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.

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.

BACKGROUND: We evaluated the effect of recombinant human hepatocyte growth factor (rh-HGF) on intestinal adaptation in a rat model of short-bowel syndrome (SBS). METHODS: Sprague-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. RESULTS: The 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. CONCLUSIONS: The administration of rh-HGF appears to be more effective in the jejunum than in the ileum. TYPE OF STUDY: Experimental Research. LEVEL OF EVIDENCE: N/A.

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.

Muscle hypertrophy and neuroplasticity in the small bowel in short bowel syndrome.

Short bowel syndrome (SBS) is a severe, life-threatening condition and one of the leading causes of intestinal failure in children. Here we were interested in changes in muscle layers and especially in the myenteric plexus of the enteric nervous system (ENS) of the small bowel in the context of intestinal adaptation. Twelve rats underwent a massive resection of the small intestine to induce SBS. Sham laparotomy without small bowel transection was performed in 10 rats. Two weeks after surgery, the remaining jejunum and ileum were harvested and studied. Samples of human small bowel were obtained from patients who underwent resection of small bowel segments due to a medical indication. Morphological changes in the muscle layers and the expression of nestin, a marker for neuronal plasticity, were studied. Following SBS, muscle tissue increases significantly in both parts of the small bowel, i.e., jejunum and ileum. The leading pathophysiological mechanism of these changes is hypertrophy. Additionally, we observed an increased nestin expression in the myenteric plexus in the remaining bowel with SBS. Our human data also showed that in patients with SBS, the proportion of stem cells in the myenteric plexus had risen by more than twofold. Our findings suggest that the ENS is tightly connected to changes in intestinal muscle layers and is critically involved in the process of intestinal adaptation to SBS.

Impact of Dietary Protein on the Management of Pediatric Short Bowel Syndrome.

Essential amino acids (AAs) play a key role in stimulating intestinal adaptation after massive small gut resection. The nutritional effect of dietary amino acids during intestinal regrowth has received considerable attention in recent years. This review explores the significance of dietary amino acids in the nutritional management of infants and children with intestinal failure and short bowel syndrome (SBS) as reported in the medical literature over the last three decades. A literature search was conducted using electronic databases. Breast milk emerged as the first-line enteral regimen recommended for infants with SBS. Hydrolyzed formulas (HFs) or amino acid formulas (AAFs) are recommended when breast milk is not available or if the infant cannot tolerate whole protein milk. The superiority of AAFs over HFs has never been demonstrated. Although glutamine (GLN) is the main fuel for enterocytes, GLN supplementation in infants with SBS showed no difference in the child's dependence upon parenteral nutrition (PN). Circulating citrulline is considered a major determinant of survival and nutritional prognosis of SBS patients. Early enteral nutrition and dietary supplementation of AAs following bowel resection in children are essential for the development of intestinal adaptation, thereby eliminating the need for PN.

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

PURPOSE: 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 effect of hepatocyte growth factor (HGF) on structural intestinal adaptation and cell proliferation in a rat model of SBS. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Dysbiosis and reduced small intestinal function are required to induce intestinal insufficiency in mice.

Extensive bowel resection can lead to short bowel syndrome and intestinal failure. Resection-induced dysbiosis may be related to the specific anatomic site of resection and influences the disease progression. Although patients with end-jejunostomy are at high risk for intestinal failure, preservation of the ileocecal valve and colon counteracts this risk. The present study investigated the role of the cecum in maintaining microbial homeostasis after different types of small bowel resection. Male C57BL6/J mice were anesthetized by intraperitoneal injection of ketamine-xylazine and received extended ileocecal resection (extended ICR), limited ileocecal resection (limited ICR), or mid-small bowel resection (SBR). Stool samples were collected before surgery and between postoperative days 2-7, for 16S rRNA gene sequencing. Only extended ICR, but neither limited ICR nor SBR, induced intestinal insufficiency. α-Diversity was reduced in both ICR variants but not after SBR. All resections resulted in an increase in Proteobacteria. Pathobionts, such as Clostridia, Shigella, and Enterococcus, increased after SBR while Muribaculaceae, Lactobacillus, and Lachnospiraceae decreased. Limited ICR resulted in an increase of members of the Clostridium sensu stricto group, Terrisporobacter and Enterococcus and a decrease of Muribaculaceae. The increase of Enterococcus was even more pronounced after extended ICR while Muribaculaceae and Akkermansia were dramatically reduced. Both ICR variants caused a decrease in steroid biosynthesis and glycosaminoglycan degradation-associated pathways, suggesting altered bile acid transformation and mucus utilization.NEW & NOTEWORTHY Resection-induced dysbiosis affects disease progression in patients with short bowel syndrome. Severe dysbiosis occurs after removal of the ileocecal valve, even in the absence of short bowel conditions, and is associated with the loss of Muribaculaceae and Akkermansia and an increase of Clostridium and Enterococcus. The preservation of the cecum should be considered in surgical therapy, and dysbiosis should be targeted based on its specific anatomical signature to improve postoperative bacterial colonization.

Bone marrow oxalosis with pancytopenia in a patient with short bowel syndrome: Report of a case and review of the literature.

Systemic oxalosis is a condition in which calcium oxalate crystals deposit into various bodily tissues. Although this may occur as the result of a rare primary syndrome in which an error of glyoxylate metabolism causes an overproduction of oxalate, it is more often seen as a secondary process characterized by increased enteric oxalate absorption. Here, we describe a patient with short bowel syndrome on long-term parenteral nutrition support who developed a unique manifestation of systemic oxalosis, leading to deposition of oxalate crystals within the bone marrow contributing to pancytopenia. In this report, in addition to reviewing the literature on this presumably rare manifestation of oxalosis, we also discuss its pathogenesis in the setting of short bowel syndrome and its management, including prevention.

Novel Therapeutic Approaches for Mitigating Complications in Short Bowel Syndrome.

Short bowel syndrome (SBS) is a particularly serious condition in which the small intestine does not absorb sufficient nutrients for biological needs, resulting in severe illness and potentially death if not treated. Given the important role of the gut in many signaling cascades throughout the body, SBS results in disruption of many pathways and imbalances in various hormones. Due to the inability to meet sufficient nutritional needs, an intravenous form of nutrition, total parental nutrition (TPN), is administered. However, TPN presents difficulties such as severe liver injury and altered signaling secondary to the continued lack of luminal contents. This manuscript aims to summarize relevant studies into the systemic effects of TPN on systems such as the gut-brain, gut-lung, and gut-liver axis, as well as present novel therapeutics currently under use or investigation as mitigation strategies for TPN induced injury.

The dual GLP-1 and GLP-2 receptor agonist dapiglutide promotes barrier function in murine short bowel.

Short bowel syndrome can occur after extensive intestinal resection, causing intestinal insufficiency or intestinal failure, which requires long-term parenteral nutrition. Glucagon-like peptide-2 (GLP-2) pharmacotherapy is now clinically used to reduce the disease burden of intestinal failure. However, many patients still cannot be weaned off from parenteral nutrition completely. The novel dual GLP-1 and GLP-2 receptor agonist dapiglutide has previously been shown to be highly effective in a preclinical murine short bowel model. Here, we studied the effects of dapiglutide on intestinal epithelial barrier function. In the jejunum, dapiglutide increased claudin-7 expression and tightened the paracellular tight junction leak pathway. At the same time, dapiglutide promoted paracellular tight junction cation size selectivity in the jejunum. This was paralleled by extension of the cation selective tight junction proteins claudin-2 and claudin-10b and preserved claudin-15 expression and localization along the crypt-villus axis in the jejunum. In the colon, no barrier effects from dapiglutide were observed. In the colon, dapiglutide attenuated the short bowel-associated, compensatorily increased epithelial sodium channel activity, likely secondary, by improved volume status. Future studies are needed to address the intestinal adaptation of the colon.

Apraglutide, a novel once-weekly glucagon-like peptide-2 analog, improves intestinal fluid and energy absorption in patients with short bowel syndrome: An open-label phase 1 and 2 metabolic balance trial.

BACKGROUND: Apraglutide is a novel long-acting glucagon-like peptide-2 (GLP-2) analog designed for once-weekly subcutaneous dosing, with the potential to increase fluid and nutrient absorption by the remnant intestine of patients who have short bowel syndrome (SBS) with intestinal insufficiency (SBS-II) or intestinal failure (SBS-IF). This trial investigated the safety and effects on intestinal absorption of apraglutide in patients with SBS-II and SBS-IF. METHODS: In this open-label, phase 1 and 2 trial, adult patients with SBS-II (n = 4) or SBS-IF (n = 4) and a fecal output of ≥1500 g/day received once-weekly subcutaneous 5 mg apraglutide for 4 weeks. Safety was the primary end point. Secondary end points included change from baseline in intestinal absorption of wet weight (indicative of fluid absorption), electrolytes, and energy (by bomb calorimetry) measured by inpatient metabolic balance studies. RESULTS: Common treatment-related adverse events were decreased gastrointestinal (GI) stoma output (n = 6), stoma complications (n = 6), GI stoma complications (n = 5), nausea (n = 5), flatulence (n = 4), abnormal GI stoma output (n = 4), polyuria (n = 3), and abdominal pain (n = 3). The only treatment-related serious adverse event (experienced in one patient) was abdominal pain. Apraglutide significantly increased wet weight and energy absorption by an adjusted mean of 741 g/day (95% CI, 194 to 1287; P = 0.015) and 1095 kJ/day (95% CI, 196 to 1994; P = 0.024), respectively. Sodium and potassium absorption significantly increased by an adjusted mean of 38 mmol/day (95% CI, 3 to 74; P = 0.039) and 18 mmol/day (95% CI, 4 to 32; P = 0.020), respectively. CONCLUSION: Once-weekly 5 mg apraglutide was well tolerated in patients with SBS-II and SBS-IF and significantly improved the absorption of fluids, electrolytes, and energy.

Fecal microbiome and bile acid metabolome in adult short bowel syndrome.

Loss of functional small bowel surface area causes short bowel syndrome (SBS), intestinal failure, and parenteral nutrition (PN) dependence. The gut adaptive response following resection may be difficult to predict, and it may take up to 2 yr to determine which patients will wean from PN. Here, we examined features of gut microbiota and bile acid (BA) metabolism in determining adaptation and ability to wean from PN. Stool and sera were collected from healthy controls and from patients with SBS (n = 52) with ileostomy, jejunostomy, ileocolonic, and jejunocolonic anastomoses fed with PN plus enteral nutrition or who were exclusively enterally fed. We undertook 16S rRNA gene sequencing, BA profiling, and 7α-hydroxy-4-cholesten-3-one (C4) quantitation with LC-MS/MS and serum amino acid analyses. Patients with SBS exhibited altered gut microbiota with reduced gut microbial diversity compared with healthy controls. We observed differences in the microbiomes of patients with SBS with ileostomy versus jejunostomy, jejunocolonic versus ileocolonic anastomoses, and PN dependence compared with those who weaned from PN. Stool and serum BA composition and C4 concentrations were also altered in patients with SBS, reflecting adaptive changes in enterohepatic BA cycling. Stools from patients who were weaned from PN were enriched in secondary BAs including deoxycholic acid and lithocholic aicd. Shifts in gut microbiota and BA metabolites may generate a favorable luminal environment in select patients with SBS, promoting the ability to wean from PN. Proadaptive microbial species and select BA may provide novel targets for patient-specific therapies for SBS.NEW & NOTEWORTHY Loss of intestinal surface area causes short bowel syndrome, intestinal failure, and parenteral nutrition dependence. We analyzed the gut microbiota and bile acid metabolome of a large cohort of short bowel syndrome adult patients with different postsurgical anatomies. We report a novel analysis of the microbiome of patients with ileostomy and jejunostomy. Enrichment of specific microbial and bile acid species may be associated with the ability to wean from parenteral nutrition.

Small and Large Intestine (II): Inflammatory Bowel Disease, Short Bowel Syndrome, and Malignant Tumors of the Digestive Tract.

The small intestine is key in the digestion and absorption of macro and micronutrients. The large intestine is essential for the absorption of water, to allow adequate defecation, and to harbor intestinal microbiota, for which their nutritional role is as important as it is unknown. This article will describe the causes and consequences of malnutrition in patients with inflammatory bowel diseases, the importance of screening and replacement of micronutrient deficits, and the main indications for enteral and parenteral nutrition in these patients. We will also discuss the causes of short bowel syndrome, a complex entity due to anatomical or functional loss of part of the small bowel, which can cause insufficient absorption of liquid, electrolytes, and nutrients and lead to complex management. Finally, we will review the causes, consequences, and management of malnutrition in patients with malignant and benign digestive tumors, including neuroendocrine tumors (present not only in the intestine but also in the pancreas).

Changes of Drug Pharmacokinetics in Patients with Short Bowel Syndrome: A Systematic Review.

BACKGROUND AND OBJECTIVES: Short bowel syndrome is a clinical condition defined by malabsorption of nutrients and micronutrients, most commonly following extensive intestinal resection. Due to a loss of absorptive surfaces, the absorption of orally administered drugs is also often affected. The purpose of this study was to systematically review the published literature and examine the effects of short bowel syndrome on drug pharmacokinetics and clinical outcomes. METHODS: Studies were identified through searches of databases MEDLINE, EMBASE, Web of Science, and SCOPUS, in addition to hand searches of studies' reference lists. Two reviewers independently assessed studies for inclusion, yielding 50 studies involving 37 different drugs in patients with short bowel syndrome. RESULTS: Evidence of decreased drug absorption was observed in 29 out of 37 drugs, 6 of which lost therapeutic effect, and 14 of which continued to demonstrate clinical benefit through drug monitoring. CONCLUSIONS: The influence of short bowel syndrome on drug absorption appears to be drug-specific and dependent on the location and extent of resection. The presence of a colon in continuity may also influence drug bioavailability as it can contribute significantly to the absorption of drugs (e.g., metoprolol); likewise, drugs that have a wide absorption window or are known to be absorbed in the colon are least likely to be malabsorbed. Individualized dosing may be necessary to achieve therapeutic efficacy, and therapeutic drug monitoring, where available, should be considered in short bowel syndrome patients, especially for drugs with narrow therapeutic indices.

The islet's bridesmaid becomes the bride: Proglucagon-derived peptides deliver transformative therapies.

The 2021 Gairdner Prize is awarded to Daniel Drucker, Joel Habener, and Jens Juul Holst for the discovery of novel peptides encoded in the proglucagon sequence and the establishment of their physiological roles. These discoveries underpinned the development of therapeutics that are now benefiting patients with type 2 diabetes and other disorders worldwide.

Liver injury after small bowel resection is prevented in obesity-resistant 129S1/SvImJ mice.

Intestinal failure-associated liver disease is a major morbidity associated with short bowel syndrome. We sought to determine if the obesity-resistant mouse strain (129S1/SvImJ) conferred protection from liver injury after small bowel resection (SBR). Using a parenteral nutrition-independent model of resection-associated liver injury, C57BL/6J and 129S1/SvImJ mice underwent a 50% proximal SBR or sham operation. At postoperative week 10, hepatic steatosis, fibrosis, and cholestasis were assessed. Hepatic and systemic inflammatory pathways were evaluated using oxidative markers and abundance of tissue macrophages. Potential mechanisms of endotoxin resistance were also explored. Serum lipid levels were elevated in all mouse lines. Hepatic triglyceride levels were no different between mouse strains, but there was an increased accumulation of free fatty acids in the C57BL/6J mice. Histological and serum markers of hepatic fibrosis, steatosis, and cholestasis were significantly elevated in resected C57BL/6J SBR mice as well as oxidative stress markers and macrophage recruitment in both the liver and visceral white fat in C57BL/6J mice compared with sham controls and the 129S1/SvImJ mouse line. Serum endotoxin levels were significantly elevated in C57BL/6J mice with significant elevation of hepatic TLR4 and reduction in PPARα expression levels. Despite high levels of serum lipids, 129S1/SvImJ mice did not develop liver inflammation, fibrosis, or cholestasis after SBR, unlike C57BL/6J mice. These data suggest that the accumulation of hepatic free fatty acids as well as increased endotoxin-driven inflammatory pathways through PPARα and TLR4 contribute to the liver injury seen in C57BL/6J mice with short bowel syndrome.NEW & NOTEWORTHY Unlike C57BL/6 mice, the 129S1/SvImJ strain is resistant to liver inflammation and injury after small bowel resection. These disparate outcomes are likely due to the accumulation of hepatic free fatty acids as well as increased endotoxin-driven inflammatory pathways through PPARα and TLR4 in C57BL/6 mice with short bowel syndrome.

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.