Obeticholic acid attenuates the intestinal barrier disruption in a rat model of short bowel syndrome.

BACKGROUND: Short bowel syndrome (SBS) features nutrients malabsorption and impaired intestinal barrier. Patients with SBS are prone to sepsis, intestinal flora dysbiosis and intestinal failure associated liver disease. Protecting intestinal barrier and preventing complications are potential strategies for SBS treatment. This study aims to investigate the effects of farnesoid X receptor (FXR) agonist, obeticholic acid (OCA), have on intestinal barrier and ecological environment in SBS. METHODS AND RESULTS: Through testing the small intestine and serum samples of patients with SBS, impaired intestinal barrier was verified, as evidenced by reduced expressions of intestinal tight junction proteins (TJPs), increased levels of apoptosis and epithelial cell damage. The intestinal expressions of FXR and related downstream molecules were decreased in SBS patients. Then, global FXR activator OCA was used to further dissect the potential role of the FXR in a rat model of SBS. Low expressions of FXR-related molecules were observed on the small intestine of SBS rats, along with increased proinflammatory factors and damaged barrier function. Furthermore, SBS rats possessed significantly decreased body weight and elevated death rate. Supplementation with OCA mitigated the damaged intestinal barrier and increased proinflammatory factors in SBS rats, accompanied by activated FXR-related molecules. Using 16S rDNA sequencing, the regulatory role of OCA on gut microbiota in SBS rats was witnessed. LPS stimulation to Caco-2 cells induced apoptosis and overexpression of proinflammatory factors in vitro. OCA incubation of LPS-pretreated Caco-2 cells activated FXR-related molecules, increased the expressions of TJPs, ameliorated apoptosis and inhibited overexpression of proinflammatory factors. CONCLUSIONS: OCA supplementation could effectively ameliorate the intestinal barrier disruption and inhibit overexpression of proinflammatory factors in a rat model of SBS and LPS-pretreated Caco-2 cells. As a selective activator of FXR, OCA might realize its protective function through FXR activation.

Long-term outcomes and adverse effects of teduglutide in patients with short bowel syndrome: Highlighting hyperamylasemia and hyperlipasemia.

PURPOSE: Short bowel syndrome is a malabsorptive condition that occurs due to surgical removal or a congenital absence of a significant portion of the small intestine. Patients with short bowel syndrome often rely on parenteral support for extended periods or even their entire lives. Teduglutide, a glucagon-like peptide-2 analog, has shown promising results in reducing dependency on parenteral support in these patients by promoting intestinal adaptation and enhancing nutrient absorption. However, the long-term safety of teduglutide remains a concern, particularly with respect to its potential for the development of hyperamylasemia and hyperlipasemia. METHODS: This study involved patients who received teduglutide from December 2012 to December 2022 at Boston Medical Center. We evaluated outcomes and adverse events, focusing on hyperamylasemia and hyperlipasemia, through chart review. RESULTS: Thirteen eligible patients were identified who had used teduglutide. Of these, the majority (84.6%) experienced a reduction in parenteral support. A high incidence (72.7%) of nonpathological pancreatic enzyme elevation was observed in patients treated with teduglutide. These elevations were often dose dependent and were not associated with any clinical signs of acute pancreatitis or abnormal imaging findings. CONCLUSION: This study highlights the need for further investigations into the long-term safety of teduglutide and the importance of closely monitoring amylase and lipase levels in patients undergoing treatment with teduglutide.

Featuring molecular regulation of bile acid homeostasis in pediatric short bowel syndrome.

BACKGROUND: Disturbed bile acid homeostasis may foster development of short bowel syndrome (SBS) associated liver disease during and after weaning off parenteral nutrition (PN). Our aim was to study hepatic molecular regulation of bile acid homeostasis in relation to serum and fecal bile acid profiles in pediatric SBS. METHODS: Liver histopathology and mRNA expression of genes regulating synthesis, uptake and export of bile acids, and cellular receptors involved in bile acid signaling were measured in SBS patients (n = 33, median age 3.2 years). Simultaneously, serum (n = 24) and fecal (n = 10) bile acid profiles were assessed. Sixteen patients were currently on PN. Results of patients were compared to healthy control subjects. RESULTS: Nine of ten (90 %) patients with histological cholestasis received current PN, while portal inflammation was present in 60 % (6/10) of patients with cholestasis compared to 13 % (3/23) without cholestasis (P = 0.01). In all SBS patients, hepatic synthesis and uptake of bile acids was increased. Patients on current PN showed widespread repression of hepatic FXR target genes, including downregulated canalicular (BSEP, MDR3) and basolateral (MRP3) bile acid exporters. Serum and fecal primary bile acids were increased both during and after weaning off PN. CONCLUSIONS: Bile acid homeostasis in SBS is characterized by interrupted enterohepatic circulation promoting increased hepatic synthesis and conservation of bile acids. In PN dependent SBS patients with hepatic cholestasis and inflammation, the molecular fingerprint of downregulated hepatocyte canalicular and basolateral bile acid export with simultaneously increased synthesis and uptake of bile acids could favor their accumulation in hepatocytes and predispose to liver disease.

Fecal microbiota transplantation in a rodent model of short bowel syndrome: A therapeutic approach?

Extensive intestinal resection leads to Short Bowel Syndrome (SBS), the main cause of chronic intestinal failure. Colon preservation is crucial for spontaneous adaptation, to improve absorption and reduce parenteral nutrition dependence. Fecal microbiota transplantation (FMT), a promising approach in pathologies with dysbiosis as the one observed in SBS patients, was assessed in SBS rats with jejuno-colonic anastomosis. The evolution of weight and food intake, the lenght of intestinal villi and crypts and the composition of fecal microbiota of Sham and SBS rats, transplanted or not with high fat diet rat microbiota, were analyzed. All SBS rats lost weight, increased their food intake and exhibited jejunal and colonic hyperplasia. Microbiota composition of SBS rats, transplanted or not, was largely enriched with Lactobacillaceae, and α- and ß-diversity were significantly different from Sham. The FMT altered microbiota composition and α- and ß-diversity in Sham but not SBS rats. FMT from high fat diet rats was successfully engrafted in Sham, but failed to take hold in SBS rats, probably because of the specific luminal environment in colon of SBS subjects favoring aero-tolerant over anaerobic bacteria. Finally, the level of food intake in SBS rats was positively correlated with their Lactobacillaceae abundance. Microbiota transfer must be optimized and adapted to this specific SBS environment.

A rare cause of mechanical intestinal obstruction due to small bowel intussusception: 'A solitary Peutz-Jeghers type hamartomatous polyp'.

Peutz-Jeghers Syndrome (PJS) is a rare autosomal dominant disorder which is characterized by hyperpigmentation in mucocutaneous membranes and hamartomatous polyps in the gastrointestinal tract (GIT). Common complications reported in patients with PSJ are bleeding and mechanical intestinal obstruction due to the hamartomatous polyps. There is also an increased risk of gastrointestinal and extra-intestinal malignancies in patients with PJS. A 28-year-old female patient was admitted to the emergency service with complaints of abdominal pain and vomiting. In addition to distention and tenderness on abdominal examination, revealed hyperpigmented lesions on her lips. An abdominal examination did not reveal any scar from the previous abdominal operation. The patient with suspected mechanical intestinal obstruction at pre-diagnosis demonstrated intussusception in the distal jejunal loops on abdominal tomography. In the diagnostic laparoscopy observed intussusception in jejunal loops. After a minimal suprapubic incision, small intestine loops were checked through alexis with bidigital palpation and no other intraluminal mass were detected. Laparoscopy-assisted jejunojejunal re-section and anastomosis was performed for the intussusception segment, where the polyb is located. It has been recommended that endoscopic polyps removal should be performed to avoid multiple surgical resections, which lead to short bowel syndrome. It has been recommended that endoscopic polyps removal should be performed to avoid multiple surgical resections, which lead to short bowel syndrome. By the nature of the disease, there may be multiple polyps simultaneously in the GIT and the associated risk of recurrent intussusception attacks in patients with PJS. To prevent short bowel syndrome and intra-abdominal adhesions due to repeated, laparo-tomies treatment with combined endoscopy and laparoscopic/laparoscopy-assisted surgery should be preferred in patients with PJS.

A Model of Short Bowel Syndrome in Rodents in a Long-Term Experiment.

Simulation of short bowel syndrome (SBS) in experimental animals is of great interest for studies in translational medicine. The processes of intestinal adaptation are most often studied in rats aged 8-10 weeks with up to 70% resection the small bowel. In this case, the animals are euthanized in 2 weeks after the surgery; further development of the pathological process remains practically unexplored. In our experiment, a number of blood biochemical parameters and morphological signs of intestinal adaptation were assessed within 34 weeks after surgery. It was shown that after resection of 70% of the small bowel in rats (180±15 g), clinical symptoms are observed only during the first 2 weeks, however, the mortality in the group was observed throughout the entire period of the study in the absence of clear clinical signs. Morphological compensatory changes in the walls of the small intestine continued up to 34 weeks after resection, and their morphometry can be used to describe adaptation in the dynamics of the study.

Bile acid-farnesoid X receptor-fibroblast growth factor 19 axis in patients with short bowel syndrome: The randomized, glepaglutide phase 2 trial.

BACKGROUND: The gut-liver axis and enterohepatic circulation have gained increasing attention lately. Patients with short bowel syndrome (SBS) are, in fact, human knock-out models that may assist in the understanding of bile acid synthesis and regulation. We evaluated effect of glepaglutide (a long-acting glucagon-like peptide-2 analog) on bile acid synthesis (the enterohepatic circulation of bile acids and liver biochemistry in patients with SBS). METHOD: In a single-center, double-blinded, dose-finding, crossover phase 2 trial, 18 patients with SBS were randomly assigned to 2 of 3 treatment arms (0.1, 1, and 10 mg) with daily subcutaneous injections of glepaglutide for 3 weeks. The washout period between the 2 treatment periods was 4-8 weeks. Measurements were performed at baseline and at the end of each treatment period and included postprandial plasma samples for fibroblast growth factor 19 (FGF19), 7α-hydroxy-4-cholesten-3-one (C4), total excretion of fecal bile acids, gene expression of farnesoid X receptor (FXR) in intestinal mucosal biopsies, total plasma bile acids, and liver biochemistry. RESULTS: Compared with baseline, the median (interquartile range) postprandial response (area under the curve 0-2h) of FGF19 increased by 150 h × ng/L (41, 195; P = 0.001) and C4 decreased by 82 h × µg/L (-169, -28; p = 0.010) in the 10-mg dose. FXR gene expression did not change in any of the groups. Alkaline phosphatase significantly decreased. CONCLUSION: Glepaglutide may stimulate the bile acid/FXR/FGF19 axis, leading to increased plasma concentrations of FGF19. Thereby, glepaglutide may ameliorate the accelerated de novo bile acid synthesis and play a role in the prevention and/or treatment of intestinal failure-associated liver disease.

Teduglutide in short bowel syndrome patients: A way back to normal life?

BACKGROUND: The glucagon-like peptide 2 analogue teduglutide is an effective drug for the treatment of short bowel syndrome patients with intestinal failure (SBS-IF). This intestinotrophic peptide improves intestinal capacity for fluid and nutrient absorption through induction of mucosal growth and reduction of gastrointestinal motility. Clinical trials demonstrated the efficacy of teduglutide in reducing the need for parenteral support (PS). This study describes an SBS-IF patient population receiving teduglutide therapy in a specialized medical care setting. METHOD: A retrospective analysis was performed using data of patients experiencing nonmalignant SBS-IF. They were treated with teduglutide in a multidisciplinary SBS-IF program at a single university medical center between June 2016 and June 2020. RESULTS: Thirteen patients under teduglutide treatment were included in the final analysis. Mean small bowel length was 82 ± 31 cm, with 77% of patients having their colon in continuity. Over a median follow-up of 107 weeks, all patients (13 of 13, 100%) responded to the therapy with a clinically significant reduction of PS volume. Mean PS reduction increased with therapy duration and ranged from -82.5% at week 24 (n = 13) to -100% in patients (n = 5) who were treated for 144 weeks. Enteral autonomy was achieved in 12 of 13 (92%) patients. Teduglutide therapy improved stool frequency and consistency, changed dietary habits, and reduced disease-associated sleep disruptions. CONCLUSION: Integrating SBS-IF patients treated with teduglutide in a proactive and tight-meshed patient care program significantly improves the clinical outcome, leading to an increased proportion of patients reaching enteral autonomy.

Therapeutic potential of an intestinotrophic hormone, glucagon-like peptide 2, for treatment of type 2 short bowel syndrome rats with intestinal bacterial and fungal dysbiosis.

BACKGROUND: Previous studies showed that type 2 short bowel syndrome (SBS) rats were accompanied by severe intestinal bacterial dysbiosis. Limited data are available for intestinal fungal dysbiosis. Moreover, no effective therapeutic drugs are available for these microbiota dysbiosis. The aims of our study were to investigate the therapeutic potential of glucagon-like peptide 2 (GLP-2) for these microbiota dysbiosis in type 2 SBS rats. METHODS: 8-week-old male SD rats which underwent 80% small bowel resection, ileocecum resection, partial colon resection and jejunocolostomy, were treated with saline (SBS group, n = 5) or GLP-2 (GLP2.SBS group, n = 5). The Sham group rats which underwent transection and re-anastomosis were given a saline placebo (Sham group, n = 5). 16S rRNA and ITS sequencing were applied to evaluate the colonic bacterial and fungal composition at 22 days after surgery, respectively. RESULTS: The relative abundance of Actinobacteria, Firmicutes and proinflammatory Proteobacteria increased significantly in SBS group rats, while the relative abundance of Bacteroidetes, Verrucomicrobia and Tenericutes decreased remarkably. GLP-2 treatment significantly decreased Proteus and increased Clostridium relative to the saline treated SBS rats. The diversity of intestinal fungi was significantly increased in SBS rats, accompanied with some fungi abnormally increased and some resident fungi (e.g., Penicillium) significantly decreased. GLP-2 treatment significantly decreased Debaryomyces and Meyerozyma, and increased Penicillium. Moreover, GLP-2 partially restored the bacteria-fungi interkingdom interaction network of SBS rats. CONCLUSION: Our study confirms the bacterial and fungal dysbiosis in type 2 SBS rats, and GLP-2 partially ameliorated these microbiota dysbiosis.

An organoid-based organ-repurposing approach to treat short bowel syndrome.

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 vitro1, but reconstruction of the whole small intestine, including the complex lymphovascular system, has remained challenging2. 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.

Intestinal dysmotility after bowel resection in rats is associated with decreased ghrelin and vimentin expression and loss of intestinal cells of Cajal.

This study provides novel insight into the mechanisms of intestinal dysmotility following massive small bowel resection. We show that 2 wk after bowel resection in rats, impaired intestinal motility was associated with loss of interstitial cells of Cajal (ICC; downregulation of transmembrane member 16A (TMEM16A) and c-kit expression) as well as with decreased vimentin, desmin, and ghrelin levels. Impaired intestinal motility led to a decrease in final body weight, suggesting less effective nutrient absorption. The purpose of this study was to evaluate the mechanisms of intestinal motility in a rat model of short bowel syndrome (SBS). Rats were divided into three groups: Sham rats underwent bowel transection; SBS-NSI rats underwent a 75% bowel resection and presented with normal intestinal size (NSI) at euthanasia and hypermotility patterns; SBS-DYS showed dysmotile (DYS) enlarged intestine and inhibited motility patterns. Animals were euthanized after 2 wk. Illumina's digital gene expression (DGE) analysis was used to determine the intestinal motility-related gene expression profiling in mucosal samples. Intestinal motility-related and ICC genes and protein expression in intestinal muscle layer were determined using real-time PCR, Western blotting, and immunohistochemistry. Gastrointestinal tract motility was studied by microcomputer tomography. From 10 Ca2+ signaling pathway-related genes, six genes in jejunum and seven genes in ileum were downregulated in SBS vs. Sham animals. Downregulation of TMEM16A mRNA and protein was confirmed by real-time PCR. Rapid intestinal transit time in SBS-NSI rats correlated with a mild decrease in TMEM16A, c-kit, and vimentin mRNA and protein expression (vs/. Sham animals). SBS-DYS rats demonstrated enlarged intestinal loops and delayed small intestinal emptying (on imaging studies) that were correlated with marked downregulation in TMEM16A, c-kit, vimentin, and ghrelin mRNA and protein levels compared with the other two groups. In conclusion, 2 wk following massive bowel resection in rats, impaired intestinal motility was associated with decreased vimentin and ghrelin gene and protein levels as well as loss of ICC (c-kit and TMEM16A).NEW & NOTEWORTHY This study provides novel insight into the mechanisms of intestinal dysmotility following massive small bowel resection. We show that 2 weeks after bowel resection in rats, impaired intestinal motility was associated with loss of interstitial cells of Cajal (downregulation of TMEM 16A, and c-kit expression) as well as with decreased vimentin, desmin, and ghrelin levels. Impaired intestinal motility led to decrease in final body weight, suggesting less effective nutrient absorption.

Exosomes-mediated Transfer of miR-125a/b in Cell-to-cell Communication: A Novel Mechanism of Genetic Exchange in the Intestinal Microenvironment.

Glucagon-like peptide-2 (GLP-2), a key factor in intestinal rehabilitation therapy of short bowel syndrome (SBS), may require cell-to-cell communication to exert its biological functions. However, understanding of the mechanism remains elusive. Here, we report participation of exosomal miR-125a/b in GLP-2 mediated intestinal epithelial cells-myofibroblasts cross-talk in intestinal microenvironment. Methods: The effects of GLP-2 on the proliferation and apoptosis of intestinal epithelial cells in SBS rat models were evaluated. Exosomes were extracted from residual jejunum tissue of GLP-2 or vehicle treated SBS rats using ultracentrifugation method, and identified by nanoparticle trafficking analysis (NTA), transmission electron microscopy and western blotting. miRNA sequencing combined with qRT-PCR validation were used to identify differentially expressed miRNAs. miRNAs, which might be involved in proliferation and apoptosis of intestinal epithelial cells, were screened and further verified by miRNA functional experiments. Moreover, the proliferation-promoting and anti-apoptosis effects of GLP-2 on intestinal myofibroblasts, which expressing GLP-2 receptor, and whether GLP-2 could influence the content of miRNAs in the derived exosomes were studied. The downstream pathways were explored by miRNA function recovery experiment, luciferase reporter assay, pull down experiment, knockdown and overexpression of target gene and other experiments based on the bioinformatics prediction of miRNA target gene. Results: GLP-2 significantly promoted intestinal growth, facilitated the proliferation of intestinal crypt epithelial cells and inhibited the apoptosis of intestinal villi epithelial cells in type II SBS rats. GLP-2 significantly down-regulated exosomal miR-125a/b both in residual jejunums derived exosomes and in exosomes secreted by GLP-2R positive cells. Exosomal miR-125a/b was responsible for GLP-2 mediated intestinal epithelial cells proliferation promotion and apoptosis attenuation. miR-125a/b inhibited the proliferation and promotes apoptosis of intestinal epithelial cells by suppressing the myeloid cell leukemia-1 (MCL1). Conclusions: miR-125a/b shuttled by intestinal myofibroblasts derived exosomes regulate the proliferation and apoptosis of intestinal epithelial cells. GLP-2 treatment significantly decreases the level of miR-125a/b in the exosomes of intestinal myofibroblasts. miR-125a/b modulates the proliferation and apoptosis of intestinal epithelial cells by targeting the 3'UTR region of MCL1. Hence, this study indicates a novel mechanism of genetic exchange between cells in intestinal microenvironment.

A Central Role for Lipocalin-2 in the Adaptation to Short-Bowel Syndrome Through Down-Regulation of IL22 in Mice.

BACKGROUND & AIMS: In short-bowel syndrome (SBS), inadequate intestinal adaptation is responsible for the majority of complications, including sepsis, liver failure, and death. In this study, we sought to further delineate the adaptive response to identify potential therapeutic targets. METHODS: We performed a 75% small-bowel resection (SBR) or sham operation on C57Bl/6J wild-type (WT), lipocalin-2 (LCN2)-/-, and interleukin 22 (IL22)-/- mice. Exogenous IL22 was administered to SBR WT mice. Cecal fecal matter from SBR WT and SBR LCN2-/- mice were transplanted into germ-free mice. Intestinal permeability, inflammation, proliferation, and the microbiome were evaluated 1 week after surgery. CD4+IL22+ laminal propria lymphocytes were sorted by flow cytometry. Naïve T cells were polarized to T-helper cells with or without LCN2. RESULTS: A 75% SBR in a mouse re-creates the increased intestinal permeability, enterocyte proliferation, and intestinal dysbiosis seen in SBS. LCN2 expression increases after 75% SBR, and this increase can be abrogated with broad-spectrum antibiotic treatment. LCN2-/- mice have less intestinal inflammation, increased IL22 expression, and greater adaptation as evidenced by less intestinal permeability, increased carbohydrate enzyme expression, less weight loss, and less dysbiosis after 75% SBR than WT mice. The proinflammatory and anti-adaptive effects of LCN2 can be transferred to germ-free mice via a fecal transplant. Administration of exogenous IL22 improves adaptation and restores the normal microbiome after 75% SBR in WT mice. CONCLUSIONS: LCN2 promotes inflammation and slows intestinal adaptation through changes in the microbiome and IL22 inhibition in a mouse SBS model. Strategies to reduce LCN2 may offer novel therapeutic approaches to enhance adaptation in SBS.

Development and validation of an ambulatory piglet model for short bowel syndrome with ileo-colonic anastomosis.

IMPACT STATEMENT: Short bowel syndrome is associated with significant comorbidities and mortality. This study is important as unlike current systems, it provides a validated piglet model which mirrors anatomical, histological, and serological characteristics observed in human SBS. This model can be used to advance knowledge into mechanistic pathways and therapeutic modalities to improve outcomes for SBS patients. This study is novel in that in addition to significant reduction in the remnant bowel and noted liver disease, we also developed a method to emulate ileocecal valve resection and described gut adaptive responses which has important clinical implications in humans.

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.

Propionate promotes vitamin D receptor expression via yes-associated protein in rats with short bowel syndrome.

Vitamin D deficiency and refractory osteoporosis are common complications in patients with short bowel syndrome (SBS). The symptom of bone loss is not effectively alleviated, even after the oral administration of vitamin D in SBS patients who had been weaned off parenteral nutrition. In this study, we aimed to investigate the effect of propionate on the expression of the vitamin D receptor (VDR) in the small intestine of rats with SBS. Firstly, IEC-6 (intestinal epithelioid cell line No. 6) cells were incubated in vitro with 1 mM sodium propionate for 24 h. This resulted in a significant increase in the expression of VDR and yes-associated protein (YAP) compared with that in the control group. Transfection of IEC-6 cells with YAP siRNA significantly down-regulated the expression of VDR. By contrast, after incubating IEC-6 cells with lysophosphatidic acid, an agonist of YAP, upregulation of VDR and YAP was observed. Next, we investigated whether this effect occurs in vivo. Five-week-old male Sprague-Dawley rats underwent 80% small bowel resection to establish an SBS model. Rats treated with 1% w/v sodium propionate had high levels of VDR and YAP expression in the intestine and intestinal adaptation was clearly observed compared to the control group. However, these effects were blocked by intraperitoneal injection of verteporfin. Thus, this study showed that propionate promoted VDR expression in the intestine via the activity of YAP, both in vitro and in vivo. Moreover, propionate was shown to play an active role in postoperative intestinal adaptation in SBS rats.

Citrulline correlations in short bowel syndrome-intestinal failure by patient stratification: Analysis of 24 weeks of teduglutide treatment from a randomized controlled study.

BACKGROUND & AIMS: Disease-associated factors influence parenteral support (PS) reduction in response to teduglutide in patients with intestinal failure associated-short bowel syndrome (SBS-IF). We sought to determine correlative relationships between plasma citrulline levels, small bowel length, and PS volume. METHODS: A post hoc analysis of plasma citrulline levels from patients in the STEPS 24-week study of teduglutide in patients with SBS-IF. Plasma citrulline was assessed in all patients; patients were stratified 3 times into subgroups based on bowel anatomy, cause of SBS-IF, and baseline PS volumes. Correlation analyses used simple linear regression models. Statistical comparisons between study groups were conducted using 2-sided t tests for 2 independent mean differences. RESULTS: Baseline plasma citrulline correlated with remnant small bowel length (r = 0.355, P = 0.002), but not with baseline PS volume (r = -0.167, P = 0.14), in the overall population. There was a robust correlation between the baseline and Week 24 citrulline (r = 0.705, P < 0.0001), and an inverse correlation between change from baseline in citrulline and PS volume from baseline to Week 24 (r = -0.359, P = 0.001). In all subgroups, patients treated with teduglutide showed numerically greater increases in plasma citrulline at Week 24 compared with placebo. CONCLUSION: Baseline plasma citrulline showed significant correlations with small bowel length in patients with ≥50% colon remaining/no stoma/colon-in-continuity, and patients with SBS-IF causes other than IBD/vascular disease. Citrulline levels may correlate with PS changes in response to teduglutide and more research may reveal a relationship between citrulline levels within the heterogeneous population of patients with SBS-IF. ClinicalTrials.gov NCT00798967, ClinicalTrialsRegister.eu 2008-006193-15.

Botulinum toxin as a treatment for short bowel syndrome in rats.

PURPOSE: The denervation of the intestine with benzalkonium chloride (BAC) reduces mortality and improves weight gain in rats with short bowel syndrome (SBS). Nevertheless, translating these promising findings from bench to bedside is not feasible because BAC promotes peritonitis and irreversible denervation which may be followed by an uncontrolled dilatation of the viscera. The use of botulinum toxin (BT) instead of BAC to achieve the denervation of the remaining small intestine in SBS could be an interesting option because it leads to a mild and transient denervation of the intestine. METHODS: Here we evaluated the effects of the ileal denervation with BT in rats with SBS by verifying the body weight variation and intestinal morphological parameters. Four groups with 6 animals each were submitted to enterectomy with an ileal injection of saline (group E) or BT (group EBT). Control groups were submitted to simulated surgery with an ileal injection of BT (group BT) or saline (group C - control). RESULTS: We observed that the treatment of the remaining ileum with BT completely reversed the weight loss associated to extensive small bowel resection. CONCLUSION: This may provide a new promising approach to the surgical treatment of SBS.

Risk Factors for Nephrolithiasis in Adults with Short Bowel Syndrome.

INTRODUCTION: Patients with short bowel syndrome (SBS) commonly develop nephrolithiasis. However, the risk factors for nephrolithiasis in patients with SBS remain unclarified. The present study aimed to identify the risk factors for nephrolithiasis in adults with SBS. METHODS: All eligible adults diagnosed with SBS and admitted to a tertiary referral center from December 2008 to 2018 were retrospectively identified from a prospectively maintained database. Patients' demographic and clinical characteristics were analyzed using univariate and multivariate analyses to identify the risk factors for nephrolithiasis. RESULTS: Of 231 adults with SBS, 42 (18.2%) developed nephrolithiasis. The mean age was 46.4 ± 17.8 years, the mean body mass index was 18.2 ± 3.8 kg/m2, and median duration of SBS was 11 months (range 2-324 months). Multivariate binary logistic regression analysis revealed that the independent risk factors for nephrolithiasis in adults with SBS were jejuno-ileal anastomosis and colon-in-continuity (OR 4.335; 95% CI 1.175-16.002; p = 0.028), prolonged duration of SBS (OR 1.008; 95% CI 1.002-1.014; p = 0.010), and increased serum creatinine concentration (OR 1.005; 95% CI 1.001-1.009; p = 0.012). CONCLUSIONS: Nephrolithiasis is common in adults with SBS. As nephrolithiasis can have adverse clinical consequences, patients with SBS should be closely monitored, and prophylactic interventions should be considered.

[Efficacy of the intestinal rehabilitation program in patients with short bowel syndrome]. / Eficacia del programa de rehabilitación intestinal en pacientes con síndrome de intestino corto.

INTRODUCTION: In recent decades, intestinal rehabilitation programs, advances in parenteral nutrition (PN) and intestinal lengthening techniques have improved the results of patients with short bowel syndrome (SBS). OBJECTIVE: To evaluate the growth, the independence of PN and the survival of patients with SBS diagnosed in the last 12 years. MATERIAL AND METHOD: Retrospective review between the years 2007-2016. Defining SBS as the inability of the intestine to provide complete absorption via the enteral route being necessary PN. A multivariate analysis was performed to assess the prognostic factors regarding the autonomy of the NE controlled by Cox regression: ileocecal valve presence (qualitative variable: yes/no), small intestine length and gestational age (both quantitative variables). RESULTS: 18 patients were evaluated. The most frequent causes of SBS: necrotizing enterocolitis (6, 33.3%), jejunal atresia and Hirschsprung (4 cases each pathology, 22.2%) and others (4). The average intestinal length was 51.17 cm at diagnosis, 72.2% lacked an ileocecal valve. The mean PN at the start was 115.8 hours / week, currently: 56.9. The 22.2% achieved complete enteral nutrition (CEN) after an average time of 4.62 years. Serial transverse enteroplasty was performed in 3 patients.The presence of an ileocecal valve was a protective factor to achieve CEN (p<0.018). In contrast, intestinal length and gestational age were not significant. After a follow-up of 5.38 years (3 exitus, 9.6 months on average), no patient was a candidate for intestinal transplantation. CONCLUSIONS: The survival of patients with SBS has improved in recent decades due to intestinal rehabilitation programs, advances in PN and intestinal lengthening techniques. It is possible to achieve NEC and avoiding intestinal transplantation.

INTRODUCCION: En las últimas décadas, los programas de rehabilitación intestinal, los avances en la nutrición parenteral (NP) y las técnicas de alargamiento intestinal han mejorado los resultados de los pacientes con síndrome de intestino corto (SIC). OBJETIVO: Valorar el crecimiento, la independencia de la NP y la supervivencia de los pacientes con SIC diagnosticados en los últimos 12 años. MATERIAL Y METODO: Revisión retrospectiva entre los años 2007-2016. Definiéndose SIC como la incapacidad del intestino para proporcionar la absorción completa por vía enteral siendo necesaria la NP. Se realizó un análisis multivariante para valorar los factores pronósticos respecto a la autonomía de la nutrición enteral (NE) mediante regresión de Cox controlado por: presencia de válvula ileocecal (variable cualitativa: sí/no), longitud de intestino delgado y edad gestacional (ambas variables cuantitativas). RESULTADOS: Fueron evaluados 18 pacientes. Las causas más frecuentes de SIC: enterocolitis necrotizante (6, 33,3%), atresia yeyunal y Hirschsprung (4 casos cada patología, 22,2%) y otros (4). La longitud intestinal media era 51,17 cm al diagnóstico, el 72,2%, carecían de válvula ileocecal. La media NP al inicio era de 115,8 horas/semana, actualmente: 56,9. El 22,2% lograron la nutrición enteral completa (NEC) tras un tiempo medio de 4,62 años. En 3 pacientes se realizó una enteroplastia transversa seriada. La presencia de válvula ileocecal fue un factor protector para lograr la NEC (p<0,018). En cambio, la longitud y la edad gestacional no fueron significativos. Tras un seguimiento de 5,38 años (3 exitus, 9,6 meses de media), ningún paciente fue candidato a trasplante intestinal. CONCLUSIONES: La supervivencia de pacientes con SIC ha mejorado en las últimas décadas debido a los programas de rehabilitación intestinal, los avances en la NP y las técnicas de alargamiento intestinal. Es posible lograr la NEC y reducir la NP evitando el trasplante intestinal.