Compromised duodenal mucosal integrity in children with short bowel syndrome after adaptation to enteral autonomy.

BACKGROUND: Intestinal adaptation has been extensively studied experimentally, but very limited data is available on human subjects. In this study we assessed intestinal adaption in humans with short bowel syndrome (SBS). METHODS: We comparatively evaluated mucosal hyperplasia, inflammation, barrier function and nutrient transport using histology, immunohistochemistry and qPCR for selected 52 key genes in duodenal biopsies obtained from children with SBS after weaning off parenteral nutrition (n = 33), and matched controls without intestinal pathology (n = 12). Small bowel dilatation was assessed from contrast small bowel series. RESULTS: Duodenal mucosa of SBS children showed increased histologic inflammation of lamina propria (p = 0.033) and mucosal mRNA expression of tumor necrosis factor (p = 0.027), transforming growth factor (TGF)-ß2 (p = 0.006) and caveolin-1 (CAV1; p = 0.001). Villus height, crypt depth, enterocyte proliferation, apoptosis and expression of proliferation and nutrient transport genes remained unchanged. Pathologic small bowel dilatation reduced crypt depth (p = 0.045) and downregulated mRNA expression of interleukin (IL)-6 by three-fold (p = 0.008), while correlating negatively with IL6 (r = -0.609, p = 0.004). Loss of ileocecal valve (ICV) upregulated mRNA expression of toll-like receptor 4 (TLR4), TGF-ß1, CAV1, several apoptosis regulating genes, and mRNA expression of zonulin (p < 0.05 for all). CONCLUSIONS: Despite successful adaptation to enteral autonomy, duodenal mucosa of SBS children displayed histologic and molecular signs of abnormal inflammation and regulation of epithelial permeability, whereas no structural or molecular signs of adaptive hyperplasia or enhanced nutrient transport were observed. Excessive dilatation of the remaining small bowel paralleled impaired duodenal crypt homeostasis, while absence of ICV modified regulation of mucosal inflammation, regeneration and permeability. LEVEL OF EVIDENCE: II.

Parenteral Nutrition-Dependent Children With Short-Bowel Syndrome Lack Duodenal-Adaptive Hyperplasia but Show Molecular Signs of Altered Mucosal Function.

BACKGROUND: Although adaptive mucosal growth of the remaining small intestine is an essential compensatory mechanism to bowel resection in experimental short-bowel syndrome (SBS), only scarce clinical data are available. We studied structural and molecular mechanisms of intestinal adaptation in children with SBS. METHODS: Fourteen patients, who had been dependent on parenteral nutrition (PN) since neonatal period for a median (interquartile range)1.4 (0.7-6.5) years, were studied at the age of 1.5 (1.0-6.5) years. Median length of remaining small bowel was 33 (12-60) cm, and 6 patients had their ileocecal valve preserved. Six children without gastrointestinal disorders served as age-matched and gender-matched controls. All patients underwent duodenal biopsies. Mucosal microarchitecture, proliferation, apoptosis, inflammation, and epithelial-barrier function were addressed using histology, immunohistochemistry, and quantitative real-time polymerase chain reaction. RESULTS: Villus height, crypt depth, enterocyte proliferation, and apoptosis were similar in patients and matched controls. Messenger RNA (mRNA) expression of numerous genes regulating gut epithelial-barrier function (TGFB2, CAV1, CLDN1, MUC2, and NLRC4) was significantly altered. Of various nutrient transporters studied, only expression of SLC2A1 encoding facilitative glucose transporter GLUT1 was increased among patients, whereas RNA expression of genes encoding sodium-dependent glucose, sterol, fatty-acid, and peptide transport remained unchanged. CONCLUSION: Duodenal mucosal hyperplasia has a limited role in mediating physiological adaptation following intestinal resection among PN-dependent children with SBS. Further clinical studies addressing functional significance of the observed alterations in mucosal RNA expression are warranted.

Duodenal Disaccharidase Activities During and After Weaning off Parenteral Nutrition in Pediatric Intestinal Failure.

OBJECTIVES: Data on factors affecting absorptive function in children with intestinal failure (IF) are sparse. We evaluated duodenal disaccharidase activities and inflammation in relation to parenteral nutrition (PN) and intestinal resection in pediatric onset IF. METHODS: Disaccharidase (maltase, sucrase, and lactase) activities and histologic inflammation were evaluated from duodenal biopsies in 58 patients during PN (n = 23) or full enteral nutrition (n = 40) and in 43 matched controls. The first and the last postresection biopsies were analyzed separately after 4.3 (1.2-9.7) years and 6.5 (2.3-12.4) years, respectively. RESULTS: During PN, maltase and sucrase activities were 1.6-fold lower and mucosal inflammation more frequent (22% vs 3%) when compared to matched controls (P < 0.05 for both). In patients on full enteral nutrition, activities of maltase and sucrase were significantly higher than that in patients receiving PN and comparable to those of matched controls. Postresection time correlated positively (r = 0.448 and r = 0.369) and percentage length of the remaining small intestine inversely (r = -0.337 and r = -0.407) with maltase and sucrase activity in patients on full enteral nutrition (P < 0.05 for all), whereas proportional length of remaining colon correlated positively with maltase and lactase activity (r = 0.424-0.544, P < 0.05) in patients receiving PN. CONCLUSIONS: In children with IF, PN dependency associated with decreased duodenal maltase and sucrase activities and mucosal inflammation, which may disturb intestinal absorptive function. Localization and extent of intestinal resection and post-resection time correlated with duodenal disaccharidase activities.