Short Gut Research Articles

Tuber indicum polysaccharide relieves fatigue by regulating gut microbiota in mice

Abstract Excessive exercise-induced fatigue has become a serious health issue and can cause gut dysbiosis. Tuber indicum (T. indicum) polysaccharide can act as prebiotics to regulate gut microbiota and this effect may play an important role in relieving fatigue. Therefore, T. indicum polysaccharide was prepared and mainly consisted of glucose linked with β-glycosidic bonds. Based on a mouse model of exhaustive swimming-induced fatigue, such polysaccharide decreased blood lactic acid content and increased ATPase activity of fatigue mice, which was accompanied by improved short chain fatty acids concentration and gut integrity. Additionally, T. indicum polysaccharide ameliorated gut dysbiosis by decreasing the ratio of Firmicutes to Bacteroidetes and increasing Bacteroides in fatigue mice. Spearman's correlation analysis suggested that T. indicum polysaccharide-modulated microbiota was significantly correlated with its anti-fatigue effect. These findings suggested the potential of T. indicum polysaccharide as prebiotics, to protect mice against excessive exercise-induced fatigue by regulating gut microbiota.

The Long Road to the Development of Effective Therapies for the Short Gut Syndrome: A Personal Perspective.

The ability to provide parenteral support represents a revolutionary change in medical therapy for patients with temporary and inadequate intestinal absorptive capacity or for patients with chronic intestinal failure due to digestive diseases. Nevertheless, due to the rarity of intestinal failure, a de facto policy of "discrimination by organ failure treatment" exists in many countries whereby this problem is under-recognized and under-treated. With the increasing recognition of the pathophysiological consequences of intestinal resection and the occurrence of new pro-adaptive treatments for patients suffering from short bowel syndrome, this review reflects on the history of developments in this area and discusses current practice and future directions of the field.

Soluble fibre supplementation with and without a probiotic in adults with asthma: A 7-day randomised, double blind, three way cross-over trial

SummaryBackgroundSoluble fibre modulates airway inflammation in animal models. The aim of this study was to investigate the effects of soluble fibre supplementation, with and without a probiotic, on plasma short chain fatty acids (SCFA), airway inflammation, asthma control and gut microbiome in adults with asthma.MethodsA randomised, double-blinded, placebo controlled 3-way cross-over trial in 17 subjects with stable asthma at the Hunter Medical Research Institute, Newcastle, Australia. Subjects received 3 × 7 day oral interventions in random order; soluble fibre (inulin 12 g/day), soluble fibre + probiotic (inulin 12 g/day + multi-strain probiotic >25 billion CFU) and placebo. Plasma SCFA, sputum cell counts and inflammatory gene expression, asthma control gut microbiota, adverse events including gastrointestinal symptoms were measured.FindingsThere was no difference in change in total plasma SCFA levels (μmol/L) in the placebo versus soluble fibre (Δmedian [95% CI] 16·3 [−16·9, 49·5], p = 0·335) or soluble fibre+probiotic (18·7 [−14·5, 51·9], p = 0·325) group. Following the soluble fibre intervention there was an improvement in the asthma control questionnaire (ACQ6) (∆median (IQR) -0·35 (−0·5, −0·13), p = 0·006), sputum %eosinophils decreased (−1.0 (−2·5, 0), p = 0·006) and sputum histone deacetylase 9 (HDAC9) gene expression decreased (−0.49 (−0.83, −0.27) 2-ΔCt, p = .008). Individual bacterial operational taxonomic units changed following both inulin and inulin+probiotic arms.InterpretationSoluble fibre supplementation for 7 days in adults with asthma did not change SCFA levels. Within group analysis showed improvements in airway inflammation, asthma control and gut microbiome composition following inulin supplementation and these changes warrant further investigation, in order to evaluate the potential of soluble fibre as a non-pharmacological addition to asthma management.FundJohn Hunter Hospital Charitable Trust.

A Case Report of Intraoperative Coagulopathy Secondary to Chronic Vitamin K Deficiency.

Dietary Vitamin K is a well-known anti-hemorrhagic agent that plays an integral role in the coagulation pathway. Vitamin K is involved in synthesis of coagulation factors; II, VII, IX and factor X. Vitamin K deficiency leads to bleeding diathesis. Hemorrhages usually present in deep soft tissue, rather than mucosal or epithelial membranes, bleeding that is generally caused by disorders of platelets. Major causes of vitamin K deficiency include; medications and diseases involving fat metabolism with a resultant fat malabsorption. Warfarin and Cephalosporins are one of the commonly prescribed medications that lead to vitamin K deficiency. Disease affecting fat metabolism pathway, such as; diseases of the pancreas (cystic fibrosis), short gut syndrome and certain pathologies of the biliary tree. Vitamin K deficiency is more common in newborns. In adults it is uncommon because of its ubiquitous nature and the abundance of its sources. Hemorrhagic disorders in adults due to Vitamin K deficiency are not commonly encountered in practice. We are presenting a case of an adult who presented with a compartment syndrome secondary to a traumatic intramuscular bleeding. Our case highlights the importance of considering vitamin K deficiency in the differential diagnosis of unexplained hemorrhages resulting from a coagulopathy.

300.7: Isolated intestinal transplantation: Are we shifting the paradigm?

Introduction: Isolated intestinal transplant (IIT) is the definitive therapy for intestinal failure. Outcomes have improved tremendously in the last decade. Our center has performed almost 500 intestinal inclusive transplants. Intestine-Colon may be the best nomenclature for better defining the current procedure. Method: We describe all the patients who received IIT from 2013 to 2018 in our center. It represents our most recent Era with the evolution of surgical technique, immunosuppression regimen, graft monitoring and patient management. Immunosuppression consisted of induction with thymoglobulin and rituximab, maintenance with tacrolimus and mTOR inhibitor and use of basiliximab or vedolizumab for the first 3 months. Results: 31 IIT were performed in 30 patients at our center. 13 were male. 11 of the recipients were pediatric. Recipient age went from 1 year old to 65 years old. Main indication for transplant was short gut. Positive crossmatch was found in 14% of the transplants. Moderate or severe rejection has happened in 32% of the patients. Only 1 patient underwent to enterectomy within 90 days due to rejection. One patient lost the graft due to volvulus. One patient had the graft removed during emergent surgery due to rupture of mycotic aneurism. Two patients developed PTLD. GVHD was not seen in this cohort. Chronic rejection or chronic graft dysfunction was not observed. Kaplan Meyer 5 year patient and graft survival for primary, non-renal transplants, was 92% and 77% respectively. 5 year patient survival including re-transplants and intestine-kidneys transplants is 87%. Patient survival 1 year remains 100% for all the patients. Discussion: Survival of intestine-colon transplant has greatly improved over time. Historically, rejection was the main reason for graft and patient loss. In this cohort, only half of the graft losses were due to rejection. Mortality or graft loss due to causes unrelated directly to transplant was the majority in our experience. New immunosuppressive strategies have shown excellent results preventing rejection. Chronic rejection is a well-known long term complication for IIT, although no cases were seen up to date. 100% patient survival for the first year and 92% patient survival for 5 years surpasses all the data available not only for intestines but for all other organs. We believe we are entering a new era in intestinal transplant, with extremely high patient survival even when compared with other modalities of treatment for intestinal failure.

P3.55: Allointestine colon conduit urinary diversion in combined intestine and kidney transplant: A case report

Introduction: In intestinal transplant candidates, the incidence of renal failure is high and is associated with increased mortality. Additionally previous surgeries and loss of abdominal domain may make standard kidney transplant with ureterocystostomy impossible. . Methods: We present an extreme case of combined small intestine, colon, and kidney transplant in a patient with short gut syndrome due to radiation enteritis, severe loss of abdominal domain, failed previous kidney transplant, and absence of native urinary system. Results: Our patient is a forty years old female with a past history of bladder Rabdomyosarcoma as an infant, who underwent bladder resection and post resection radiation. She developed radiation enteritis, renal failure, and eventually received a living related kidney transplant. Her renal allograft subsequently failed due to multiple urinary obstructions despite multiple revision surgeries, as well as chronic immunosuppression toxicity. As a result, she had short gut syndrome and renal failure with no feasible route of urinary drainage. In addition, she had severe loss of abdominal domain due to abnormal abdominal development from the radiation she received as an infant. She had multiple complications of her short gut syndrome and she underwent a simultaneous small intestine, colon, and kidney transplant. Donor was an eight years old female (132 cm, 23.4 kg), who became brain dead after severe exacerbation of asthma attack. Since there were no viable routes for urinary drainage, as there were no viable native intestines, and native and previous transplanted kidney ureter had been obstructed, a 10 cm allograft colon segment was used as a urinary conduit. The patient also underwent a complex abdominal closure with pedicled left anterior lateral thigh perforator flap by the plastic surgery team. One hundred days post transplant the patient is parenteral nutritional independent with normal renal function and her transplant colon conduit is healthy and functional. Conclusion: In extreme cases of kidney transplant in intestinal transplant recipient patients with no feasible urinary drainage path, transplant intestine can successfully be used as a conduit. In review of literature, and to the best of our knowledge, this is the first description of utilization of allograft intestine as a urinary conduit.

P3.53: Do patients with gastroschisis have worst outcomes after pediatric intestinal transplantation?

Introduction: Gastroschisis (Gx) is the leading cause of short gut syndrome in our intestinal rehabilitation population and the principal reason for intestinal transplantation (ITx). We investigated the results after ITx in this group of children and compared them to those with other etiologies. Methods: A retrospective review of all ITx performed at our center was done. Eighteen ITx were done in 18 children between 2004–2018. Outcome data was collected for both surgical and non-surgical factors, and analyzed. Chi-square and independent t-test were used for statistical analysis. p<0.05 was considered significant. The study was approved by our Institutional Review Board (IRB #2019–2474). Results: Eighteen patients underwent ITx. The most common diagnosis leading to ITx was Gx (7/18, 39%). Other causes included midgut volvulus (3), necrotizing enterocolitis (2), Hirschsprung’s disease (2), motility disorders (2) and other causes (2). Boys predominated in both groups (4/7 Gx vs. 6/11 in all others, p=0.91). Mean age at listing was similar (3.4±5.1 in Gx vs. 3.1±2.7 years in all others, p=0.70). The mean time on the waitlist prior to ITx was also similar in both groups (1.4±1.5 vs. 0.9±1.2 years, p=0.41). Both groups were transplanted at a similar age (5.3±4.7 vs. 4.0±3.2 years, p=0.5). One of 7 patients in the Gx group underwent multivisceral transplant compared to 2/11 in the all others group (p=0.83). Initial feeds were started later after the transplant in the Gx group (48.9 ±72.9 vs. 18.6±13.4 days, p=0.24) and mean post-operative hospital stay was also longer in the Gx group (112.9±165.5 vs. 78.7±53.9 days, p=0.53). However, a significantly greater proportion of Gx patients (6/7, 86%) were discharged on full enteral feeds compared to the patients in the all other group (4/11, 36%), p=0.04. Overall patient and graft survival in the entire cohort at 1 year was 89% and 83% respectively. 1-year patient survival was similar in either group: Gx 6/7 (86%) vs 10/11 (91%) in all others (p=0.73). 1-year graft survival was also equal in both groups: 5/7 (71%) in the Gx group vs 10/11 (91%) in all others (p=0.28). Conclusions: Outcomes after pediatric ITx appear satisfactory and similar regardless of the underlying diagnosis and represents a viable alternative to long-term parenteral nutrition. Gastroschisis patients appear to have longer lengths of stay after ITx, but also appear to achieve a more complete recovery in terms of independence from parenteral nutrition.

P4.28: Renal function outcomes in paediatric intestinal transplant recipients

Background: Renal dysfunction after intestinal transplantation is a well recognised complication. Calcineurin inhibitors have a direct impact on the kidney with post-operative day 7 tacrolimus associated with kidney function at 1yr. Catheter related sepsis, prolonged usage of intravenous fluid, parental nutrition, diabetes and graft failure have all been associated with chronic kidney disease. Methods: Review of first-time paediatric intestinal graft recipients at a single centre between August’09-June’18. CKD was defined as Cystatin-C(CysC)>1mg/l measured at baseline, 6mths,1yr,2yr and 5yr post-transplant. Demographic and data associated with CKD post-transplantation were collected (Tac lvls at POD 7,3,6 and 12mths). Immunosuppression protocol consisted of Basiliximab induction then maintenance with tacrolimus and prednisolone +/- sirolimus. Target tacrolimus levels were between 12–15µ/L in the first 3wks, 8–12µ/L 3wks -3mths, 5–8µ/L out to1yr post transplantation. Statistical analysis was applied when appropriate, and analyses performed using SPSS. Results: 21 paediatric patients(53% male; 43%short gut syndrome, 38%paediatric intestinal pseudo-obstruction), median age of 5 yrs(4,7.8) underwent either isolated intestinal(43%), liver and intestinal(28%) or multivisceral transplantation(29%). 38% continued with tacrolimus and steroids alone, 57% sirolimus added. 4 patients required re-transplantation at a median time from first transplantation of 33.5mths (3.5,80). 4 patients died at a median time of 9.5mths(4.8,16). CysC level of all patients at baseline was 1.01(0.8,1.2), with 38% of children having evidence of pre-existing CKD (CysC lvl 1.16(1.1,1.5). There was significant association with CysC level at 6mth and Tacrolimus lvl at 3mths, r=-0.5 p=0.03. CysC lvl improved between 6mths and 1yr post transplant. No significant association was found between CKD at 6mths or 1yr and type of immunosuppression, prolonged use of intravenous fluids, parental nutrition, diabetes, graft failure, line sepsis or Tac lvl POD 7. Conclusion: Renal dysfunction is already prevalent at the time of intestinal transplantation therefore continuing close monitoring of renal function and tacrolimus levels is advisable. In our cohort renal dysfunction peaked at 6mths post transplant then improved following titration of tacrolimus level. A larger prospective study is required to identify paediatric variables that effect renal function following intestinal transplantation.

P2.46: RESTORE project (improve underSTanding of small bOwel syndRomE in Argentina): First report of a prospective, observational, epidemiological, multicenter study of adult patients with Short Gut Syndrome in Argentina.

Introduction: There is no centralized registered information regarding patients (pts) suffering from Short Bowel Syndrome (SBS) in Argentina. Estimations based on other countries epidemiology predict an incidence of 8–10 new adult pts/year. In order to compile this information, we started a prospective multicenter observational and epidemiological registry for adults with SBS, independent from the etiology and the treatment proposed. We aim to present the first report of the RESTORE project. M-M: From 2015 to 2017, design, funding, Institutional Review Board and Ethical approvals were obtained. Since June 2017, 11 centers started activity. Data collection was made using case report forms; a monitor visited and supervised each center initiation and performance. The registered pts are followed at each center at weeks 4, 8, 12, 20 and 24, and yearly thereafter. Dead, intestinal adaptation and transplant have been considered as end-points of the study. The principal investigator developed a prospective database. Statistical analysis was done on SPSS v20.0. Results: 12 centers were initiated, 10 enrolled 42 pts; 33 pts were actively monitored and analyzed,12 pts completed 1 year of follow up (FU); 19 pts (57.6%) were female; mean age: 52.15 ± 15.4 years. Diagnoses in Figure 1. Mean intestinal length: 51.5 ± 42.4 cm. Anatomy type: T1: 22 pts; T2: 8 pts and T3: 3 pts; ileo-cecal valve was present in 11pts. Colon in 27 pts; Ostomies in 22 pts. Mean ostomy output: 1514 ± 1078 ml/day; Autologous GI tract Reconstruction Surgery (AGIRS) was done in 11 pts before enrollment. Meantime on parenteral nutrition (PN) before enrollment: 27.4 ± 37.18 months; PN and biochemical variables overtime are shown in Table 1; Espen Clinical Classification in Figure 1. Treatments proposed at first visit: PN+ Medical Rehabilitation: 20 pts (60%), AGIRS: 4 pts (12%); post-surgical teduglutide (TED): 8 pts (24%); transplant: 1 pt (3%); at the end of FU: 1pt was lost of FU; 4 pts adapted with AGIRS alone, or in combination with TED. One pt was transplanted and another pt. listed due to liver disease. The overall actuarial survival is 87%; sepsis was the main cause of death (3/4 pts). Conclusions: Although this report still has a limited number of centers, it has registered more SBS adult patients than expected according to theoretical estimations; reinforcing the importance of having registries to understand the behavior of SBS patients overtime and their outcome.

P2.48: Safety and efficacy of mTOR inhibitors following intestine and multivisceral transplantation

Purpose: Review the indications, outcomes and frequency of the use of mTOR inhibitors (mTORs) after intestine (IT) and multivisceral transplantation (MVT) assessed across two transplant centers in the United States. Methods: We evaluated patients receiving everolimus or sirolimus following MVT or IT and compiled retrospective data between 2009–2018 at multiple transplant centers. Results: 22 patients received immunosuppression including an mTOR. Twenty patients were over 18 years. Twelve patients received isolated IT. The most common reason for transplant was short gut syndrome (45%) followed by dysmotility (22%) and neuroendocrine tumor (18%). Mean age at transplant was 46 years (range 22 - 62) in adults and 2.5 in children. 54% patients were started on mTORs beyond 1 year post transplant. Mean time from transplant to initiation of mTOR was 24 months (range 1 - 78). 63.6% received sirolimus and 36.4% received everolimus. Other medications at the time of mTORs initiation included tacrolimus, prednisone, mycophenolate mofetil (MMF) and azathioprine. 18%, 13.6% and 59% of patients on mTORs were able to discontinue MMF, prednisone or reduce tacrolimus respectively. Only one patient was weaned to mTOR as single immunosuppression agent. Reason for mTOR use was renal dysfunction in 59% of cases; of these, only one patient had chronic kidney disease pre transplant. Mean glomerular filtration rate (GFR) prior to mTORs initiation was 40mL/min/1.73sqm. Of those placed on mTORs for renal insufficiency 69.2% had substantial improvement in GFR (defined as increase of 10 points). Nine patients developed some worsening of proteinuria but none were taken off treatment due to this. 27.3% cases developed acute cellular rejection (ACR), 13.6% had cytomegalovirus and two patients died while being on mTOR therapy. mTORs were discontinued in 11/22 cases due to side effects (54.5%), surgeries (18.1%) or ACR (9%). Sirolimus was discontinued in 8/14 (57%), everolimus was discontinued in 3/8 (37.5%). The mean duration of mTORs use in those stopping therapy was 7 months and 18 months in those remaining on therapy. Conclusion: Tolerance of therapy remains challenging with almost a third of those started on mTors unable to tolerate long term treatment due to side effects. If well tolerated, mTORs were generally safe and efficacious following IT and MVT. Further studies with a control group are warranted.

P2.56: Outcomes after pediatric intestinal transplantation: A comparative analysis between a single program and the national database

Introduction: Thirty-seven intestinal transplant (ITx) programs have performed ≥1 pediatric ITx since 1990 according to the 2017 United Network for Organ Sharing (UNOS) database. The median number of ITx per center was 8. Our institution is an aggressive center for pediatric intestinal rehabilitation (IRP), with relatively low volumes for ITx. We hypothezised that outcomes from a medium-size program like ours compared favorably to national data. Methods: A retrospective review of all ITx done at a main pediatric IRP and ITx program was performed (2004–2019). Demographic, medical, and surgical data were collected. National data was obtained from the UNOS database (n=1500). Mann-Whitney and Chi-Square tests were used for analysis. p<0.05 was considered significant. Institutional Review Board approval was obtained (IRB #2019–2474). Results: Since 2004, 18 ITxp were performed at our institution. The proportion of girls at our center, 8/18 (44%), was identical to UNOS, 598/1346 (p=1.0). Gastroschisis was the main cause of short gut syndrome in both groups (7/18, 39% locally, vs. UNOS 341/1500, 23%, p=0.13). Mean age at transplant was similar (3.94±3.72 vs. UNOS 3.61±4.35 years, p=0.33). Mean waitlist time was longer for our patients, although not significantly (394.11±480.37 vs. UNOS 220.23±336.92 days, p=0.062). There was a trend in shorter mean distance between donor and recipient hospitals in our program (466.47±335.93 vs. UNOS 547.39±436.09 days, p=0.65) while the mean cold ischemia time was significantly shorter in our group (6.98±1.73 vs. UNOS 7.88±2.58 hours, p=0.049). There was a significant difference between groups regarding intestinal venous drainage through the portal vein for isolated small bowel ITx (3/15, 27%, vs. UNOS 247/440, 57%, p=0.005). The incidence of multivisceral transplants was significantly higher nationally (UNOS 1034/1500, 69%, vs. 3/18, 17%, p<0.001). There was no statistical difference in overall graft survival (11/18, 61%, vs. UNOS 46%, p=0.19) although it was higher in our group. There was a trend in improved overall patient survival in our patients (15/18, 83%, vs UNOS 832/1347, 62%, p=0.062). Conclusion: Timelier listing for isolated ITx is associated with a lower incidence and need for multivisceral transplantation in aggressive intestinal rehabilitation program. Shorter cold ischemia times associated with shorter travel distance between donor and recipient hospitals may contribute to higher patient and graft survival.

Schlafen 3 knockout mice display gender-specific differences in weight gain, food efficiency, and expression of markers of intestinal epithelial differentiation, metabolism, and immune cell function.

Self-renewal and differentiation are essential for intestinal epithelium absorptive functioning and adaptation to pathological states such as short gut syndrome, ulcers, and inflammatory bowel disease. The rodent Slfn3 and its human analog Slfn12 are critical in regulating intestinal epithelial differentiation. We sought to characterize intestinal function in Slfn3 knockout (KO) mice. Male and female pair-fed Slfn3KO mice gained less weight with decreased food efficiency than wild type (WT) mice, with more pronounced effects in females. RNA sequencing performed on intestinal mucosa of Slfn3KO and WT mice showed gene ontology decreases in cell adhesion molecule signaling, tumor necrosis factor receptor binding, and adaptive immune cell proliferation/functioning genes in Slfn3KO mice, with greater effects in females. qPCR analysis of fatty acid metabolism genes, Pla2g4c, Pla2g2f, and Cyp3c55 revealed an increase in Pla2g4c, and a decrease in Pla2g2f in Slfn3KO females. Additionally, adipogenesis genes, Fabp4 and Lpl were decreased and ketogenesis gene Hmgcs2 was increased in female Slfn3KO mice. Sequencing did not reveal significant changes in differentiation markers, so qPCR was utilized. Slfn3KO tended to have decreased expression of intestinal differentiation markers sucrase isomaltase, dipeptidyl peptidase 4, villin 1, and glucose transporter 1 (Glut1) vs. WT males, although these trends did not achieve statistical significance unless data from several markers was pooled. Differentiation markers, Glut2 and sodium-glucose transporter 1 (SGLT1), did show statistically significant sex-dependent differences. Glut2 mRNA was reduced in Slfn3KO females, while SGLT1 increased in Slfn3KO males. Notch2 and Cdx2 were only increased in female Slfn3KO mice. Although Slfn3KO mice gain less weight and decreased food efficiency, their biochemical phenotype is more subtle and suggests a complex interplay between gender effects, Slfn3, and another regulatory pathway yet to be identified that compensates for the chronic loss of Slfn3.

P3.49: GLP-2 therapy for patients with short gut syndrome and intestinal insufficiency: A single center experience with future considerations

Introduction: The field of gut rehabilitation has recently evolved to restore nutritional autonomy without the need for home parenteral nutrition (PN) and subsequent transplantation. Methods: A total of 35 short gut syndrome (SGS) patients received glucagon-like peptide-2 (GLP-2) and were followed from April 2013 through February 2019 in the Cleveland Clinic-Center for Gut Rehabilitation and Transplantation. Of these, 34 were adults with a mean age of 53.4 ± 12.6 years (range: 14–72) and a female to male ratio of 2.5:1. Thirty-two (91%) of the 35 patients, were PN-dependent and 3 required IV fluid with micronutrient replacement. Leading causes of SGS were vascular occlusion (n=11), inflammatory bowel disease (n=10) and secondary motility disorders (n=5). Autologous gut reconstruction was performed in 32 of the patients (20 at our center and 12 at other institutions) with a mean small bowel length of 88.8 ± 56cm (range 10-220cm). Intestinal lengthening utilizing serial transverse enteroplasty (STEP) was performed in 11 patients. The retained colon was partial in 31 (88.6%) patients and full with intact ileocecal valve in the remaining 4 (11.4%). The duration of GLP-2 therapy ranged from 2 to 63 months with an average dose of 0.32mL/d. Results: With a mean follow up of 34 ± 19 months, 33 patients (94.3%) are currently alive and 2 died of PN-related liver failure and advanced systemic arteriosclerosis. Full nutritional autonomy was achievable in 18 (54.5%) of the 33 current survivors with an overall success rate of 54.5%. Of these 18 patients, 14 (78%) continued to sustain the restored nutritional autonomy for 1 to 48 months after discontinuation of GLP-2 therapy. Meanwhile, a reduction in PN and IV fluid requirements was observed in 19 patients who failed to restore (n=15) or sustain (n=4) nutritional autonomy. None of the patients developed significant complications that warranted permanent discontinuation of GLP-2 therapy. There were no documentation of recurrent or de novo malignancy except in one adult patient who developed prostate cancer. Conclusion: GLP-2 is an effective therapy for patients with SGS-associated intestinal insufficiency. This novel treatment should be more frequently utilized as a primary therapy or as an adjunct to autologous reconstruction and bowel lengthening. In addition, such a biologic agent should considered as an innovative approach to enhance the recovery and function of rejected intestinal allografts.

P313 Short gut syndrome and bacterial overgrowth in children with cystic fibrosis - experience from a tertiary paediatric cystic fibrosis centre

P313 Short gut syndrome and bacterial overgrowth in children with cystic fibrosis - experience from a tertiary paediatric cystic fibrosis centre

Vangl2 coordinates cell rearrangements during gut elongation.

The embryonic gut tube undergoes extensive lengthening to generate the surface area required for nutrient absorption across the digestive epithelium. In Xenopus, narrowing and elongation of the tube is driven by radial rearrangements of its core of endoderm cells, a process that concomitantly opens the gut lumen and facilitates epithelial morphogenesis. How endoderm rearrangements are properly oriented and coordinated to achieve this complex morphogenetic outcome is unknown. We find that, prior to gut elongation, the core Wnt/PCP component Vangl2 becomes enriched at both the anterior and apical aspects of individual endoderm cells. In Vangl2-depleted guts, the cells remain unpolarized, down-regulate cell-cell adhesion proteins, and, consequently, fail to rearrange, leading to a short gut with an occluded lumen and undifferentiated epithelium. In contrast, endoderm cells with ectopic Vangl2 protein acquire abnormal polarity and adhesive contacts. As a result, endoderm cells also fail to rearrange properly and undergo ectopic differentiation, resulting in guts with multiple torturous lumens, irregular epithelial architecture, and variable intestinal topologies. Asymmetrical enrichment of Vangl2 in individual gut endoderm cells orients polarity and adhesion during radial rearrangements, coordinating digestive epithelial morphogenesis and lumen formation with gut tube elongation.

Case report: Cholecystoduodenostomy for cholestatic liver disease in a premature infant with cystic fibrosis and short gut syndrome

BackgroundCholecystoduodenostomy is a surgical procedure that bypasses the extrahepatic biliary tree and connects the gallbladder directly to the duodenum. This case describes the successful use of this procedure in a novel situation.Case presentationA premature (34 weeks gestation) female infant with cystic fibrosis required a laparotomy on day 1 of life due to an intrauterine small bowel perforation. Resection of small bowel and ileostomy formation resulted in short gut syndrome, with 82 cm residual small bowel and intact ileocaecal valve. Post-ileostomy reversal at 2 months old, she developed conjugated hyperbilirubinaemia. Despite conservative management including increased enteral feeding, ursodeoxycholic acid, cholecystostomy drain insertion and flushes, her cholestatic jaundice persisted. A liver biopsy revealed an “obstructive/cholestatic” picture with fibrosis. To avoid further shortening her gut with an hepatoportoenterostomy, cholecystoduodenostomy was performed at 3 months of age with subsequent post-operative improvement and eventual normalisation of her clinical jaundice and liver biochemistry.ConclusionsThis is the first reported case of a cholecystoduodenostomy being used successfully to treat an infant with persistent conjugated hyperbilirubinemia, cystic fibrosis and short gut syndrome. Cholecystoduodenostomy is a treatment option that with further study, may be considered for obstruction of the common bile duct in patients with short gut and/or where a shorter operating time with minimal intervention is preferred.

Potential probiotic salami with dietary fiber modulates antioxidant capacity, short chain fatty acid production and gut microbiota community structure

Dry-fermented sausages are an important and abundant component of the diet of many people. Improving their composition and thus their potential health effects is therefore important. Here we quantified the antioxidant capacity, short chain fatty acids (SCFAs) production, and gut microbiota structure of different salami formulations after in vitro digestion and subsequent fermentation with human gut microbiota. The addition of different types of fiber (citrus fiber, arabinogalactan, and inulin), a probiotic Lactobacillus rhamnosus, and an herbal extract to the salami formulation was tested. Incorporating any dietary fiber into salami formulation increased sausage antioxidant capacity and the amount of SCFAs produced during microbiota fermentation. These effects were highest for salami with citrus fiber and citrus fiber with herbal extract. Presence of fiber in salami also led to an altered gut microbiota structure. Citrus fiber and arabinogalactan but not inulin promoted an increase in the abundance of several known polysaccharide degrading genera and resulted in a reduction in the abundance of Escherichia, a bacterial genus known to contain many human intestinal pathogens. Overall, the addition of dietary fiber to salami formulation prior to curing improved beneficial health markers of this food product.

Application of Parafilm As a Physical Barrier on CVC Connections Is Feasible and May Reduce Clabsi Among Pediatric HCT Patients

Central line associated bloodstream infections (CLABSI) result in significant morbidity and mortality in hematopoietic cell transplantation (HCT) patients. Pediatric data is sparse, and previous/current interventions may impact bacterial flora and antibiotic resistance. Risks in pediatric HCT patients include prolonged immunosuppression, long-term central venous catheter (CVC) need, and external environmental contamination. Parafilm is made of paraffin and primarily utilized to seal/protect containers in laboratories; applied as a barrier, it significantly reduced CLABSI in TPN-dependent pediatric short gut patients. We hypothesized that parafilm application on CVC connections would be feasible and reduce CLABSI occurrence in pediatric HCT patients. The aims of this non-randomized pilot quality improvement initiative were to examine the feasibility of parafilm as a physical barrier on CVC tubing connections and obtain preliminary data to support its use preventing CLABSI among pediatric HCT patients. This IRB-approved cohort study included pediatric patients ages 0-21, with a tunneled external CVC, who were undergoing allogeneic or autologous HCT for any indication. Patients receiving other interventions to prevent CLABSI were ineligible. Parafilm was supplied in pre-cut 2 × 2 inch, single-use sections. It was applied over the CVC hub (if not connected) or around the CVC connection sites (if connected) and was reapplied at least once daily, as well as when connections were accessed or at the caregiver's discretion. Data were collected on patient, disease, and HCT characteristics as well as standard HCT outcomes and compared to a historical control group. The occurrence of NHSN/CDC-defined CLABSI was compared between groups using pairwise comparison, with significance defined as p Forty-eight patients undergoing first HCT from 6/2015-1/2017 received parafilm and were compared to historical control patients (n=71; HCT in preceding 16 months). No difference in age, sex, indication for HCT, stem cell source, or type of HCT was observed between groups. Patients receiving parafilm had a CLABSI rate of 3.69 per 1000 line days, compared to 4.37 for historical controls (p=0.6919). Univariate analysis of all patients demonstrated no impact of HCT type or sex on CLABSI rate, although the rate was lower in patients transplanted for a non-malignant disease compared to solid tumor (p=0.0326). Application of parafilm as a protective CVC barrier in pediatric HCT patients is feasible, and it may lead to a decrease in CLABSI. Sub-analyses are ongoing to see if parafilm may be more beneficial in subset(s) of patients, such as younger aged patients who remain in diapers or patients with graft-versus-host disease. Future trials will examine the use of a novel device, created specifically to protect CVC hubs/connection sites from environmental contamination, to reduce CLABSI.

Single-Cell Analysis Reveals Regional Reprogramming During Adaptation to Massive Small Bowel Resection in Mice.

Background & AimsThe small intestine (SI) displays regionality in nutrient and immunological function. Following SI tissue loss (as occurs in short gut syndrome, or SGS), remaining SI must compensate, or “adapt”; the capacity of SI epithelium to reprogram its regional identity has not been described. Here, we apply single-cell resolution analyses to characterize molecular changes underpinning adaptation to SGS.MethodsSingle-cell RNA sequencing was performed on epithelial cells isolated from distal SI of mice following 50% proximal small bowel resection (SBR) vs sham surgery. Single-cell profiles were clustered based on transcriptional similarity, reconstructing differentiation events from intestinal stem cells (ISCs) through to mature enterocytes. An unsupervised computational approach to score cell identity was used to quantify changes in regional (proximal vs distal) SI identity, validated using immunofluorescence, immunohistochemistry, qPCR, western blotting, and RNA-FISH.ResultsUniform Manifold Approximation and Projection-based clustering and visualization revealed differentiation trajectories from ISCs to mature enterocytes in sham and SBR. Cell identity scoring demonstrated segregation of enterocytes by regional SI identity: SBR enterocytes assumed more mature proximal identities. This was associated with significant upregulation of lipid metabolism and oxidative stress gene expression, which was validated via orthogonal analyses. Observed upstream transcriptional changes suggest retinoid metabolism and proximal transcription factor Creb3l3 drive proximalization of cell identity in response to SBR.ConclusionsAdaptation to proximal SBR involves regional reprogramming of ileal enterocytes toward a proximal identity. Interventions bolstering the endogenous reprogramming capacity of SI enterocytes—conceivably by engaging the retinoid metabolism pathway—merit further investigation, as they may increase enteral feeding tolerance, and obviate intestinal failure, in SGS.

The antidiarrheal efficacy of a proprietary amino acid mixture in neuroendocrine tumor (NET) patients.

218 Background: Gastroenteropancreatic neuroendocrine tumor (GEPNET) incidence has risen 6-fold over past 3 decades. North American Neuroendocrine Tumor Society estimates that over 100,000 GEPNET patients are currently living in the United States. One of the common quality of life limiting symptom seen in GEPNET patient is diarrhea. Diarrhea in these patients could be due to excessive serotonin production, secondary to post-operative short gut syndrome, steatorrhea from somatostatin analogs, bile acid colitis or intestinal bacterial overgrowth. A novel amino acid based oral rehydration solution (enterade) is currently being evaluated in a Phase II clinical trial for antidiarrheal effects in post bone marrow transplant patients (NCT02919670). We conducted a pilot study of enterade in neuroendocrine tumor (NET's) patients with quality of life limiting diarrhea. Methods: Medical records of all the NET patients given enterade to alleviate symptomatic diarrhea were evaluated. Patients were treated at Markey Cancer Center between May 2017-June 2018. Results: Total 69 NETs patients were treated with enterade. Enterade was administered as 8 Oz bottle BID for 1 a week. Antidiarrheal efficacy data was available on 41 patients at the time of abstract submission. 15 patients had small bowel NETs, 5 had bronchial NETs, 1 had colorectal NETs, 3 had NETs of unknown primary, 3 had gastric NETS, 3 had pancreatic NETs and one had high grade neuroendocrine carcinoma of the prostate. Data regarding primary site was unavailable in 10/41 patients. 21 patients had history of prior bowel resection either for primary neuroendocrine tumor resection or debulking. 25 patients were on somatostatin analogs at the time of initiation of enterade. 31 out of 41 patients reported some reduction in diarrhea frequency. 21 out of these 41 patients reported at least a 50% reduction in diarrhea frequency. Conclusions: 75.6% (31/41) neuroendocrine tumor patients reported improvement in diarrhea frequency with enterade. 51.2% (21/41) reported more than 50% reduction in diarrhea frequency. A prospective Phase II study of enterade in neuroendocrine tumor patients with quality of life limiting diarrhea is currently planned.