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Background and aimsTeduglutide, a GLP-2 analogue, may restore intestinal structural and functional integrity by promoting repair and growth of the mucosa and reducing gastric emptying and secretion, thereby increasing fluid and nutrient absorption in patients with short bowel syndrome (SBS). This 24-week placebo-controlled study evaluated the ability of teduglutide to reduce parenteral support in patients with SBS with intestinal failure.MethodsIn 83 patients randomised to receive subcutaneous teduglutide 0.10 mg/kg/day (n=32), 0.05 mg/kg/day (n=35) or placebo (n=16) once daily, parenteral fluids were reduced at 4-week intervals if intestinal fluid absorption (48 h urine volumes) increased ≥10%. Responders were subjects who demonstrated reductions of ≥20% in parenteral volumes from baseline at weeks 20 and 24. The primary efficacy end point, a graded response score (GRS), took into account higher levels and earlier onset of response, leading to longer duration of response. The intensity of the response was defined as a reduction from baseline in parenteral volume (from 20% to 100%), and the duration of the response was considered the response at weeks 16, 20 and 24. The results were tested according to a step-down procedure starting with the 0.10 mg/kg/day dose.ResultsUsing the GRS criteria, teduglutide in a dose of 0.10 mg/kg/day did not have a statistically significant effect compared with placebo (8/32 vs 1/16, p=0.16), while teduglutide in a dose of 0.05 mg/kg/day had a significant effect (16/35, p=0.007). Since parenteral volume reductions were equal (353±475 and 354±334 ml/day), the trend towards higher baseline parenteral volume (1816±1008 vs 1374±639 ml/day, p=0.11) in the 0.10 mg/kg/day group compared with the 0.05 mg/kg/day group may have accounted for this discrepancy. Three teduglutide-treated patients were completely weaned off parenteral support. Serious adverse events were distributed similarly between active treatment groups and placebo. Villus height, plasma citrulline concentration and lean body mass were significantly increased with teduglutide compared with placebo.ConclusionsTeduglutide was safe, well tolerated, intestinotrophic and suggested pro-absorptive effects facilitating reductions in parenteral support in patients with SBS with intestinal failure.ClinicalTrials.gov numberNCT00172185.

The small intestine is the main organ for nutrient absorption, and its extensive resection leads to malabsorption and wasting conditions referred to as short bowel syndrome (SBS). Organoid technology enables an efficient expansion of intestinal epithelium tissue in vitro 1 , but reconstruction of the whole small intestine, including the complex lymphovascular system, has remained challenging 2 . Here we generate a functional small intestinalized colon (SIC) by replacing the native colonic epithelium with ileum-derived organoids. We first find that xenotransplanted human ileum organoids maintain their regional identity and form nascent villus structures in the mouse colon. In vitro culture of an organoid monolayer further reveals an essential role for luminal mechanistic flow in the formation of villi. We then develop a rat SIC model by repositioning the SIC at the ileocaecal junction, where the epithelium is exposed to a constant luminal stream of intestinal juice. This anatomical relocation provides the SIC with organ structures of the small intestine, including intact vasculature and innervation, villous structures, and the lacteal (a fat-absorbing lymphatic structure specific to the small intestine). The SIC has absorptive functions and markedly ameliorates intestinal failure in a rat model of SBS, whereas transplantation of colon organoids instead of ileum organoids invariably leads to mortality. These data provide a proof of principle for the use of intestinal organoids for regenerative purposes, and offer a feasible strategy for SBS treatment. In a rat model of short bowel syndrome, transplantation of small intestinal organoids into the colon partially restores intestinal function and improves survival—a proof of principle that organoid transplantation might have therapeutic benefit.

Once virtually uniformly fatal, pediatric intestinal failure is now considered a complex but survivable syndrome that afflicts tens of thousands of children. This article reviews the approach to children with intestinal failure.

Short bowel syndrome (SBS) is an intestinal disorder characterized by reduced length of the gut most due to intestinal resection, resulting in malabsorption, malnutrition, and water and electrolyte disturbances. Intestinal adaptation is a long-term process in which GIT hormones, growth peptides, cytokines etc. are involved. These mechanisms have not been fully clarified yet. The most important seem to be GLP-2 and other gut hormones. The aim of our study was to consider the changes of the levels of selected gut hormones and parameters of glucose homeostasis during the mixed liquid meal test in one year of follow up after the gut resection. Seventeen patients with SBS type I were included into our study. The meal test and measuring of selected parameters (GLP-2, GLP-1, ghrelin, insulin, glucagon, GIP, amylin) were conducted after 2 weeks, 6 and 12 months from its initiation, respectively. During one year of this study patients´ nutritional status improved due to sufficient parenteral nutrition, despite no change in body weight. Hormones possibly involved in intestinal adaptation (GLP-2, GLP-1, ghrelin) did not differ in meal test, neither levels nor AUC. Only higher insulin and glucose levels after one year of follow-up may indicate the beginning of intestinal adaptation process and improving intestinal functions. We conclude that impaired GLP-2 secretion is probably the main reason for the limited adaptation ability in patients with SBS type I.

Our objective was to understand the functional link between the composition of faecal microbiota and the clinical characteristics of adults with short bowel syndrome (SBS). Sixteen patients suffering from type II SBS were included in the study. They displayed a total oral intake of 2661 +/- 1005 Kcal/day with superior sugar absorption (83 +/- 12%) than protein (42 +/- 13%) or fat (39 +/- 26%). These patients displayed a marked dysbiosis in faecal microbiota, with a predominance of Lactobacillus/Leuconostoc group, while Clostridium and Bacteroides were under-represented. Each patient exhibited a diverse lactic acid bacteria composition (L. delbrueckii subsp. bulgaricus, L. crispatus, L. gasseri, L. johnsonii, L. reuteri, L. mucosae), displaying specific D and L-lactate production profiles in vitro. Of 16 patients, 9/16 (56%) accumulated lactates in their faecal samples, from 2 to 110 mM of D-lactate and from 2 to 80 mM of L-lactate. The presence of lactates in faeces (56% patients) was used to define the Lactate-accumulator group (LA), while absence of faecal lactates (44% patients) defines the Non lactate-accumulator group (NLA). The LA group had a lower plasma HCO3(-) concentration (17.1 +/- 2.8 mM) than the NLA group (22.8 +/- 4.6 mM), indicating that LA and NLA groups are clinically relevant sub-types. Two patients, belonging to the LA group and who particularly accumulated faecal D-lactate, were at risk of D-encephalopathic reactions. Furthermore, all patients of the NLA group and those accumulating preferentially L isoform in the LA group had never developed D-acidosis. The D/L faecal lactate ratio seems to be the most relevant index for a higher D-encephalopathy risk, rather than D-and L-lactate faecal concentrations per se. Testing criteria that take into account HCO3(-) value, total faecal lactate and the faecal D/L lactate ratio may become useful tools for identifying SBS patients at risk for D-encephalopathy.

Critical for cellular maintenance and repair, autophagy recycles damaged or redundant cellular components. Dysregulated autophagy is associated with progressive cellular injury in various liver pathologies. However, the role of autophagy in intestinal failure-associated liver disease has not previously been investigated. Using a preclinical murine model of short bowel syndrome, we explored the role of autophagy impairment at early and late time points. Regardless of sex, small bowel resected (SBR) mice demonstrated significant liver injury compared to sham controls, exhibiting elevated serum transaminases, altered liver histology, and increased mRNA expression of endoplasmic reticulum stress marker (Ddit3) and oxidative stress marker ( Nqo1) . Autophagy impairment was supported by increased p62 mRNA and protein expression in SBR liver and then confirmed with qualitative autophagy flux assay which suggested alteration of autophagy induction in SBR liver. Single nuclear RNA sequencing identified a cluster of hepatocytes in the SBR liver with increased p62 expression. These hepatocytes showed enrichment of genes related to the PI3K-Akt and ErbB pathways both which converge on mTORC1. Immunohistochemical distribution of pS6 confirmed increased mTORC1 activation in the SBR hepatocytes. Overall autophagy dysregulation is correlated with mTORC1 activation in SBR mice and is associated with greater liver injury.

Short bowel syndrome (SBS) leads to severe morbidity and mortality. Intestinal adaptation is crucial in improving outcomes. To understand the human gene pathways associated with adaptation, we perform single-cell transcriptomic analysis of human small intestinal organoids explanted from mice with experimental SBS. We show that transmembrane ion pathways, specifically the transepithelial zinc transport pathway genes SLC39A4 and SLC39A5 , are upregulated in SBS. This discovery is corroborated by an external dataset, bulk RT-qPCR, and Western blots. Oral zinc supplementation is shown to improve survival and weight gain of SBS mice and increase the proliferation of intestinal crypt cells in vitro. Finally, we identify the upregulation of SLC39A5 and associated transcription factor KLF5 in biopsied intestinal tissue specimens from patients with SBS. Thus, we identify zinc supplementation as a potential therapy for SBS and describe a xenotransplantation model that provides a platform for discovery in other intestinal diseases. SBS leads to severe morbidity and mortality. Here, using a xenotransplantation model, the authors uncover the role of zinc transport pathways in intestinal adaptation in SBS, highlighting the potential of zinc supplementation as a therapeutic approach.

Pediatric patients with short bowel syndrome (SBS) often require long-term parenteral nutrition and intravenous fluid support (PN) until enteral autonomy (EA). However, long-term PN accounts for many complications. We aimed to investigate the outcome and predictors of EA in these patients. This retrospective observational study was conducted in Children's Medical Center, Chang Gung Memorial Hospital, a tertiary hospital in Northern Taiwan. Twenty-four patients afflicted with short bowel syndrome between 2002 and 2021 were included. Demographics, operation results, follow-up status, complications, and outcomes were reviewed. Among the 24 patients, 14 were males (58%). The median age at bowel resection was 3 days (IQR, 1.3-28.8 days). The most common etiologies were total/subtotal intestinal aganglionosis (TIA) (N = 6) and malrotation with midgut volvulus (N = 6). The median length of the residual small intestine was 25 cm (IQR, 7.8-71.3 cm). Ten (41.7%) had preserved ileocecal valve, and 14 (58.3%) had colon-in-continuity. Intestinal failure-associated liver disease (IFALD) occurred in 14 patients (58.3%), but none had advanced disease. Seven patients (29.2%) achieved enteral autonomy after 10.1 ± 7.3 months. Five patients (21%) expired due to sepsis. Logistic regression and Kaplan-Meier analysis showed the predictors of enteral autonomy were remaining-to-expected small bowel length ratio >25% and the absence of IFALD. In this pediatric short bowel syndrome study, enteral autonomy was achieved in 29% after a mean PN duration of 10 months. The remaining-to-expected small bowel length ratio at bowel resection was the most critical predictor of enteral autonomy.