Background & Aims: Loss of functional small bowel surface area causes short bowel syndrome (SBS), intestinal failure, and parenteral nutrition (PN) dependence. The gut adaptive response following resection may be difficult to predict, and it may take up to two years to determine which patients will wean from PN. Here we examined features of gut microbiota and bile acid (BA) metabolism in determining adaptation and ability to wean from PN. Methods: Stool and sera were collected from healthy controls and from SBS patients (n=52) with ileostomy, jejunostomy, ileocolonic and jejunocolonic anastomoses fed with PN plus enteral nutrition or who were exclusively enterally fed. We undertook 16S rRNA gene sequencing, BA profiling and 7α-hydroxy-4-cholesten-3-one (C4) quantitation with LC-MS/MS, and serum amino acid analyses. Results: SBS patients exhibited altered gut microbiota with reduced gut microbial diversity compared to healthy controls. We observed differences in the microbiomes of SBS patients with ileostomy vs. jejunostomy, jejunocolonic vs. ileocolonic anastomoses, and PN-dependence compared to those who weaned from PN. Stool and serum BA composition and C4 concentrations were also altered in SBS patients, reflecting adaptive changes in enterohepatic BA cycling. Stools from patients who weaned from PN were enriched in secondary BAs including deoxycholic acid and lithocholic acid. Conclusions: Shifts in gut microbiota and BA metabolites may generate a favorable luminal environment in select SBS patients, promoting the ability to wean from PN. Pro-adaptive microbial species and select BA may provide novel targets for patient-specific therapies for SBS.

Loss of functional small bowel surface area following surgical resection for disorders such as Crohn's disease, intestinal ischemic injury, radiation enteritis, and in children, necrotizing enterocolitis, atresia and gastroschisis, may result in short bowel syndrome, with attendant high morbidity, mortality and health care costs in the U.S. Following resection, the remaining small bowel epithelium mounts an adaptive response resulting in increased crypt cell proliferation, increased villus height, crypt depth and enhanced nutrient and electrolyte absorption. Although these morphologic and functional changes are well-described in animal models, the adaptive response in humans is less well understood, and clinically the response is unpredictable and often inadequate. Here we address the hypotheses that human intestinal stem cell populations are expanded and the stem cell niche is regulated following massive gut resection in short bowel syndrome. We use intestinal enteroid cultures from SBS patients to show that the magnitude and phenotype of the adaptive stem cell response is regulated by stromal niche cells including intestinal subepithelial myofibroblasts, which are activated by intestinal resection to enhance epithelial stem and proliferative cell responses. Our data suggest that myofibroblast regulation of bone morphogenetic protein signaling pathways plays a role in the gut adaptive response post resection.

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Purpose A palatal fistula is an adverse outcome of cleft palate repair. It is unknown if a palatal fistula will influence velopharyngeal closure, even after repair of the fistula. This study determines the effect of a soft palate fistula on the risk of developing velopharyngeal insufficiency. Methods A retrospective chart review was conducted on patients who underwent primary cleft palate repair between 2000 and 2015, with complete records at 4 years of age. Fistulae involving the secondary palate following primary palatoplasty were classified as the soft or hard palate. A forced-entry multivariate logistic regression model was built to detect predictors of velopharyngeal dysfunction. Results Records of 329 patients were analyzed with a mean follow-up of 8.7 years. A palatal fistula was identified in 89/329 patients (27%) and 29/329 patients (9%) underwent an independent fistula repair. Of the patients with fistula, 44% were located in the hard palate only and 56% had soft palate involvement. Compared to patients without a fistula, rates of velopharyngeal dysfunction were significantly higher in patients with a fistula involving the soft palate (OR 3.875, CI: 1.964-7.648, P < .001) but not in patients with a hard palate fistula (OR 1.140, CI: 0.497-2.613, P = .757). Veau class, age at primary repair, and syndromic status were not significant predictors of VPI (0.128≤ P ≤ .975). Conclusions A palatal fistula involving the soft palate is a significant predictor for development of velopharyngeal dysfunction after primary palatoplasty. Surgical intervention, at the time of fistula repair, to add vascularized tissue may be indicated to prophylactically decrease the risk of velopharyngeal dysfunction.

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