Model Of Short Bowel Syndrome Research Articles

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

BackgroundShort 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 resultsThrough 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. ConclusionsOCA 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.

Dietary polyamines promote intestinal adaptation in an experimental model of short bowel syndrome

Intestinal adaptation does not necessarily recover absorptive capacity in short bowel syndrome (SBS), sometimes resulting in intestinal failure-associated liver disease (IFALD). Additionally, its therapeutic options remain limited. Polyamines (spermidine and spermine) are known as one of the autophagy inducers and play important roles in promoting the weaning process; however, their impact on intestinal adaptation is unknown. The aim of this study was to investigate the impact of polyamines ingestion on adaptation and hepatic lipid metabolism in SBS. We performed resection of two-thirds of the small intestine in male Lewis rats as an SBS model. They were allocated into three groups and fed different polyamine content diets (0%, 0.01%, 0.1%) for 30 days. Polyamines were confirmed to distribute to remnant intestine, whole blood, and liver. Villous height and number of Ki-67-positive cells in the crypt area increased with the high polyamine diet. Polyamines increased secretory IgA and mucin content in feces, and enhanced tissue Claudin-3 expression. In contrast, polyamines augmented albumin synthesis, mitochondrial DNA copy number, and ATP storage in the liver. Moreover, polyamines promoted autophagy flux and activated AMP-activated protein kinase with suppression of lipogenic gene expression. Polyamines ingestion may provide a new therapeutic option for SBS with IFALD.

Superiority of Intestinal Adaptation by Hepatocyte Growth Factor in the Jejunum: An Experimental Study in a Short-Bowel Rat Model

BackgroundWe evaluated the effect of recombinant human hepatocyte growth factor (rh-HGF) on intestinal adaptation in a rat model of short-bowel syndrome (SBS). MethodsSprague–Dawley rats underwent jugular vein catheterization for continuous total parenteral nutrition (TPN) and 90 % small bowel resection. The animals were divided into 3 groups: TPN/SBS (control group, n = 7), TPN/SBS/intravenous recombinant human hepatocyte growth factor (HGF) (0.3 mg/kg/day) (HGF group, n = 7), and TPN/SBS/intravenous c-Met inhibitor (0.3 mg/kg/day) (anti-HGF group, n = 5). On day 7, rats were euthanized and histologically evaluated. Serum diamine oxidase (S-DAO) levels were evaluated using an enzyme-linked immunosorbent assay. The nutrient transporter and glucagon-like peptide-2 (GLP-2) receptor expression were evaluated using real-time polymerase chain reaction. ResultsThe jejunal and ileal villus heights were higher and the S-DAO concentrations significantly higher (p = 0.04) in the HGF group than in the control and anti-HGF groups. The sodium-dependent glucose transporter 1 expression in the HGF group was significantly higher than in the control group and significantly suppressed in the anti-HGF group (p < 0.01). The peptide transporter 1 expression in the jejunum was higher in the HGF group than in the other groups and significantly suppressed in the anti-HGF group (p < 0.01). The GLP-2 receptor expression in the jejunum was higher in the HGF group than the other groups, and it was significantly suppressed in the anti-HGF group (p < 0.01). These jejunal results regarding nutrient transporter an GLP-2 receptor were not found in the ileum. ConclusionsThe administration of rh-HGF appears to be more effective in the jejunum than in the ileum. Type of StudyExperimental Research. Level of EvidenceN/A.

Metabolomic Alterations of Volatile Organic Compounds and Bile Acids as Biomarkers of Microbial Shifts in a Murine Model of Short Bowel Syndrome

Pediatric short bowel syndrome (SBS) is a rare condition characterized by a massive loss of the small intestine, leading to the inability to meet nutritional requirements without the use of parenteral or enteral supplementation. SBS causes profound alterations in the intestinal microbiome and metabolome. The aim of this study was a detailed assessment of the intestinal microbiome and metabolome in a murine model of SBS. We performed a 60% proximal small bowel resection versus a sham operation in C57BL/6 mice. Four weeks postoperatively, the microbial communities of different intestinal segments (jejunum, ileum, colon) and stool were assessed by 16S rRNA gene sequencing. Bile acids in serum and stool and volatile organic compounds (VOCs) in the fecal headspace were assessed using LC-MS and GC-MS techniques. The α-diversity of the different intestinal segments did not significantly differ between the two groups. β-diversity significantly differed between sham and SBS mice. While in the jejunum, Faecalibaculum was significantly increased in SBS animals, a significant reduction in Lactobacillus and Sporosarcina was detected in the ileum of SBS mice. In the colon of SBS mice, a significant decrease in Ruminococcaceae and a significant increase in Proteobacteria such as Faecalibaculum and Escherichia-Shigella were found. Serum levels of deoxycholic, taurocholic and taurochenodeoxycholic acids were significantly higher in the SBS group. Of the 29 VOCs tested, hexane, isoflurane and pentane were significantly higher in the SBS group, and pyrrole was significantly lower. We were able to show that SBS causes shifts in the murine intestinal microbiome and metabolome including serum BAs and fecal VOCs.

Potential mechanisms underlying the effect of hepatocyte growth factor on liver injury in short bowel syndrome model rats.

The purpose of this study was to investigate the autophagy associated with apoptosis in hepatic damage in the short bowel syndrome rat model. SD rats underwent jugular vein catheterization for continuous total parenteral nutrition (TPN) and 90% small bowel resection. Animals were divided into two groups: TPN plus SBS (Control group) or TPN plus SBS plus intravenous administration of HGF (HGF group). On day 7, the rats were harvested, and hepatocellular injury was evaluated. In an SBS rat model, hepatic steatosis and lobular inflammation were histologically suppressed in the HGF group (p < 0.01). The expression of tumor necrosis factor-α in the HGF group tend to be higher than that in the control group (p = 0.13). The gene expression of transforming Growth Factor-β in the HGF group was suppressed compared to the control group (p < 0.01). HGF treatment may have an antiapoptotic effect via the intrinsic pathway by caspase 9. Protein expressions of Rubicon (p = 0.03) and p62 (p < 0.01) in the HGF group were found to have increased compared to those in the control group. The inhibitory effect of HGF on hepatic steatosis remains unclear, and further studies focusing on the mechanisms of fat accumulation are needed.

SAT030 HM15912, A Novel Long-Acting GLP-2 Analog, Improves Intestinal Growth And Absorption Capacity In Rat Model Of Short Bowel Syndrome

Abstract Disclosure: J. Choi: Employee; Self; Hanmi Pharm. Co., Ltd. C. Park: Employee; Self; Hanmi Pharm. Co., Ltd. E. Park: Employee; Self; Hanmi Pharm. Co., Ltd. H. Kwon: Employee; Self; Hanmi Pharm. Co., Ltd. S. Bae: Employee; Self; Hanmi Pharm. Co., Ltd. D. Kim: Employee; Self; Hanmi Pharm. Co., Ltd. S. Lee: Employee; Self; Hanmi Pharm. Co., Ltd. I. Choi: Employee; Self; Hanmi Pharm. Co., Ltd. Short bowel syndrome (SBS) with intestinal failure requires partial or total parenteral nutrition (PN) to maintain health and growth. However, long-term use of PN may lead to life-threatening complications. Although teduglutide was firstly approved, the widespread use of it is still limited due to insufficient efficacy and leading to a significant burden for patients by daily administration. Hence, there is a medical unmet needs for more effective and longer lasting GLP-2 analog drugs. Here, we investigated the potential therapeutic effect of HM15912, which is currently under clinical development for once a month use, in small bowel resected rat model of SBS. To evaluate in vitro activity of HM15912, cAMP accumulation in CHO cells overexpressed human GLP-2 receptor (GLP-2R) was measured, and HM15912 was potently activated GLP-2R with a full agonistic activity as native human GLP-2 (EC50= 0.327 vs 0.173 nM, relative activity= 52.5%). Next, to demonstrate that GLP-2R stimulation by HM15912 results in the production and release of insulin-like growth factor-1 (IGF-1) as a known mechanism of GLP-2, HM15912 was treated to mice primary intestinal subepithelial myofibroblasts. mRNA transcription and protein secretion levels of IGF-1 was dose-dependently increased by treatment of HM15912 (p &amp;lt; 0.05 and p &amp;lt; 0.001, respectively). Longer-lasting property was evaluated in rats after single administration, and HM15912 exhibited 70-fold extended elimination half-life (42.4 h) compared to teduglutide (0.6 h). Based on this prolonged mode of action with the potent in vitro activity, intestinotrophic effect of HM15912 was investigated in 80% of small intestine (SI) resected jejuno-ileal anastomosis model rats. The SBS rats given HM15912 every week for 2 weeks significantly increased wet weight of jejunum compared to resection vehicle or b.i.d treatment of teduglutide. This result was well-correlated with histological analysis such as villus height, crypt depth, and mucosal area. In addition, HM15912 treated group was associated with a significant increase in absorption capacity of SI such as plasma D-xylose concentrations. Furthermore, the mice given HM15912 with various administration intervals for 2 weeks significantly increased SI weight compared to b.i.d treatment of teduglutide (35% over vehicle). In Q2D, Q4D and Q1W dosing intervals of HM15912, SI weights were dose-dependently increased 66∼112% (p &amp;lt; 0.001), 91∼103% (p &amp;lt; 0.001) and 55∼74% over vehicle (p &amp;lt; 0.05∼0.001), respectively. The results supported that small bowel hypertrophic effect of HM15912 are well-correlated with functional improvement of SI in short bowel condition, and superior efficacy to teduglutide was still observed even after once weekly administration in mice. Therefore, HM15912 could be a novel therapeutic option for SBS by providing remarkable small bowel tropic effect with extended administration interval. Presentation: Saturday, June 17, 2023

Altered fecal microbiome and metabolome profiles in rat models of short bowel syndrome.

Short bowel syndrome (SBS) is featured by impaired nutrients and fluids absorption due to massive small intestine resection. Gut dysbiosis has been implicated in SBS, this study aimed to characterize the metagenomic and metabolomic profiles of SBS and identify potential therapeutic targets. Fecal samples from SBS and Sham rats (n = 8 per group) were collected for high-throughput metagenomic sequencing. Fecal metabolomics was measured by untargeted liquid chromatography-mass spectrometry. We found that the species-level α-diversity significantly decreased in SBS rats, accompanied by altered microbiome compositions. The beneficial anaerobes from Firmicutes and Bacteroidetes were depleted while microorganisms from Lactobacillus, Escherichia, Enterococcus, and Streptococcus were enriched in faces from SBS rats. LEfSe analysis identified 17 microbial species and 38 KEGG modules that were remarkably distinct between SBS and Sham rats. In total, 1,577 metabolites with known chemical identity were detected from all samples, among them, 276 metabolites were down-regulated and 224 metabolites were up-regulated in SBS group. The typical signatures of SBS fecal metabolome comprised reduced short-chain fatty acids and products of amino acid metabolism (indole derivatives and p-cresol), as well as altered bile acid spectrum. We revealed 215 robust associations between representative differentially abundant microbial species and metabolites, the species with the same changing trend tended to have a similar correlation with some certain metabolites. The fecal microbiome and metabolome significantly altered in SBS. Our findings may lay the foundation for developing new strategies to facilitate intestinal adaptation in SBS patients.

Pediatric Surgery.

Journal of the American College of Surgeons ():10.1097/XCS.0000000000000629, February 13, 2023. | DOI: 10.1097/XCS.0000000000000629

A Digestive Cartridge Reduces Parenteral Nutrition Dependence and Increases Bowel Growth in a Piglet Short Bowel Model.

To determine whether the use of an immobilized lipase cartridge (ILC) to hydrolyze fats in enteral nutrition (EN) reduces parenteral nutrition (PN) dependence in a porcine model of short bowel syndrome with intestinal failure (SBS-IF). SBS-IF occurs after intestinal loss resulting in malabsorption and PN dependence. Limited therapeutic options are available for achieving enteral autonomy. Eleven Yorkshire piglets underwent 75% jejunoileal resection and were randomized into control (n=6) and treatment (n = 5) groups. PN was initiated postoperatively and reduced as EN advanced if predefined clinical criteria were fulfilled. Animals were studied for 14 days and changes in PN/EN calories were assessed. Intestinal adaptation, absorption, and nutrition were evaluated at the end of the study (day 15). Comparisons between groups were performed using analysis of covariance adjusted for baseline. ILC animals demonstrated a 19% greater reduction in PN calories ( P < 0.0001) and higher mean EN advancement (66% vs 47% of total calories, P < 0.0001) during the 14-day experiment. Treatment animals had increased intestinal length (19.5 vs 0.7%, P =0.03) and 1.9-fold higher crypt cell proliferation ( P =0.02) compared with controls. By day 15, ILC treatment resulted in higher plasma concentrations of glucagon-like peptide-2 ( P = 0.02), eicosapentaenoic acid ( P < 0.0001), docosahexaenoic acid ( P = 0.004), vitamin A ( P = 0.02), low-density lipoprotein ( P = 0.02), and high-density lipoprotein ( P = 0.04). There were no differences in liver enzymes or total bilirubin between the two groups. ILC use in conjunction with enteral feeding reduced PN dependence, improved nutrient absorption, and increased bowel growth in a porcine SBS-IF model. These results support a potential role for the ILC in clinical SBS-IF.

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 β-diversity were significantly different from Sham. The FMT altered microbiota composition and α- and β-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.

The effect of hepatocyte growth factor on intestinal adaption in an experimental model of short bowel syndrome

Nowadays, the standard therapy for patients with short bowel syndrome is parenteral nutrition (PN). Various growth factors have been tested to achieve weaning from prolonged PN administration. We evaluated the effectof hepatocyte growth factor (HGF) on structural intestinal adaptation and cell proliferation in a rat model of SBS. Thirty Sprague-Dawley rats were divided into three groups; group A rats (sham) underwent bowel transection, group B rats underwent a 75% bowel resection, and group C rats underwent the same procedure but were treated postoperatively with HGF. Histopathologic parameters of intestinal adaptation were determined, while microarray and rt-PCR analyses of ileal RNA were also performed. Treatment with HGF resulted in significant increase in body weight, while the jejunal and ileal villus height and crypt depth were increased in HGF rats (36%, p < 0.05 and 27%, p < 0.05 respectively).Enterocyte proliferation was also significantly increased in HGF rats (21% p < 0.05). Microarray and quantitative rt-PCR analyses showed that the genes hgfac, rac 1, cdc42, and akt 1 were more than twofold up-regulated after HGF treatment. HGF emerges as a growth factor that enhances intestinal adaptation. The future use of HGF may potentially reduce the requirement for PN in SBS patients.

Decreased liver damage in rat models of short bowel syndrome through DPP4 inhibition.

Total parenteral nutrition causes liver damage in patients with short bowel syndrome (SBS), in whom intestinal failure-associated liver disease (IFALD) is the strongest risk factor for mortality. We previously demonstrated the efficacy of dipeptidyl peptidase-4 inhibitors (DPP4-Is) for nutritional absorption and intestinal barrier function enhancement. Herein, we investigated the efficacy of DPP4-Is in preventing liver damage in SBS rat models. Rats were allocated to one of five groups: normal saline (NS) + sham, DPP4-I + sham, NS + SBS, DPP4-I + SBS, and GLP-2 + SBS. DPP4-I or NS was administered orally once daily. Serum aspartate aminotransferase, alanine aminotransferase (ALT), alkaline phosphatase, and total bile acid levels were measured to assess liver function. Moreover, we evaluated liver damage using the SAF (steatosis activity fibrosis) score, which is also used to assess nonalcoholic steatohepatitis. ALT levels and SAF scores were significantly lower in the DPP4-I + SBS group than in the NS + SBS group. Jejunal and ileal villus heights were significantly higher in the DPP4-I + SBS group than in the GLP-2 + SBS group. The downregulation of ALT levels and SAF scores triggered by DPP4-I use may be correlated with DPP4-I-induced adiposis inhibition in SBS and NASH models. Therefore, DPP4-I may be used to reduce IFALD in patients with SBS.

HM15912, a Novel Long-Acting Glucagon-Like Peptide-2 Analog, Improves Intestinal Growth and Absorption Capacity in a Male Rat Model of Short Bowel Syndrome.

Extensive bowel resection caused by various diseases that affect the intestines, such as Crohn's disease, volvulus, and cancer, leads to short bowel syndrome (SBS). Teduglutide is the only approved glucagon-like peptide-2 (GLP-2) drug for SBS; however, it requires daily administration. A novel GLP-2 analog with a prolonged duration of action to reduce dosing frequency and promote a greater efficacy may provide patients with a better quality of life. In the present study, the sustained exposure of HM15912 was characterized in normal male rats. The efficacy of HM15912 on intestinal growth and absorption capacity was also evaluated in normal male mice, rats, and SBS rats. HM15912 exhibited a remarkably extended half-life (42.3 hours) compared with teduglutide (0.6 hours) in rats. Despite somewhat lower in vitro potency on GLP-2 receptor than human GLP-2 or teduglutide, this longer-lasting mode of action promotes HM15912 to be more effective in terms of small intestinal growth than existing GLP-2 analogs even with a less frequent dosing interval of as little as once a week in rodents, including SBS rats. Furthermore, the small intestinal weight was approximately doubled, and the D-xylose absorption was significantly increased after pre-treatment of existing GLP-2 analogs on the market or under clinical development followed by HM15912 in rodents. These results indicate that HM15912 possesses a significant small bowel trophic effect driven by continuously increased exposure, supporting that HM15912 may be a novel treatment option with greater efficacy and the longest dosing interval among existing GLP-2 analogs for SBS with intestinal failure. SIGNIFICANCE STATEMENT: HM15912, a novel long-acting glucagon-like peptide-2 (GLP-2) analog, has a significant small bowel hypertrophic effect in rodents with a reduced frequency of administration compared to the existing GLP-2 analogs on the market or currently under clinical development. This study supports the possibility that HM15912 could be administered much less frequently than other long-acting GLP-2 analogs for patients with short bowel syndrome.

Segmental reversal of the distal small intestine in a short bowel syndrome model in piglets showed detrimental effect on weight gain

BackgroundTo investigate the effects of a reversed segment of the distal small intestine to improve weight gain in an experimental short bowel syndrome (SBS) model in piglets.MethodsTwenty-four piglets underwent resection of 70% of the distal small intestine. In half of the animals a conventional anastomosis was performed, and in the other half, the distal 25 cm of the remnant jejunum was reversed before the intestinal continuity was recreated. Weight was measured daily until day 28, where the animals were euthanized. Glucagon-Like Peptide-2 (GLP-2) and Glucose-dependent Insulinotropic Peptide (GIP) was measured pre- and postoperatively at day 28.ResultsThe group with reversal of small intestine had a significant lower weight gain at 5.26 ± 3.39 kg (mean ± SD) compared to the control group with 11.14 ± 3.83 kg (p < 0.05). In the control group greater villus height and crypt depth was found distally, and greater muscular thickness was found proximally in the intervention group. GLP-2 and GIP levels increased significantly in the control group.ConclusionsTreatment of short bowel syndrome with a reversed jejunal segment of 25 cm had a detrimental effect on the weight gain.

Outcomes and Perioperative Nutritional Management in a Porcine Model of Short Bowel Syndrome.

Short bowel syndrome (SBS) results from significant intestinal loss and is characterized by insufficient absorption of nutrients and fluids. Preclinical large animal SBS models typically require parenteral nutrition (PN) support and may not be appropriate for studying interventions to improve intestinal absorption or adaptation. Here, we describe the development of a porcine SBS model that does not require PN support. Eight male Yorkshire piglets underwent either a 75% or 90% jejunoileal resection (n=5) or no resection (n=3). Continuous enteral nutrition (EN) was provided via a gastrostomy tube. The final SBS model consisted of a 75% resection and nutrition provided via combination EN (60%) and per oral pig chow (40%). Body weight and concentration of fat-soluble vitamins were assessed on postoperative days (POD) 7, 14, and 21. For assessing fat malabsorption, the coefficient of fat absorption (CFA) was calculated following a 72-h stool collection. Resected animals had decreased weight gain compared to unresected controls (POD21+8.3% versus +28.8%, P=0.048). Vitamin D concentration was significantly lower in resected animals compared to controls on POD 7, POD 14, and POD 21. Serum vitamin E concentration was also lower on POD 21. Resected animals developed fat malabsorption with lower CFA (76.5% versus 95.3%, P=0.014). We describe the development of a porcine SBS model that does not require PN support. Piglets in this model gain less weight, demonstrate fat malabsorption, and develop fat-soluble vitamin deficiencies. This model will benefit investigations of intestinal absorption or adaptation while potentially decreasing costs and confounding complications related to PN administration.

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.

An in-line digestive cartridge increases enteral fat and vitamin absorption in a porcine model of short bowel syndrome

Short bowel syndrome (SBS) occurs after intestinal loss resulting in parenteral nutrition dependence and micronutrient deficiencies, which may lead to life-limiting complications. ALC-078 is a cartridge containing immobilized lipase that connects in-line with enteral feeding sets and digests fats in enteral nutrition (EN). In this study, we evaluate the efficacy of ALC-078 to improve fat and nutrient absorption in a porcine SBS model. Fifteen male Yorkshire piglets were assessed. Animals were randomized to no intestinal resection (n=5), 75% resection (n=5), or 75% resection+ALC-078 (n=5). After recovery, animals were treated for 14 days. Piglets received 60% of nutrition from continuous EN and 40% from chow. The degree of fat malabsorption was determined by the coefficient of fat absorption (CFA) following a 72-hstool collection. Body weight, fat-soluble vitamins, and nutritional markers were assessed. Adverse events were similar across the three groups (P=1.00). ALC-078-treated animals had similar weight gain compared to resected piglets. Resected animals had a lower CFA compared to unresected controls (79.3% vs. 95.2%, P=0.01) while there was no significant difference in the ALC-078 animals (87.1% vs. 95.2%, P=0.19). Between Study Days 1 and 15, ALC-078 animals had increased concentrations of vitamin D (12.2 vs. 8.7ng/mL, P=0.0006), and vitamin E (4.3 vs. 2.5mg/L, P=0.03). These markers did not significantly change in untreated resected animals. ALC-078 increases the absorption of fat-soluble vitamins and may improve fat malabsorption. Future studies should determine whether ALC-078 can reduce PN dependence and if these findings translate to human patients with SBS.

The preventive effect of recombinant human hepatocyte growth factor for hepatic steatosis in a rat model of short bowel syndrome

PurposeShort bowel syndrome (SBS) patients require total parenteral nutrition (TPN) following massive small bowel resection (SBR), which may cause intestinal failure-associated liver disease (IFALD), a life-threatening complication. Hepatocyte growth factor (HGF) acts as a potent hepatocyte mitogen with anti inflammatory and antioxidant actions. The present study evaluated the effect of recombinant human HGF (rh-HGF) on SBR and subsequent IFALD using a parentally fed rat model of SBS. MethodsRats underwent jugular vein catheterization for continuous TPN and 90% SBR. They were divided into 2 groups: TPN alone (SBS/TPN group: n = 7) or TPN plus the intravenous administration of rh-HGF (0.3 mg/kg/day) (SBS/TPN+HGF group: n = 7). On day 7, their tissues and stool were harvested to evaluate the effects of HGF. ResultsRegarding the histological findings, based on the nonalcoholic fatty liver disease (NAFLD) activity score, the SBS/TPN+HGF group showed significantly less hepatic steatosis and inflammatory cell infiltration than the SBS/TPN group (NAFLD activity score, 4.00 ± 1.83 vs. 1.00 ± 0.82; p < 0.01). The SBS/TPN+HGF group showed a higher expression of Farnesoid X receptor in the liver and lower expression of Toll-like receptor 4 in the ileum than the SBS/TPN group. Regarding the composition of the bacterial gut microbiota, Actinobacteria, Bacteroidetes and Proteobacteria were decreased in the SBS/TPN+HGF group compared with the SBS/TPN group. ConclusionIn our SBS with TPN rat model, rh-HGF administration had a preventive effect against hepatic steatosis and dysbiosis. rh-HGF may therefore be a potentially effective therapeutic agent for SBS and subsequent IFALD. Type of studyExperimental research.

Milk Fat Globule Membrane Alleviates Short Bowel Syndrome-Associated Liver Injury in Rats Through Inhibiting Autophagy and NLRP3 Inflammasome Activation.

BackgroundThe milk fat globule membrane (MFGM), a tri-layer membrane structure surrounding the milk fat globule, has been shown to have immune-modulating properties. This study aimed to investigate the effects of MFGM supplementation in a rat model of short bowel syndrome (SBS) associated liver disease and its possible mechanisms.Materials and MethodsTwenty one male Sprague-Dawley rats were randomly divided into three groups: Sham, SBS (underwent massive small bowel resection), and SBS+MFGM (SBS rats supplemented with 1.5 g/kg/d MFGM). Liver pathology, myeloperoxidase (MPO) staining, serum levels of aspartate aminotransferase (AST)/alanine aminotransferase (ALT), endotoxin concentration, protein expression of autophagy and nucleotide binding oligomerization domain, leucine-rich repeat and pyrin domain-containing protein 3 (NLRP3) pathway in the liver tissue were measured.ResultsBoth SBS and SBS + MFGM groups had higher serum levels of ALT and liver endotoxin levels than the Sham group (P < 0.05), with no difference detected between each other. Compared with the SBS group, the SBS+MFGM group showed lower liver pathology scores of steatosis and inflammation, less MPO positive cells and reduced expressions of NLRP3, apoptosis-associated speck-like protein containing a CARD (ASC), Caspase-1, interleukin (IL)-1β(P < 0.05) in the liver. Additionally, the expression of Beclin-1 and microtubule-associated protein1 light chain 3(LC3) B, the fluorescence intensity of NLRP3 and LC3B in the SBS + MFGM group were lower than the SBS group (P < 0.05). The LC3B expression was positively correlated with the NLRP3 level.ConclusionEnteral supplementation of MFGM help to alleviate liver injury in SBS rats, which might be related to inhibition of aberrant activation of autophagy and NLRP3 inflammasome pathways.

Intestinotrophic effect of a novel long-acting GLP-2 analog, HM15912, in animal model of short bowel syndrome and potential as monthly administration

Rationale: Teduglutide, the only approved GLP-2 drug for short bowel syndrome (SBS), may lead to significant burden due to frequent dosing with complicated reconstitution step and limited efficacy. Here, we developed a long-acting GLP-2 analog, HM15912, to provide a benefit of a less SC dosing with read-to-use, and investigated its efficacy in animal models.