hypothesis that trefoil peptides are important in stimulating gastrointestinal repair.
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