Drug Crystal-Related Gastrointestinal Complications Involve Crystal-Induced Release of Neutrophil and Monocyte Extracellular Traps.

Ion-exchange resins are commonly used to manage complications of chronic kidney disease, such as hyperphosphatemia, hyperkalemia, and hypercholesterolemia. Occasionally, these drugs can irritate the gastrointestinal lining and cause life-threatening intestinal necrosis. Currently, the pathophysiology of drug crystal-induced intestinal necrosis is not well understood. We hypothesized that crystals of ion-exchange resins like sevelamer, polystyrene sulfonate, and cholestyramine can trigger the formation of neutrophil and monocyte extracellular traps by contributing to intestinal barrier dysfunction. Light and fluorescence microscopy of the colonic resection specimen from a patient with chronic kidney disease revealed severe intestinal necrosis, ulceration, sevelamer crystals, and inflammation upon oral intake of sevelamer, as well as the formation of neutrophil extracellular traps in proximity to small sevelamer crystals. Indeed, drug crystals reduced metabolic activity and induced barrier dysfunction and cell death in human intestinal epithelial cells in vitro. In addition, drug crystals triggered the release of neutrophil and monocyte extracellular traps. Taken together, these data raise the possibility that besides other factors including chronic kidney disease, diabetes mellitus, and hypertension, drug crystals may further amplify a pre-existing barrier dysfunction and necroinflammation in a crescendo of local intestinal necrosis and systemic inflammation/infection, as occasionally observed in patients on ion-exchange resin therapy.

Early weaning stimulates intestinal brush border enzyme activities in piglets, mainly at the posttranscriptional level.

BACKGROUND: Weaning-associated anorexia is the main factor responsible for structural alterations of the small intestine. However, whether weaning and the postweaning feed intake level affect disaccharidase and peptidase gene expression remains to be elucidated. METHODS: Adaptation of the small intestine to early weaning at 7 days of age and the effects of postweaning feed intake were investigated on 56 pigs in two trials. Structural parameters and gene expression and activities of intestinal lactase, maltase, sucrase, aminopeptidases A and N, and dipeptidyl peptidase IV were determined along the small intestine. RESULTS: Within 3 days, weaning induced increases in maltase, sucrase, and peptidase specific activities (P < 0.05) and a decrease in lactase activity and villous height (P < 0.05). Only for maltase activity were the weaning-induced changes closely correlated with corresponding mRNA levels. In weaned piglets, aminopeptidase N activity was consistently stimulated and dipeptidyl peptidase IV depressed by high level of feed intake but without effects on the corresponding mRNA levels. Furthermore, the longitudinal distribution of enzyme activities along the small intestine showed poor correlation with the corresponding mRNA levels. CONCLUSION: Early weaning in pigs is associated with a remarkable capacity of the small intestine to rapidly increase the activity of key brush border enzymes. This adaptation, largely independent on feed intake for intestinal enzyme mRNAs and disaccharidase activities, occurred at the posttranscriptional rather than at the transcriptional level of enzyme biosynthesis (except for maltase). The length of the postweaning anorexia period did not affect the subsequent intestinal capacity for villous elongation but may postpone maturation of peptidase activities.

Weaning and feed intake alter pancreatic enzyme activities and corresponding mRNA levels in 7-d-old piglets.

We investigated the changes in the capacity for synthesis of the exocrine pancreas of piglets during the 2 wk after weaning at 7 d of age (trial 1) by measuring the expression of digestive enzymes at mRNA and activity levels in pancreas homogenates, and the effects of high and low feed intakes during the 1st wk postweaning (trial 2) on these measures. The trypsin mRNA level was transiently decreased 43% 3 d postweaning (P < 0.05). Thereafter, trypsin and lipase mRNAs linearly increased (P < 0.05). During the 1st wk postweaning, trypsin- and lipase-specific activities were reduced 44 and 79% (P < 0.05), respectively, whereas 14 d after weaning, trypsin was at the preweaning value and lipase was at a low level. Amylase-specific activity did not change with weaning. Plasma cholecystokinin (CCK) and gastrin concentrations decreased 1 d postweaning and increased afterward up to 3 and 5 d postweaning, respectively. By 3 d after weaning, the mRNA level of trypsin was twofold higher (P < 0.05) in piglets that consumed more feed than in those that consumed less, whereas 7 d after weaning, the groups did not differ. By 7 d after weaning, the specific activity of amylase was higher, and lipase-specific activity was lower, in piglets that consumed more feed than in those that consumed less. Plasma CCK and gastrin concentrations measured 7 d after weaning were correlated with feed intake (r = +0.56 and r = +0.68, P < 0.05, respectively). In conclusion, by 3 d postweaning, pancreatic exocrine function was adapting to the new diet. Afterward, the expression of specific genes coding digestive enzymes and the levels of pancreatic enzyme activities were restored or stimulated, except for lipase-specific activity. Therefore, the pancreas can adjust to weaning and dry food intake as early as wk 2 of life.

Early postnatal food intake alters myofiber maturation in pig skeletal muscle.

We examined the effects of undernutrition on muscle development during the first postnatal week in pigs. Eighteen piglets were subjected to three nutritional levels (300, 200 or 100 g/(kg body. d) of colostrum then milk) between birth and slaughter at 7 d of age. Longissimus lumborum (LL), a fast-twitch glycolytic muscle, and rhomboideus (RH), a mixed slow- and fast-twitch oxido-glycolytic muscle, were taken for myofiber typing and biochemical analyses. Enzyme activities of lactate dehydrogenase (LDH), citrate synthase (CS) and beta-hydroxy-acyl-CoA-dehydrogenase (HAD) were used as markers of glycolytic, oxidative and lipid beta-oxidation capacities, respectively. Undernutrition selectively decreased (P < 0.001) hypertrophy of the future fast-twitch glycolytic fibers in LL. Contractile and metabolic maturation was delayed in the later maturing LL, as reflected by a decrease in muscle protein concentration (P < 0.01), an increase (P < 0.05) in the percentage of myofibers still expressing the fetal myosin heavy chain (MyHC), a lower postnatal increase in LDH activity (P < 0.001) and a delayed decrease in the percentage of IIa MyHC positive fibers (P < 0.001). Otherwise, restriction tended (P < 0.10) to increase the percentage of slow type I MyHC containing fibers in both muscles and of alpha-cardiac MyHC positive fibers in RH (P < 0.05). The LDH/CS ratio decreased dramatically (P < 0.001) after restriction, to a greater extent in LL than in RH. These changes denoted a more oxidative metabolism using fewer carbohydrates and more lipids in restricted pigs, as suggested by the increased activity of HAD (P < 0.001) and decreased respiratory quotient (P < 0.001).

Small intestine growth and morphometry in piglets weaned at 7 days of age. effects of level of energy intake.

Two trials involving a total of 56 pigs were conducted to examine the effects of weaning at 7 d of age (trial 1) and of energy intake level and length of post-weaning underfeeding period (trial 2) on small intestinal (SI) development and morphometry. At 3 d after weaning, weight of the SI and mucosa (g/kg body weight) and villous height along SI were reduced by 20, 36 and 41%, respectively, compared to the day of weaning. Intestinal morphometrical changes are dependent on SI site and days post-weaning. Villous atrophy on d 3 and recovery on d 14 post-weaning were greater and occurred earlier in the proximal than in the medial and distal SI. Villous height was dependent on the level of energy intake which explains 56% of the variations in proximal SI villous height in weaned pigs and 73% when data of the sow-reared pigs were included in the analysis. Moreover, after 4 d of refeeding, underfed piglets showed similar villous characteristics to piglets fed a continuously high feeding level after weaning stressing that capacities of intestinal restoration were not affected by the length of the post-weaning underfeeding period. Overall, the present results suggest a spatial and temporal effect of weaning on villous atrophy and recovery, and that the level of energy intake is a major factor accounting for the post-weaning villous height.