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Background and Purpose: Glucagon‐like peptide‐2 (GLP‐2) is secreted postprandially by enteroendocrine L‐cells and stimulates growth of the gut and bone. One GLP‐2 analogue is approved for short bowel syndrome (SBS). To improve therapeutic efficacy, we developed biased GLP‐2 receptor (GLP‐2R) agonists through N‐terminal modifications. Experimental Approach: Variants with Ala and Trp substitutions of the first seven positions of GLP‐2(1‐33) were studied in vitro for affinity, G protein activation (cAMP accumulation), recruitment of β‐arrestin 1 and 2, and internalization of the human and mouse GLP‐2R. The intestinotrophic actions of the most efficacious (cAMP) biased variant were examined in mice. Key Results: Ala substitutions had more profound effects than Trp substitutions. For both, alterations at positions 1, 3 and 6 most severely impaired activity. β‐arrestin recruitment was more affected than cAMP accumulation. Among Ala substitutions, [H1A], [D3A] and [F6A] impaired potency (EC50) for cAMP‐accumulation >20‐fold and efficacy (Emax) to 48%–87%, and were unable to recruit arrestins. The Trp substitutions, [A2W], [D3W] and [G4W] were partial agonists (Emax of 46%–59%) with 1.7–12‐fold decreased potencies in cAMP and diminished β‐arrestin recruitment. The biased variants, [F6A], [F6W] and [S7W] induced less GLP‐2R internalization compared with GLP‐2, which induced internalization in a partly arrestin‐independent manner. In mice, [S7W] enhanced gut trophic actions with increased weight of the small intestine, increased villus height and crypt depth compared with GLP‐2. Conclusion and Implications: G protein‐biased GLP‐2R agonists with diminished receptor desensitization have superior intestinotrophic effects and may represent improved treatment of intestinal insufficiency including SBS. [ABSTRACT FROM AUTHOR]

Background: While operational tolerance has been previously described in isolated intestinal transplant, reports of this phenomenon in combined liver‐intestine transplant are lacking. Case Description: We detail a unique case of a patient who received a composite allograft including liver, pancreas, and small bowel due to short gut syndrome secondary to gastroschisis complicated by volvulus. The indication for transplantation was permanent dependence on total parenteral nutrition, end‐stage liver disease, recurrent sepsis, and persistent stomal variceal hemorrhage. The patient developed severe graft‐versus‐host disease with grade 3 skin involvement, ophthalmic, and pulmonary involvement with 53% donor T‐cell chimerism. She required aggressive therapy including high‐dose methylprednisolone, rituximab, cyclophosphamide, and alemtuzumab. Due to infection concerns following depletion of her lymphocytes, immunosuppression was discontinued with close surveillance of her allograft. Nearly 10 years later, the patient has continued off all immunosuppression without evidence of rejection or graft dysfunction and demonstrates immunocompetence with normal functional immune assays and development of appropriate live vaccination titers. Conclusion: This report of operational tolerance following pediatric composite liver‐pancreas‐intestine transplantation provides evidence that the complex immunologic balance in intestinal transplantation may on rare occasions favor immunosuppression reduction or even discontinuation. Future trials of immunosuppression minimization in this population may be warranted. [ABSTRACT FROM AUTHOR]

Intestinal failure–associated liver disease (IFALD) can lead to increased morbidity and mortality in patients with intestinal failure (IF). We report the case of a premature infant born at 25 weeks' gestation at a neighboring facility that developed surgical necrotizing enterocolitis and secondary IF with 6 cm of small bowel remaining measured from the ligament of treitz with jejunocolonic anastomosis. The patient's course was complicated by IFALD and transferred to our intestinal rehabilitation program at 3 months of age. He was treated with SMOF lipid in reduced lipid dosages to prevent and treat IFALD, including cycling of parenteral nutrition, monitoring of the glucose infusion rate, and adjusting the micronutrient, trace elements, and aggressive enteral feeding. Omegaven had not yet been approved during the time of this case presentation. During the course of his treatment, he experienced normalization of his liver profile tests and progressed toward enteral autonomy. [ABSTRACT FROM AUTHOR]

Background: In treating short-bowel syndrome (SBS), autonomy from parenteral nutrition (PN) relies upon intestinal adaptation, which can be augmented by glucagon-like peptide-2 (GLP-2) analogues. In neonatal piglets with SBS, we compared intestinal adaptation following treatment with 2 GLP-2 analogues: teduglutide (TED) and apraglutide (APRA) METHODS: Following 75% distal small-intestinal resection, piglets were allocated to 4 treatment groups: saline (CON: n = 8), twice weekly APRA (5 mg/kg/dose; n = 8), and TED once daily (TED, 0.05 mg/kg/dose; n = 8) or twice daily (TEDBID, 0.05 mg/kg/dose; n = 7). Pharmacokinetic (PK) studies were undertaken, and on day 7, small-intestinal length and weight were measured and jejunal tissue collected for histology.Results: PK profiles were different between the 2 analogues. To achieve a comparable exposure to APRA, TED requires twice daily injection (TEDBID). Compared with CON, APRA and TEDBID increased small-bowel length (cm) (CON: 141, APRA: 166, TED: 153, TEDBID: 165; P = .004), whereas APRA increased small-bowel weight (g) (CON: 26, APRA: 33, TED: 28, TEDBID: 31; P = .007) and villus height (mm) (CON: 0.59, APRA: 0.90, TED: 0.58, TEDBID: 0.74; P < .001).Conclusion: APRA injected only twice during the 7 consecutive days demonstrated a superior intestinotrophic effect compared with TED injected once daily. Even at more comparable drug exposure, when TED was injected twice a day, APRA showed superior trophic activity at the mucosal level. This is highly relevant for the treatment of pediatric SBS, given the markedly lower dose frequency by subcutaneous injection of APRA. [ABSTRACT FROM AUTHOR]

The affected bowel showed strong signs of ischaemia, based on which an experienced gastrointestinal surgeon planned a bowel resection. Fluorescence angiography to assess intestinal viability during emergency laparoscopy for small bowel obstruction - A video vignette Future research should focus on establishing threshold values for the prediction of bowel viability, transforming FA into an objective decision-making system. [Extracted from the article]

Intestinal adaptation, or the ability of the small intestine to gain structural and functional capacity after resection, has long been considered the primary therapeutic goal in the treatment of intestinal failure caused by short-bowel syndrome (SBS). However, the results from this study places us 1 step closer in the realization of using medical therapy in an optimal fashion in the treatment of SBS. Comparing the Intestinotrophic Effects of 2 Glucagon-Like Peptide-2 Analogues in the Treatment of Short-Bowel Syndrome in Neonatal Piglets. [Extracted from the article]