Mid Small Intestine Research Articles

Particle size of insoluble fibres and gelation of soluble fibres influence digesta passage rate throughout the gastrointestinal tract of finishing pigs

Fibres, as abundant in agricultural by-products, exhibit a large range of physicochemical properties that can influence digestive processes such as digesta mean retention time (MRT), thereby affecting nutrient digestion kinetics. In this study, we investigated the effects of particle size of insoluble fibres, and gelation of soluble fibres on MRT of liquids, fine solids, and fibrous particles in the different segments of the gastrointestinal tract (GIT) of pigs. Twenty-four boars (51.6 ± 4.90 kg) were allocated to four diets; two diets contained 15% wheat straw, either coarsely chopped or finely ground (1-mm screen), two diets contained 27% wheat bran without or with the addition of 10% low-methylated pectin. After 14 days of adaptation to the diet, a total collection of faeces was performed to determine the total tract digestibility of nutrients. Thereafter, pigs were fed diets supplemented with tracers for at least 5 days and dissected following a frequent feeding procedure to approach steady-state passage of digesta. The MRT of liquids (Co-EDTA), fine solids (TiO2), and fibrous particles (Chromium-mordanted fibres) in the different segments of the GIT were quantified. In the stomach, particle size reduction of straw decreased the MRT of fine solids by 02:39 h, and fibrous particles by 07:21 h (P < 0.10). Pectin addition to the wheat bran diet reduced the MRT of fine solids by 03:09 h, and fibrous particles by 07:10 h (P < 0.10), but not of liquids, resulting in less separation between digesta phases in the stomach compared with the bran diet (P < 0.05). In the mid−small intestine (SI), pectin addition reduced the MRT of fibrous particles and the separation between fibrous particles and fine solids. No further effects of particle size reduction of straw nor pectin addition on MRT and digestibility of starch, nitrogen, or fat were observed in the SI. In the large intestine (LI), particle size reduction of straw reduced separation between fibrous particles and fine solids (P < 0.10), while pectin addition had no effects. Total tract, non-starch polysaccharide degradation of straw was poor (∼31%), and unaffected by particle size reduction (P > 0.10). The complete fermentation of pectin did not influence the degradation of wheat bran fibres (∼51%). In conclusion, the effects of particle size of insoluble fibres and gelling properties of soluble fibres on the passage of digesta phases were most pronounced in the stomach, but less prominent in distal segments of the GIT.

Enhanced glucose homeostasis via Clostridium symbiosum-mediated glucagon-like peptide 1 inhibition of hepatic gluconeogenesis in mid-intestinal bypass surgery.

The small intestine is known to play a crucial role in the development and remission of diabetes mellitus (DM). However, the exact mechanism by which mid-small intestinal bypass improves glucose metabolism in diabetic rats is not fully understood. To elucidate the mechanisms by which mid-small intestinal bypass improves glucose metabolism. Streptozotocin (STZ) was used to induce DM in Sprague-Dawley (SD) rats at a dose of 60 mg/kg. The rats were then randomly divided into two groups: The mid-small intestine bypass (MSIB) group and the sham group (underwent switch laparotomy). Following a 6-wk recovery period post-surgery, the rats underwent various assessments, including metabolic parameter testing, analysis of liver glycogen levels, measurement of key gluconeogenic enzyme activity, characterization of the gut microbiota composition, evaluation of hormone levels, determination of bile acid concentrations, and assessment of the expression of the intestinal receptors Takeda G protein-coupled receptor 5 and farnesoid X receptor. The MSIB group of rats demonstrated improved glucose metabolism and lipid metabolism, along with increased hepatic glycogen content. Furthermore, there was a decrease in the expression of the key gluconeogenic enzymes phosphoenolpyruvate carboxykinase 1 and glucose-6-phosphatase. Importantly, the MSIB group exhibited a substantial increase in the abundances of intestinal Lactobacillus, Clostridium symbiosum, Ruminococcus gnavus, and Bilophila. Moreover, higher levels of secondary bile acids, such as intestinal lithocholic acid, were observed in this group. Remarkably, the changes in the gut microbiota showed a significant correlation with the expression of key gluconeogenic enzymes and glucagon-like peptide 1 (GLP-1) at 6 wk postoperatively, highlighting their potential role in glucose regulation. These findings highlight the beneficial effects of mid-small intestine bypass on glucose metabolism and the associated modulation of the gut microbiota. The findings of this study demonstrate that the introduction of postoperative intestinal Clostridium symbiosum in the mid-small intestine contributes to the enhancement of glucose metabolism in nonobese diabetic rats. This improvement is attributed to the increased inhibition of hepatic gluconeogenesis mediated by GLP-1, resulting in a favorable modulation of glucose homeostasis.

The Role of Paracellular Transport in the Intestinal Absorption and Biopharmaceutical Characterization of Minoxidil.

The purpose of this study was to evaluate mechanisms behind the intestinal permeability of minoxidil, with special emphasis on paracellular transport, and elucidate the suitability of minoxidil to be a reference drug for Biopharmaceutics Classification System (BCS). The permeability of minoxidil (vs. metoprolol) was evaluated in-silico, in-vitro using both the PAMPA assay and across Caco-2 cell monolayers, as well as in-vivo in rats throughout the entire intestine. The permeability was studied in conditions that represent the different segments of the small intestine: upper jejunum (pH 6.5), mid small intestine (pH 7.0), distal ileum (pH 7.5), and colon (pH 6.5). Since we aimed to investigate the paracellular transport of minoxidil, we have also examined its permeability in the presence of quercetin (250 µM), which closes the tight junctions, and sodium decanoate (10 mM), which opens the tight junctions. While metoprolol demonstrated segmental-dependent rat and PAMPA permeability, with higher permeability in higher pH regions, the permeability of minoxidil was pH-independent. Minoxidil PAMPA permeability was significantly lower than its rat permeability, indicating a potential significant role of the paracellular route. In rat intestinal perfusion studies, and across Caco-2 monolayers, tight junction modifiers significantly affected minoxidil permeability; while the presence of quercetin caused decreased permeability, the presence of sodium decanoate caused an increase in minoxidil permeability. In accordance with these in-vitro and in-vivo results, in-silico simulations indicated that approximatelly 15% of minoxidil dose is absorbed paracellularly, mainly in the proximal parts of the intestine. The results of this study indicate that paracellular transport plays a significant role in the intestinal permeability of minoxidil following oral administration. Since this permeation route may lead to higher variability in comparison to transcellular, these findings diminish the suitability of minoxidil to serve as the low/high BSC permeability class benchmark.

Feeding milk supplemented with Ulva sp., Ascophyllum nodosum, or Saccharina latissima to preweaning dairy calves: Effects on growth, gut microbiota, gut histomorphology, and short-chain fatty acids in digesta

Emerging knowledge shows the importance of preweaning nutrition on programming the gastrointestinal microbiome and development of the gut barrier function. The aim of this study was to assess the effects of supplementing cow milk with either intact dried Ulva sp., Ascophyllum nodosum, or Saccharina latissima on growth performance and several gut health parameters of preweaning dairy calves. Forty male Holstein calves were selected based on birth weight (41 ± 4 kg) and plasma Brix percentage (≥8.7%) at d 2 of life. From d 2 to d 42 of life, the control calves (n = 10) were fed with cow milk (8 L/d) without seaweed supplementation, and the experimental calves were fed with cow milk (8 L/d) supplemented with either Ulva sp. (n = 10), A. nodosum (n = 10), or S. latissima (n = 10) at a concentration of 50 g/8 L of cow milk per day (i.e., 5% on a dry matter basis). Calves were weighed every week, and body weight gain and calf starter intake were monitored weekly. At d 42 ± 3 of life, calves were slaughtered. The organ weights and digesta pH from the reticulorumen, mid- and end small intestine, and mid-colon were recorded. A tissue sample (5 cm) collected from the mid-small intestine was analyzed for histomorphology. Digesta from the mid-small intestine and mid-colon were analyzed for lactobacilli, Escherichia coli, and Enterobacteriaceae, and short-chain fatty acid profile. Weight gain of the calves was not affected by seaweed supplementation. Proportional organ weights were not affected by seaweed supplementation except for reticulorumen weight, which was higher in calves fed Ulva sp. Both the mid-small intestinal and mid-colonic digesta populations of lactobacilli, Enterobacteriaceae, and E. coli, as well as the mid-small intestinal histomorphology in seaweed-supplemented calves were not different from control calves. However, acetic acid proportion in mid-colonic digesta was increased in calves fed Ulva sp. and A. nodosum, whereas butyric acid proportion was decreased compared with the control calves. Digesta pH in mid- and end small intestine and mid-colon were not affected, whereas ruminal pH was increased in calves fed Ulva sp. compared with the control calves. In conclusion, intact dried seaweed supplementation did not improve the growth or selected gut health parameters (i.e., histomorphology, digesta pH, bacteria, and short-chain fatty acids) in preweaning Holstein calves.

S3453 Cavernous Hemangioma: A Rare Cause of Massive Lower Gastrointestinal Bleeding

INTRODUCTION: Hemangiomas are benign vascular tumors that rarely occur in the gastrointestinal tract. However, only 37 cases of small intestine hemangioma were reported from 2000 to 2018. Small bowel hemangiomas may cause massive lower gastrointestinal bleeding. In this report, we present a case of massive, and recurrent lower GI bleeding caused by a cavernous hemangioma of the small intestine. CASE DESCRIPTION/METHODS: A 32-year-old man came to the ER frequent episodes of large bloody bowel movements with a drop of Hb level, and he was transferred to MICU. The upper and lower endoscopy showed a large amount of blood with clots throughout the colon with no source of bleeding. A massive transfusion (of a total of 34 units) was given. Surgery and interventional radiology recommended Superior mesenteric artery arteriography, which demonstrated brisk bleeding from a jejunal branch overlying the left upper quadrant. Embolization of the bleeding jejunal branch was performed. A few days after, the patient developed other episodes of rectal bleeding. Capsule endoscopy revealed active small bowel bleeding, originating most likely from the proximal and mid-small intestine. Small intestine resection was performed, and the specimen analysis showed a cavernous hemangioma, measuring 1.2 × 1 × 0.8 cm. DISCUSSION: Hemangiomas are benign vascular neoplasms that can appear anywhere in the body, including the GIT, and it is considered as 0.05% of all gastrointestinal tumors. The jejunum is the most common site of occurrence. Hemangiomas may be solitary or multiple. Multiple hemangiomas are usually associated with the presence of similar lesions in other organs, such as liver and skin. Hemangiomas of GIT typically originate from the submucosal vascular plexus and extend from the submucosa to the muscular layer of the intestinal wall and they may extend beyond the serosa, involving the mesenteric, retroperitoneal, or pelvic fat. Histologically, hemangiomas classified into capillary, cavernous, and mixed. Initial investigations usually include upper and lower endoscopy. However, in most cases, these investigations are normal. CT angiography, MRI, radionuclide imaging, selective angiography, double-balloon enteroscopy, and capsule endoscopy could be used to identify the lesion. Surgical resection has conventionally been used for the treatment of intestinal hemangiomas. In recent years, less invasive therapeutic interventions, such as non-surgical endoscopic treatment and minimally invasive laparoscopic surgery, have become more common.

Differential action of TGR5 agonists on GLP-2 secretion and promotion of intestinal adaptation in a piglet short bowel model.

Enteroendocrine L cells and glucagon-like peptide 2 (GLP-2) secretion are activated in the intestinal adaptation process following bowel resection in patients with short bowel syndrome. We hypothesized that enteral activation of Takeda G protein-coupled receptor 5 (TGR5), expressed in enteroendocrine L cells, could augment endogenous GLP-2 secretion and the intestinal adaptation response. Our aim was to assess the efficacy of different TGR5 agonists to stimulate GLP-2 secretion and intestinal adaptation in a piglet short-bowel model. In study 1, parenterally fed neonatal pigs (n = 6/group) were gavaged with vehicle, olive extract (OE; 10 or 50 mg/kg), or ursolic acid (UA; 10 mg/kg), and plasma GLP-2 was measured for 6 h. In study 2, neonatal pigs (n = 6-8/group) were subjected to transection or 80% mid-small intestine resection and, after 2 days, assigned to treatments for 10 days as follows: 1) transection + vehicle (sham), 2) resection + vehicle (SBS), 3) resection + 30 mg UA (SBS + UA), and 4) resection + 180 mg/kg OE (SBS + OE). We measured plasma GLP-2, intestinal histology, cell proliferation, and gene expression, as well as whole body citrulline-arginine kinetics and bile acid profiles. In study 1, GLP-2 secretion was increased by UA and tended to be increased by OE. In study 2, SBS alone, but not additional treatment with either TGR5 agonist, resulted in increased mucosal thickness and crypt cell proliferation in remnant jejunum and ileum sections. SBS increased biliary and ileal concentration of bile acids and expression of inflammatory and farnesoid X receptor target genes, but these measures were suppressed by UA treatment. In conclusion, UA is an effective oral GLP-2 secretagogue in parenterally fed pigs but is not capable of augmenting GLP-2 secretion or the intestinal adaptation response after massive small bowel resection. NEW & NOTEWORTHY Therapeutic activation of endogenous glucagon-like peptide 2 (GLP-2) secretion is a promising strategy to improve intestinal adaptation in patients with short bowel syndrome. This study in neonatal pigs showed that oral supplementation with a selective Takeda G protein-coupled receptor 5 (TGR5) agonist is an effective approach to increase GLP-2 secretion. The results warrant further study to establish a more potent oral TGR5 agonist that can effectively improve intestinal adaptation in pediatric patients with SBS.

Portal Hypertensive Polypoid Enteropathy Without Overt Endoscopic Features of Portal Hypertension: A Case Report

Introduction: Portal hypertensive polypoid enteropathy is an under recognized complication of portal hypertension. It is a rare manifestation of portal hypertensive enteropathy (PHE), polypoid lesions are seen in about 0.3% cases in the small intestine. Endoscopic findings of portal hypertension may or may not be present. Case description: A 60 year-old female with a history of liver cirrhosis from NAFLD and chronic GI bleeding was referred for evaluation of transfusion-dependent anemia requiring IV iron and packed red blood cells. Encephalopathy was her only known complication from cirrhosis. Previous work-up revealed a polypoid lesion in the duodenum which was removed (histology: chronic active duodenitis with ulceration, polypoid inflamed granulation tissue). EGD did not show varices, GAVE, or portal hypertensive gastropathy. She also had a history of large internal hemorrhoids and diverticulosis which were previously treated. Despite management of suspected lesions, anemia persisted with hem occult positive stools. VCE was performed using PillCam system which showed a 6-8mm villous polyp with surface erosion without bleeding in the proximal duodenum. Clusters of erythema and red villi were noted in small intestine which did not appear to be discrete angiodysplasias. At mid-small intestine (57% transit) 1cm sessile polypoid lesion with active bleeding was noted that appeared to be an inflammatory polyp or granulation tissue. Upper DBE showed small bowel findings consistent with portal enteropathy without discrete AVM (Figure 1). Small inflammatory polyps were removed from duodenum. Histopathology showed benign inflammatory polyp c/w portal enteropathy. Lower DBE revealed a 1 cm sessile polyp in mid- ileum (40 cm upstream of colon) which matched the lesion seen on VCE. Polyp was removed with hot snare. Histopathology of the polypoid specimen showed numerous ectatic vessels and ulcerations (Figure 2, 3). The findings were suggestive of polypoid portal hypertensive enteropathy.Figure: Upper DBE showed small bowel findings consistent with portal enteropathy without discrete AVM.Figure: Histopathology of the polypoid specimen showed numerous ectatic vessels and ulcerations.Figure: Histopathology of the polypoid specimen showed numerous ectatic vessels and ulcerations.Discussion: Introduction of VCE and deep enteroscopy has enabled us to perform diagnostic and therapeutic evaluation of small bowel in PHE. Portal hypertensive polypoid enteropathy should be kept high in the differential in patient s with liver cirrhosis presenting with occult GI blood loss. Management of PHE is yet to be standardized, individualized approach should be sought.

Segmental-dependent permeability throughout the small intestine following oral drug administration: Single-pass vs. Doluisio approach to in-situ rat perfusion

Intestinal drug permeability is position dependent and pertains to a specific point along the intestinal membrane, and the resulted segmental-dependent permeability phenomenon has been recognized as a critical factor in the overall absorption of drug following oral administration. The aim of this research was to compare segmental-dependent permeability data obtained from two different rat intestinal perfusion approaches: the single-pass intestinal perfusion (SPIP) model and the closed-loop (Doluisio) rat perfusion method. The rat intestinal permeability of 12 model drugs with different permeability characteristics (low, moderate, and high, as well as passively and actively absorbed) was assessed in three small intestinal regions: the upper jejunum, mid-small intestine, and the terminal ileum, using both the SPIP and the Doluisio experimental methods. Excellent correlation was evident between the two approaches, especially in the upper jejunum (R2=0.95). Significant regional-dependent permeability was found in half of drugs studied, illustrating the importance and relevance of segmental-dependent intestinal permeability. Despite the differences between the two methods, highly comparable results were obtained by both methods, especially in the medium-high Peff range. In conclusion, the SPIP and the Doluisio method are both equally useful in obtaining crucial segmental-dependent intestinal permeability data.

Emu Oil Combined with Lyprinol™ Reduces Small Intestinal Damage in a Rat Model of Chemotherapy-Induced Mucositis

ABSTRACTChemotherapy-induced mucositis is characterized by inflammation and ulcerating lesions lining the alimentary tract. Emu Oil and Lyprinol™ have independently demonstrated their therapeutic potential in intestinal inflammatory disorders, including mucositis. We investigated Emu Oil and Lyprinol™ in combination for their further potential to alleviate chemotherapy-induced mucositis in rats. Rats were gavaged with (1 ml) water, Olive Oil, Emu Oil + Olive Oil, Lyprinol™ + Olive Oil or Emu Oil + Lyprinol™ from Days 0 to 7, injected with saline (control) or 5-Fluorouracil (5-FU) on Day 5 and euthanized on Day 8. Myeloperoxidase (MPO) activity (indicative of acute inflammation), histological severity scores, and intestinal architecture were quantified. Myeloperoxidase activity was significantly increased in the jejunum and ileum following 5-FU, compared to saline controls. Both Olive Oil and Emu Oil + Lyprinol™ significantly reduced jejunal MPO levels (1.8-fold and 1.7-fold, respectively), whereas only Emu Oil + Lyprinol™ significantly decreased ileal MPO levels, relative to 5-FU controls. All oil treatments decreased histological severity scores in the jejunum and ileum, and normalized crypt depth in the mid small intestine, relative to 5-FU controls. Emu Oil combined with Lyprinol™ partially reduced acute small intestinal inflammation. Isolating bioactive constituents of these naturally sourced oils could provide a more targeted strategy to protect against intestinal mucositis.

A Quantitative Review and Meta-Models of the Variability and Factors Affecting Oral Drug Absorption-Part I: Gastrointestinal pH.

This study aimed to conduct a quantitative meta-analysis for the values of, and variability in, gastrointestinal (GI) pH in the different GI segments; characterize the effect of food on the values and variability in these parameters; and present quantitative meta-models of distributions of GI pH to help inform models of oral drug absorption. The literature was systemically reviewed for the values of, and the variability in, GI pH under fed and fasted conditions. The GI tract was categorized into the following 10 distinct regions: stomach (proximal, mid-distal), duodenum (proximal, mid-distal), jejunum and ileum (proximal, mid, and distal small intestine), and colon (ascending, transverse, and descending colon). Meta-analysis used the "metafor" package of the R language. The time course of postprandial stomach pH was modeled using NONMEM. Food significantly influenced the estimated meta-mean stomach and duodenal pH but had no significant influence on small intestinal and colonic pH. The time course of postprandial pH was described using an exponential model. Increased meal caloric content increased the extent and duration of postprandial gastric pH buffering. The different parts of the small intestine had significantly different pH. Colonic pH was significantly different for descending but not for ascending and transverse colon. Knowledge of GI pH is important for the formulationdesign of thepH-dependent dosage forms and in understanding the dissolution and absorption of orally administered drugs. The meta-models of GI pH may also be used as part of semi-physiological pharmacokinetic models to characterize the effect of GI pH on the in vivo drug release and pharmacokinetics.

Fabrication of controlled-release budesonide tablets via desktop (FDM) 3D printing

The aim of this work was to explore the feasibility of using fused deposition modelling (FDM) 3D printing (3DP) technology with hot melt extrusion (HME) and fluid bed coating to fabricate modified-release budesonide dosage forms. Budesonide was sucessfully loaded into polyvinyl alcohol filaments using HME. The filaments were engineered into capsule-shaped tablets (caplets) containing 9mg budesonide using a FDM 3D printer; the caplets were then overcoated with a layer of enteric polymer. The final printed formulation was tested in a dynamic dissolution bicarbonate buffer system, and two commercial budesonide products, Cortiment® (Uceris®) and Entocort®, were also investigated for comparison. Budesonide release from the Entocort® formulation was rapid in conditions of the upper small intestine while release from the Cortiment® product was more delayed and very slow. In contrast, the new 3D printed caplet formulation started to release in the mid-small intestine but release then continued in a sustained manner throughout the distal intestine and colon. This work has demonstrated the potential of combining FDM 3DP with established pharmaceutical processes, including HME and film coating, to fabricate modified release oral dosage forms.

Characterizing Tissue Enzyme Activities in the American Alligator (Alligator mississippiensis)

American alligators, Alligator mississippiensis, are one of 23 crocodilian species in the world, and they are common in the southeastern United States. Biochemical enzyme blood reference values have been established for the American alligator and several other crocodilians, but the tissue of origin of these enzymes has not been established. This study evaluated tissue specificity of six different enzymes in the American alligator, including alkaline phosphatase (ALP), alanine aminotransferase (ALT), aspartate aminotransferase (AST), lactate dehydrogenase (LDH), creatine kinase (CK), and gamma-glutamyl transferase (GGT). Six different tissues (liver, cardiac muscle, lung, kidney, skeletal muscle, and mid–small intestine) were collected from six subadult American alligators for enzyme analysis. The results showed that the CK and LDH enzymes were primarily derived from skeletal and cardiac muscle; ALT was derived primarily from kidney and skeletal muscle tissue; and AST was derived primarily from liver and skeletal muscle tissue. GGT and ALP appear to be of little diagnostic value regarding the tissues sampled because there was no statistical difference between the tissue levels. The results of this study should be of use to clinicians when interpreting biochemistry enzyme levels from blood samples.

Influence of ageing on the gastrointestinal environment of the rat and its implications for drug delivery

Age-mediated changes in gut physiology are considerations central to the elucidation of drug performance from oral formulations. Using rats of different age groups we measured the pH, buffer capacity, fluid volume, osmolality, and surface tension of gastrointestinal (GI) fluids, and therein explored the impact of these variables on prednisolone and mesalazine solubility in luminal fluids. We also studied the distribution of gut associated lymphoid tissue (GALT) and mucus layer thickness across the GI tract in rats of different age groups. At a mucosal level, there was an increase in GALT from young to adult rat. Gastrointestinal pH and buffer capacity remained mostly unchanged with age, except some pH differences in stomach and distal small intestine and a higher buffer capacity in the large intestinal fluids of young rats. Osmolality and surface tension also remained unaffected with the exception of a lower osmolality in elderly stomach and a lower surface tension in the small intestine of young rats. The difference in luminal environment on ageing influenced the solubility of studied drugs, for instance prednisolone solubility was shown to be higher in adult rats (mid small intestine and caecum) and solubility of mesalazine was significantly higher in the elderly distal small intestine.

Transmesosigmoid hernia with small bowel strangulation

Introduction: Internal herniation of the small bowel is difficult to diagnose before surgery. Delayed laparotomy is related to high morbidity and mortality. We present a rare case of a transmesosigmoid hernia to demonstrate the importance of high suspicion and early laparotomy. Case Report: A 44­year­old female patient had severe abdominal pain of acute onset. A CT scan at six hours after onset of the symptom showed a dilated small bowel loop of diminished attenuation. Her severe pain was not controlled even with narcotics. An emergency laparotomy eight hours after onset revealed about a 150 cm strangulated closed loop of the mid small intestine, herniated through a small mesenteric defect of the sigmoid colon. The defect in the mesosigmoid was about three cm in diameter without a sac, and functioned similarly to a napkin ring; therefore the reduction of the herniated closed intestine loop was difficult without division of the intestine. The patient recovered well after resection anastomosis and closure of the mesenteric defect. Conclusion: Congenital internal hernia is rare, but early development of incarceration and strangulation is associated with increased morbidity and mortality. Early

Surgical treatment and outcomes of severe pediatric intestinal motility disorders requiring parenteral nutrition

AimThe aim of this study was to characterize outcomes of children with severe intestinal motility disorders (IMD) requiring parenteral nutrition (PN). MethodsTwenty consecutive children with primary IMD requiring long-term PN between 1984 and 2010 were included. Median (interquartile range) follow-up was 13.1 (5.2–20.1) years. Treatment, PN dependence, growth, nutritional status, liver function, and survival were assessed. ResultsUnderlying etiology included chronic intestinal pseudo obstruction (CIPO; n=8) and Hirschsprung disease with extensive aganglionosis (n=12). CIPO and aganglionosis patients had 100 (86–100%) and 29 (19–40%) of age-adjusted small bowel length remaining, respectively. In order to facilitate enteral tolerance and avoid PN-associated liver disease, short aganglionic segment (40cm) was left in situ in four of five cases, with aganglionosis extending to duodenojejunal flexure combined with Ziegler myectomy–myotomy in two. Six of seven children with aganglionosis extending into mid small intestine underwent staged jejunoanal pull-through. Feeding/venting gastrostomies (n=13) or jejunostomies were commonly employed. Probability of PN dependence owing to IMD was markedly increased in relation to short bowel syndrome (70 versus 19% at 5years, P<0.0001). Two (10%) patients developed end-stage liver disease. A total of 11 (55%) patients (5 CIPO and 6 aganglionosis) weaned off PN after 8.2years (1.8–17years), including two patients after intestinal transplantation (ITx). Two children died before ITx-era giving overall survival of 90%. Survivors had well-preserved liver function, growth, and nutritional status. ConclusionsDespite high PN dependence, long-term survival is achievable in the majority of children with IMD requiring PN. A wide repertory of surgical options including ITx is required for optimal outcomes.

Regional gastrointestinal delivery of remogliflozin etabonate in humans

Remogliflozin etabonate (RE) is the prodrug of remogliflozin (R), an inhibitor of renal glucose transport designed to reduce blood glucose concentrations for the treatment of type 2 diabetes. This open-label, randomized, single-dose, four-way crossover study, (with one add-on arm) in eight healthy men evaluated the regional gastrointestinal absorption of RE, the systemic appearance of the active entity R, and an active metabolite, GSK279782. The InteliSite(®) Companion Capsule was used to administer a single dose of RE 100 mg to the mid-small intestine or cecum/colon. Oral administration of the IR tablet of RE showed similar bioavailability of R compared with small intestine delivery with both suspension and solution. The lowest bioavailability of remogliflozin was found with large intestine delivery and therefore not a suitable region for prodrug delivery. Although both lower permeability and decreased ester hydrolysis of remogliflozin etabonate in the colon can explain reduced plasma exposures of remogliflozin, the data suggest relatively limited remogliflozin etabonate hydrolysis in the colon and provides evidence for a diminishing gradient of esterase activity from small to large intestine.

Development of an ex vivo model for investigating the bacterial association to the gut epithelium of pigs

To study enterotoxigenic Escherichia coli (ETEC) association to the gut of pigs, a simple and reproducible experimental model would be helpful. The aim of this experiment was to establish a model for studying the association of ETEC to the gut epithelium of pigs. Intestinal segments were prepared from 4 weaned pigs, which were tested susceptible to E. coli O149:F4 (homo- and heterozygotic; 2 pigs each) and O138:F18 (all homozygotic). Five segments were taken from 50% of the intestinal length measured from duodenum [mid small intestine (SI)], and 5 segments were taken from 90% distal to the duodenum (distal SI). The segments were immersed in Dulbecco's Modified Eagle Medium (DMEM) and kept on ice. Polyethylene tubing was inserted into either end of the segment and tied. The tissue was washed with 50 mL of PBS. The other end of segment was tied, 10 mL of DMEM alone or DMEM containing either E. coli F4 or F18 was inoculated, and the segment was sealed with Teflon plug. The segment was immersed in DMEM in a 300-mL infusion bottle in a shaking water bath at 37°C. After 1 h the segment was removed, tissue was washed with 50 mL of PBS, weighed, and homogenized in PBS. Final dilution of 10(-6) was prepared from the content and homogenate. The E. coli was enumerated on MacConkey agar. Data were analyzed according to a 2 × 3 × 2 parametric model including the effects of intestinal segment, E. coli strain, and site of SI with GLM procedure in SAS. A t-test was used to analyze the effect of genotype in F4-inoculated segment. The binding of E. coli on the tissue was 10 times higher (P < 0.001) for F4 than F18. The E. coli F18 was highest (P < 0.05) in mid SI whereas differences were not observed (P > 0.05) between sites of SI for F4. Fewer (P < 0.001) bacteria bound in the control and they associated more (P = 0.10) at distal than mid SI. The E. coli did not differ (P > 0.05) between genotypes in F4-inoculated segment. In conclusion, the ex vivo model may be feasible to investigate the ETEC association to the gut epithelium of pigs.

Effect of trypsin inhibitor activity in soya bean on growth performance, protein digestibility and incidence of sub-clinical necrotic enteritis in broiler chicken flocks

1. The effect of three different levels of dietary trypsin inhibitor activity (achieved by varying the amount of non-toasted full fat soya bean in replacement for toasted full fat soya bean) on the incidence of spontaneously-occurring sub-clinical necrotic enteritis (NE) in broiler chickens was compared. A fourth dietary treatment compared the effect of a diet that used potato protein concentrate as the major protein source. The determined trypsin inhibitor activity increased with the increasing content of non-toasted soya bean: 1·90, 6·21, 8·46 and 3·72 mg/g for the three soya bean diets (0, 100 and 200 g of non-toasted soya bean/kg) and the potato protein diet respectively. 2. Although increasing amounts of the non-toasted full-fat soya bean increased the feed intakes of the birds, there was a marked reduction in protein digestibility, weight gain and feed conversion efficiency. 3. There was a linear increase in sub-clinical NE lesions in the duodenum, jejunum, mid small intestine and ileum with increasing non-toasted soya bean. Caecal Clostridium perfringens counts increased with the increasing dietary content of non-toasted soya bean. Serum α-toxin antibodies were higher in the birds fed the 200 g non-toasted soya bean/kg diet compared with the other diets. 4. The results demonstrated that variation in the amount of non-toasted dietary soya bean not only affects growth performance of broilers but also affects the incidence of sub-clinical necrotic enteritis in the flock. Ensuring the lowest possible trypsin-inhibitor activity in soya bean samples is a valuable tool to improve the health and welfare of birds and in reducing the financial losses from this disease.

Evidence that the secretory response of rat intestine to 5-hydroxytryptamine in-vivo involves more than one 5-hydroxytryptamine-receptor subtype.

The transintestinal potential difference (PD) across rat mid-small intestine and proximal colon was measured in-vivo. The 5-hydroxytryptamine (5-HT)-induced increase in PD, which reflects a stimulation of electrogenic C1 secretion, was mimicked by both 2-methyl-5-hydroxytryptamine (2-CH3-5-HT), an agonist at 5-HT3 receptors, and 5-methoxytryptamine (5-MT), an agonist that lacks affinity for 5-HT3 receptors. The 5-HT3 antagonist granisetron caused a marked inhibition of the response to 2-CH3-5-HT in both regions, but only produced a small inhibition of the small intestinal response to 5-HT, with a more pronounced effect in the colon. The failure of granisetron to produce a marked antagonism of the 5-HT-induced rise in the transintestinal PD, coupled with the ability of 5-MT to induce a secretory response, indicates that 5-HT3 receptors are not the only ones involved in the stimulation of C1 secretion. The 5-HT2 antagonist ketanserin failed to influence the response to 5-HT in either the small intestine or the colon, but it did inhibit the action of 5-MT, having a much greater effect in the small intestine. In the presence of granisetron however, ketanserin also inhibited the small intestinal response to 5-HT, having only a minimal effect in the colon. This suggests that 5-HT2 receptors can also play a role in the activation of C1 secretion. These observations suggest that both 5-HT2 and 5-HT3 receptors contribute to the stimulation of electrogenic C1 secretion by 5-HT, with 5-HT2 receptors playing a more prominent role in the small intestine and 5-HT3 receptors being more important in the colon.

High-Permeability Criterion for BCS Classification: Segmental/pH Dependent Permeability Considerations

The FDA classifies a drug substance as high-permeability when the fraction of dose absorbed (F(abs)) in humans is 90% or higher. This direct correlation between human permeability and F(abs) has been recently controversial, since the β-blocker sotalol showed high F(abs) (90%) and low Caco-2 permeability. The purpose of this study was to investigate the scientific basis for this disparity between permeability and F(abs). The effective permeabilities (P(eff)) of sotalol and metoprolol, a FDA standard for the low/high P(eff) class boundary, were investigated in the rat perfusion model, in three different intestinal segments with pHs corresponding to the physiological pH in each region: (1) proximal jejunum, pH 6.5; (2) mid small intestine, pH 7.0; and (3) distal ileum, pH 7.5. Both metoprolol and sotalol showed pH-dependent permeability, with higher P(eff) at higher pH. At any given pH, sotalol showed lower permeability than metoprolol; however, the permeability of sotalol determined at pH 7.5 exceeded/matched metoprolol's at pH 6.5 and 7.0, respectively. Physicochemical analysis based on ionization, pK(a) and partitioning of these drugs predicted the same trend and clarified the mechanism behind these observed results. Experimental octanol-buffer partitioning experiments confirmed the theoretical curves. An oral dose of metoprolol has been reported to be completely absorbed in the upper small intestine; it follows, hence, that metoprolol's P(eff) value at pH 7.5 is not likely physiologically relevant for an immediate release dosage form, and the permeability at pH 6.5 represents the actual relevant value for the low/high permeability class boundary. Although sotalol's permeability is low at pH 6.5 and 7.0, at pH 7.5 it exceeds/matches the threshold of metoprolol at pH 6.5 and 7.0, most likely responsible for its high F(abs). In conclusion, we have shown that, in fact, there is no discrepancy between P(eff) and F(abs) in sotalol's absorption; the data emphasize that, if a compound has high fraction of dose absorbed, it will have high-permeability, not necessarily in the jejunum, but at some point along the relevant intestinal regions.