Lumen Of Gastrointestinal Tract Research Articles

Manganese transporter SLC30A10 and iron transporters SLC40A1 and SLC11A2 impact dietary manganese absorption.

SLC30A10 deficiency is a disease of severe manganese excess attributed to loss of SLC30A10-dependent manganese excretion via the gastrointestinal tract. Patients develop dystonia, cirrhosis, and polycythemia. They are treated with chelators but also respond to oral iron, suggesting that iron can outcompete manganese for absorption in this disease. Here we explore the latter observation. Intriguingly, manganese absorption is increased in Slc30a10-deficient mice despite manganese excess. Studies of multiple mouse models indicate that increased dietary manganese absorption reflects two processes: loss of manganese export from enterocytes into the gastrointestinal tract lumen by SLC30A10, and increased absorption of dietary manganese by iron transporters SLC11A2 (DMT1) and SLC40A1 (ferroportin). Our work demonstrates that aberrant absorption contributes prominently to SLC30A10 deficiency and expands our understanding of biological interactions between iron and manganese. Based on these results, we propose a reconsideration of the role of iron transporters in manganese homeostasis is warranted.

The kinetics of amino acid disappearance in the small intestine is related to the extent of amino acids absorbed in growing pigs.

This study evaluated the importance of a correction for amino acids (AA) released into the hindgut on a measure of AA absorption kinetics and tested whether AA absorption kinetics are related to the extent of AA absorption using the growing pig as a model for humans. Thirty-six nine-week-old pigs (22·3 kg) received a diet containing whey protein as the sole protein source for 8 d. Pigs received their last meal containing the indigestible marker titanium dioxide before being euthanised at 1, 2, 3, 4, 6 and 12 h post-feeding. The entire content of each gastrointestinal tract (GIT) region was collected to determine AA released into the hindgut, and the kinetics and extent of AA absorption (uncorrected and corrected for AA entering the hindgut). Amounts of AA released into the hindgut increased over time (e.g. 33 and 180 mg of Glu for 4 and 6 h post-feeding). The corrected apparent amount of each AA absorbed from the GIT lumen after 4 h post-feeding was generally lower (P ≤ 0·05) than the uncorrected counterpart. Differences in both the kinetics and extent of AA absorption were observed across AA. For example, the time to reach half of the apparent AA absorption (T50) was 1·5 and 3·4 h for Met and Arg, respectively, whereas their extent of apparent absorption was 93 and 73 %. Negative correlations between parameters related to kinetics and the extent of apparent absorption were observed (e.g. for T50 r = -0·81; P < 0·001). The kinetics of AA absorption is related to the extent of AA absorption.

Do extreme postprandial levels of oxygen, carbon dioxide, and ammonia in the digestive tract equilibrate with the bloodstream in the freshwater rainbow trout (Oncorhynchus mykiss)?

The gastrointestinal tract (GIT) lumen of teleosts harbors extreme conditions, especially after feeding: high PCO2 (20-115Torr), total ammonia (415-3710μM), PNH3 (79-1760μTorr in the intestine), and virtual anoxia (PO2 < 1Torr). These levels could be dangerous if they were to equilibrate with the bloodstream. Thus, we investigated the potential equilibration of O2, CO2, and ammonia across the GIT epithelia in freshwater rainbow trout by monitoring postprandial arterial and venous blood gases in vivo and in situ. In vivo blood was sampled from the indwelling catheters in the dorsal aorta (DA) and subintestinal vein (SIV) draining the posterior intestine in the fasting state and at 4 to 48h following catheter-feeding. To investigate possible ammonia absorption in the anterior part of the GIT, blood was sampled from the DA, SIV and hepatic portal vein (HPV) from anaesthetized fish in situ following voluntary feeding. We found minimal equilibration of all three gases between the GIT lumen and the SIV blood, with the latter maintaining pre-feeding levels (PO2 = 25-49Torr, PCO2 = 6-8Torr, and total ammonia = 117-134μM and PNH3 = 13-30μTorr at 48h post-feeding). In contrast to the SIV, we found that the HPV total ammonia more than doubled 24h after feeding (128 to 297μM), indicative of absorption in the anterior GIT. Overall, the GIT epithelia of trout, although specialized for absorption, prevent dangerous levels of PO2, PCO2 and ammonia from equilibrating with the blood circulation.

Spectrum of Colorectal Polyps in Southern India: A Twin Centre Ambispective Study

Introduction: Intestinal polyps are grossly visible tumours which protrude (into lumen of gastrointestinal tract). Majority of the polyps are benign in the paediatric age group. However in adults, they may be harbingers of more serious genetic, familial or developmental disorders and some of them may be premalignant. Aim: Our aim was to study the distribution, histological varieties of colorectal polyps and to examine dysplasia in adenomatous polyps and its determinants. Materials and Methods: This is a four years retrospective and one year prospective study from June 2017 to May 2022 conducted at Upgraded Department of pathology, Osmania General Hospital and a tertiary care centre, Shadan institute of medical sciences, Hyderabad. A total of 110 cases of polyps were studied which included 62 cases in adults and 48 cases in children (0-12 years). Predictors of dysplasia in adenomatous polyps were studied. Results were analysed using PSPP software. Results: There were 62.73% (69) males and 37.27% (41) females. The commonest clinical presentation was bleeding from rectum 64.54% (71) cases. Rectosigmoid was the commonest site in 83.64% (92) cases. Juvenile polyps were the commonest in children and constituted 89.58% (43 cases). In adults, there were 63.07% (41) adenomatous polyps. A statistically significant association has been observed between high grade dysplasia and size (p-value 0.015) and villous architecture (p-value 0.02). There was no statistically significant association with site (p-value 0.2). Conclusion: A rising incidence of Colorectal Cancer (CRC) has necessitated identification of preneoplastic Adenomatous polyps which may progress to carcinoma via the Adenomacarcinoma sequence. Polyps occurring as part of polyposis syndromes have increased neoplastic potential. Their detection and treatment carries significant implications both for the patients and their families. In India, there is a need for screening colonoscopy in asymptomatic individuals which can be a potential cancer prevention tool.

Extrusion of Port Catheter Fixation Coil into Gastrointestinal Tract Lumen for Intra-arterial Chemotherapy: A Case Report

For patients with hepatocellular carcinoma, intra-arterial chemotherapy can be applied as an alternative treatment if there is concern about the occurrence of hepatic failure during transcatheter arterial chemoembolization (TACE) due to main portal vein thrombosis or if the patient does not respond to TACE. Various complications due to the port system for intra-arterial chemotherapy have been reported so far, but no case has been reported in which a coil for port catheter fixation was extruded into the gastrointestinal tract lumen. We report a case of a patient who developed persistent gastrointestinal bleeding after a coil for port catheter fixation was extruded into the gastrointestinal tract lumen.

Tropism of Severe Acute Respiratory Syndrome Coronavirus 2 for Barrett’s Esophagus May Increase Susceptibility to Developing Coronavirus Disease 2019

Tropism of Severe Acute Respiratory Syndrome Coronavirus 2 for Barrett’s Esophagus May Increase Susceptibility to Developing Coronavirus Disease 2019

Endoscopic Biopsies and Histopathological Findings in Diagnosing Chronic Gastrointestinal Disorders in Dogs and Cats.

Nowadays, endoscopic examination is a diagnostic tool gaining popularity in the management of gastrointestinal disorders in dogs and cats. Direct accessibility of the lumen of gastrointestinal tract combined with the mucosal biopsy provides a great diagnostic potential. Using endoscopy and endoscopically guided biopsy, one can conduct both macro- and microscopic assessment of lesions and perform many specialist adjunct examinations. Histopathological examination of mucosal biopsy specimens collected from the stomach and intestines allows us to distinguish between types of inflammations and to diagnose ulcerative, polypoid, and cancerous lesions.

Colonic inflammatory fibroid polyp: A differential for gastrointestinal stromal tumour

Inflammatory fibroid polyp (IFP) presents as a polypoidal finding protruding into the gastrointestinal tract lumen. On the basis of HPE study IFP is differential for GIST. The line of management changes on the basis of IHC report. IFP at colonic location found rarely.

2612 Gastrointestinal Stromal Tumor Causing Obscure Gastrointestinal Bleeding: An Uncommon Way of Diagnosing an Uncommon Disease

INTRODUCTION: Gastrointestinal stromal tumors (GISTs) are neoplasms which arise from the tissue of the gastrointestinal tract or, rarely, from other intra-abdominal tissues. CT angiography can be utilized as an alternative imaging study when endoscopic and colonoscopy results are non-diagnostic. We report a case of a 59 year-old-female who presented with recurrent episodes of obscure overt gastrointestinal bleeding and was found to have a GIST. CASE DESCRIPTION/METHODS: A 59-year old woman with history of gastro-esophageal reflux disease presented to the emergency room with bright red blood per rectum and lower abdominal pain for one month. She reported one episode of melenic stool. Physical examination was unremarkable. Laboratory findings revealed a hemoglobin of 9.4 g/dL and a positive fecal occult blood test. Esophagogastroduodenoscopy (EGD) was non-diagnostic. Colonoscopy revealed fresh blood with clots at the terminal ileum, but no evident source of bleeding was identified. As the source of bleeding could not be accurately diagnosed with routine colonoscopy and EGD, an abdominal computed tomography angiography (CTA) was obtained. Abdominal CTA revealed a large exophytic, necrotic mass with hypervascularity to the right of the uterine fundus along with extensive vessels within the bowel wall. The mass, distal portion of the distal jejunum, portion of the terminal ileum were resected. Postoperative pathological examination revealed gastrointestinal stromal tumor (high grade, spindle cell variant). The patient is doing well at a four-month follow-up. DISCUSSION: Patients with GISTs can often be asymptomatic leading to a missed initial diagnosis. When symptomatic, patients often present with bleeding, anemia, mucosal ulceration or mass effect, depending on location. Occasionally they are discovered as incidental findings in radiologic imaging or as incidental findings during surgery or autopsy. Bleeding is the most common presenting symptom and is attributed to the erosion of the gastrointestinal tract lumen with tumor invasion, resulting in hematemesis, melena or anemia. This case offers a unique perspective of GIST diagnosis. In cases where a colonoscopy and EGD along with abdominal series is undiagnostic and capsule endoscopy/balloon enteroscopy are not available - CT angiography can be considered an alternative imaging procedure for the management of GIST tumors. In our case, CT angiography provided exact tumor location preoperatively allowing for appropriate surgical resection.

Spectrum of imaging findings in trans-gastric migration of accidently ingested metallic foreign bodies

Background: An accidently ingested foreign body may get lodged within the lumen of gastrointestinal tract, pass uneventfully with feces or may migrate extraluminally into the surrounding tissues in which case it may lead to suppurative or vascular complications. The aim of the endeavor was to study the spectrum of imaging findings in patients with accidental ingestion of foreign bodies with trans-gastric migration of metallic foreign bodies.Methods: Total 33 patients with history of accidental ingestion of foreign bodies were subjected to preliminary radiograph of neck, chest and abdomen followed by upper gastrointestinal endoscopy. Failure to retrieve/ localize foreign body endoscopically from upper gastrointestinal tract with check radiograph reiterating the presence of foreign body in upper abdomen were subjected to computed tomography of abdomen.Results: A total of 33 patients comprising of 27 females and 6 males with mean age of 23.76 years with history of foreign body ingestion were studied. Ingested foreign bodies were lodged in pharynx (n=7), esophagus (n=3), stomach (n=13) or duodenum (n=3). In 7 patients in whom endoscopy failed to locate and/or retrieve foreign body, computed tomography confirmed the presence of trans-gastrically migrated foreign body in the surrounding structures. The location of migrated foreign bodies was in lesser sac (n = 2), greater omentum (n = 3), lesser omentum (n = 1) and transmural (n = 1). Two patients had evidence of collection formation around the migrated foreign bodies.Conclusions: Sharp or pointed metallic foreign bodies may migrate trans-luminally with various implications. Though radiography is the preliminary workhorse for the confirmation of ingested foreign bodies, computed tomography owing to its volumetric data acquisition helps in exact localization of migrated foreign bodies and should precede any therapeutic intervention for retrieval of migrated foreign bodies.

Symptomatology of gastrointestinal tract foreign bodies

Aim. To study the clinical problems and develop the symptomatology of the foreign bodies (FB) of the gastrointestinal tract (GIT).&#x0D; Materials and methods. Ninety patients with GIT foreign bodies were observed over the period from 1997 to 2017. To diagnose, a complex of endoscopic and radial methods was used. Localization, size and type of the detected foreign bodies were compared with the symptoms revealed.&#x0D; Results. Fifty patients intentionally swallowed foreign bodies, 40 – accidentally. Altogether, 90 patients swallowed 193 items (nails, needles, pieces of wire etc.). On the basis of the study, three forms of clinical course regarding the swallowed GIT FB were singled out: latent, manifest and complicated. The pathognomonic symptoms of GIT FB are “migrant” abdominal pains associated with migration of FB along the GIT lumen, intensification of pains while moving, exercise stress and palpation, feeling of “heaviness” in epigastric region. Multiple gastric FB cause the auscultative symptom of “ringing”. Pains, available with GIT FB, are not connected with taking food and are not ceased after taking antacids.&#x0D; Conclusions. Introduction of the developed GIT FB symptomatology into healthcare practice and training of physicians will contribute to earlier and more accurate diagnosis.

Improvement in the Predicted Partitioning of Alcohol and Polyethylene Oxide Groups Between Water and Octanol (logP) in Molecular Dynamics Simulations

Molecular dynamics simulations can be applied to explore the complex liquid phase behavior of lipid-based formulations and the gastrointestinal tract lumen. In order for the results from these simulations to be of value, the manner in which molecules interact with both aqueous and oil phases present needs to be as correct as possible. An existing molecular dynamics force field, GROMOS 53a6, was demonstrated to poorly reproduce the partitioning of straight-chain alcohol and short-chain polyethylene glycol (PEG) molecules between octanol and water phase (logP), with the molecules too hydrophobic. Force field parameters for Lennard-Jones interactions between CH2 and CH3 with water oxygen were adjusted to reproduce the experimental octanol logP, with all other Lennard-Jones and force field parameters left untouched. This parameter set, called 53a6DBW, was subsequently used to recalculate straight-chain alcohol and short-chain PEG molecules, with significant improvement in the values obtained. Simulations of a nonionic surfactant in water, octaethylene glycol monocaprylate, were also performed to observe the aggregation behavior. 53a6DBW demonstrated significant improvements in water interactions with the PEG chains, well hydrating the PEG groups, and allowing the formation of micelles. Further improvements and evaluation of the improved parameter set are ongoing.

Эндоваскулярные методы диагностики и лечения острых кровотечений в просвет желудочно-кишечного тракта

Эндоваскулярные методы диагностики и лечения острых кровотечений в просвет желудочно-кишечного тракта

Toward Bio-Inspired Tactile Sensing Capsule Endoscopy for Detection of Submucosal Tumors

Here, we present a method for lump characterization using a bio-inspired remote tactile sensing capsule endoscopy system. While current capsule endoscopy utilizes cameras to diagnose lesions on the surface of the gastrointestinal tract lumen, this proposal uses remote palpation to stimulate a bio-inspired tactile sensing surface that deforms under the impression of both hard and soft raised objects. Current capsule endoscopy utilizes cameras to visually diagnose lesions on the surface of the gastrointestinal tract. Our approach introduces remote palpation by deploying a bio-inspired tactile sensor that deforms when pressed against soft or hard lumps. This can enhance visual inspection of lesions and provide more information about the structure of the lesions. Using classifier systems, we have shown that lumps of different sizes, shapes, and hardnesses can be distinguished in a synthetic test environment. This is a promising early start toward achieving a remote palpation system used inside the GI tract that will utilize the clinician’s sense of touch.

24th Seah Cheng Siang Lecture: Seeing Better, Doing Better—Evolution and Application of Gastrointestinal (GI) Endoscopy

Gastrointestinal (GI) endoscopy has evolved tremendously from the early days when candlelight was used to illuminate scopes to the extent that it has now become an integral part of the practice of modern gastroenterology. The first gastroscope was a rigid scope first introduced by Adolf Kussmaul in 1868. However this scope suffered from the 2 drawbacks of poor illumination and high risk of instrumental perforation. Rudolf Schindler improved on this by inventing the semiflexible gastroscope in 1932. But it was Basil Hirschowitz, using the principle of light conduction in fibreoptics, who allowed us to "see well" for the first time when he invented the flexible gastroscopy in 1958. With amazing speed and innovation, instrument companies, chiefly Japanese, had improved on the Hirschowitz gastroscope and invented a flexible colonoscope. Walter McCune introduced the technique of endoscopic retrograde cholangiopancreatography (ERCP) in 1968 which has now evolved into a sophisticated procedure. The advent of the digital age in the 1980s saw the invention of the videoendoscope. Videoendoscopes have allowed us to start seeing the gastrointestinal tract (GIT) "better" with high magnification and resolution and optical/digital enhancements. Fusing confocal and light microscopy with endoscopy has allowed us to perform an "optical biopsy" of the GI mucosa. Development of endoscopic ultrasonography has allowed us to see "beyond" the GIT lumen. Seeing better has allowed us to do better. Endoscopists have ventured into newer procedures such as the resection of mucosal and submucosal tumours and the field of therapeutic GI endoscopy sees no end in sight.

Stimulation of Mucin, Mucus, and Viscosity during Lubiprostone in Patients with Chronic Constipation may Potentially Lead to Increase of Lubrication.

Objectives:The purpose of this clinical trial was to explore whether lubiprostone increases the rate of mucus and mucin secretion and its viscosity in chronic constipation (CC) patients. The secretion of chloride (CS) into the gastrointestinal tract lumen is pivotal in the body's ability to process non-digestible food components. CS sets the optimal rate of hydration for non-digestible food components, their fluidity, and their adequate propulsion along the alimentary tract. Chloride is also instrumental in the secretion of alimentary tract mucus, and the formation of a gel-like, viscous mucus-buffer layer. This layer acts as the first line and vanguard of the mucosal barrier. This barrier is essential in mucosal lubrication and protection. Lubiprostone, a novel chloride channel stimulator ClC-2, is currently approved for the treatment of CC. Its impact on mucus, mucus secretion, and viscosity is not established.Methods:A double-blind, crossover trial was approved by the IRBs at the Kansas University Medical Center (Kansas City, KS) (study site) and at the Texas Tech University HSC (El Paso, TX) (analysis site). The study included 20 patients (17 females (F); mean age: 37 years) with symptoms of CC diagnosed according to the Rome III criteria. Patients were randomized to 1 week of therapy with lubiprostone or placebo followed by a 1 week washout and 1 week of the alternative therapy. Gastric juice was collected basally and during stimulation with pentagastrin (6 μg/kg body weight subcutaneously) at the end of weeks 1 and 3. Pentagastrin stimulation mimics food stimulation. The mucus content in gastric juice was assessed gravimetrically. The mucin content was measured after its purification using ultracentrifugation. The viscosity of the gastric secretion was measured using a digital viscometer.Results:In comparison with placebo, the volume of gastric secretion in patients with CC during administration of lubiprostone increased significantly by 50% (86.3 vs. 57.5 ml/h) (P<0.001) in basal conditions and increased by 25% (210.0 vs. 167.6 ml/h) (P=0.024) during stimulation with pentagastrin. The rate of gastric mucus secretion during therapy with lubiprostone was 91% higher (257.3 vs. 135 mg/h) (P=0.001) in basal conditions and 28% higher (348.1 vs. 270.8 mg/h) (NS) in stimulated conditions, although the latter was not statistically significant. The rate of gastric mucin secretion during lubiprostone therapy was 85% higher (98.4 vs. 65.5 mg/h) (P=0.011) in basal conditions and 38% (98.3 vs. 71.7 mg/h) (NS) higher in stimulated conditions. In basal conditions, the viscosity of gastric secretion during administration of lubiprostone increased by 240% at the lowest (P<0.001) and by 106% at the highest shear rate (P<0.001). In stimulated conditions, it increased by 226% (P<0.01) at the lowest shear rate and by 67% (P<0.01) at the highest shear rate.Conclusions:The significantly higher content of gastric mucus and mucin during therapy in basal conditions with lubiprostone in patients with CC suggests and supports the potentially leading role of lubiprostone and ClC-2 stimulation in their secretion. This increased stimulation results in profoundly increased viscosity, which in turn facilitates and/or accelerates the transit and evacuation of non-digestible food components. Although increases in mucus and mucin were observed in stimulated conditions, neither increase was statistically significant. Based on this experiment, we hypothesize that, in CC patients, the significantly increased rate of mucus and its major component, mucin secretion, during lubiprostone administration may partially explain its clinical effectiveness and also have additional clinically important effects. We propose that since the increased mucus production enhances the protective quality of the mucosal barrier, it also boosts its potential to withstand luminal aggressive components such as acid/pepsin duet, Helicobacter pylori and/or nonsteroidal anti-inflammatory drugs/aspirin, or a combination of all. Further trials are needed to test this hypothesis. As this was crossover clinical trial, the patients serve as their own controls. No interaction was found with body mass index (BMI) and treatment. The observed relationships of BMI and mucus and mucin secretions and gastric juice volume are important considerations in the design of future trials, particularly if a crossover design is not used.

English

BACKGROUND: GIST is a visceral sarcoma that arises from the gastrointestinal tract. Computed tomography (CT) is an imaging modality of choice for diagnosing GIST. The clinical features and radiologic differential diagnosis of gastrointestinal stromal tumours are discussed by evaluating CT features of GIST in 40 cases. METHODS & MATERIALS: In this study, 40 biopsy proven cases of GIST attending our department from November 2010 to July 2012 are evaluated retrospectively. The CT scan was performed prior to the treatment in all these patients. CT imaging features that were taken into account include tumour location, size/diameter, degree & pattern of enhancement, intraluminal/exophytic, internal necrosis & haemorrhage, perilesional fat stranding, local spread, nodal & distant metastasis. RESULTS: In 26 out of 40 cases (65%), tumour was found in stomach, 8/40 (20%) in small bowel (jejunum & ileum), 4/40 (10%) in omentum and mesentery; and 2 (5%) tumour was found in transverse colon. 28/40 (70%) had exophytic tumour with communication to lumen of gastrointestinal tract or in omentum and mesentery; rest 12/40 (30%) had polypoidal mass. Size of tumour ranged from 4 to 15 cm, with mean of 7.9 cm. 30/40 (75%) cases showed heterogeneous enhancement with necrosis and/or calcification, rest 10/40 (25%) had homogenous enhancement. The CT HU ranged from 35 to 55, with mean of 40. 28/40 (75 %) cases had well defined margins of tumour, and rest 12 (30%) cases showed perilesional fat stranding and loss of fat plane with adjacent organ. 4/40 (10%) cases showed regional nodal involvement and 6/40 (15%) cases shows distant metastasis to liver & lungs. CONCLUSIONS: The stomach was the commonest site of GIST occurrence among our patients. The CT features of GIST were exophytic, ulcerated mass with well-defined tumour margins, and heterogeneous enhancement on post-contrast

Isolation and in vitro Activation of Mouse Peyer’s Patch Cells from Small Intestine Tissue

The lumen of gastrointestinal tract is exposed to several potentially pathogenic microorganisms, thus it is extremely relevant to understand how immunosurveilance can be established. Peyer’s Patches (PPs) are oval or round lymphoid nodules that protrude from the outer wall of the ileum portion of small intestine. PPs contain a high percentage of B and T lymphocytes, macrophages and dendritic cells. Here we summarize a protocol for isolation and culture of mouse PP cells, which can be used to get a better insight into immunopathologies of microbes and to evaluate immune responses elicited by mucosal vaccines., 胃肠道的腔暴露于几种潜在的致病微生物，因此，了解如何建立免疫耐受是非常重要的。 派尔氏贴剂（PP）是椭圆形或圆形淋巴结，其从小肠的回肠部分的外壁突出。 PP含有高百分比的B和T淋巴细胞，巨噬细胞和树突细胞。 在这里我们总结一个协议的小鼠PP细胞的分离和培养，可用于更好地了解微生物的免疫病理学和评估由粘膜疫苗引发的免疫反应。

A clinical case-based hypothesis: secretory IgA operates as an electronic transistor controlling the selection or rejection of molecules in the absorption process in the lumen of gastrointestinal tract

There is a clinical correlation between (1) an allergic patient’s ability to resist the development of symptoms that would have resulted from an allergenic challenge, (2) the magnitude of geomagnetism at a geographic site, and (3) the amount of solar energy falling on that site. It is suggested that the digestive membrane has an electronic gatekeeper that “decides” electronically which molecules to allow or not allow to pass on to the absorptive surface. The unique bipolar structure of secretory immunoglobulin A (IgA), having a central secretory piece and the resultant unique electronic function of this polarized molecule, allows it to function as an electronic transistor, producing an electronic gatekeeper in the form of an electronic sieve.

Abstract 1636: Enhancement of cyclic GMP production by guanylate cyclase-C agonists delays progression of colitis into colon cancer though downregulation of pro-inflammatory cytokines

Abstract Colon cancer is one of the most prevalent malignancies in the world; with an estimated 875,000 cases diagnosed worldwide; accounting for 8.5% of all new cancers. Patients with ulcerative colitis and Crohn's disease are at increased risk of developing colorectal cancer. It is believed that the persistent gastrointestinal (GI) inflammation may contribute to colorectal carcinogenesis. The cGMP signaling mediates anti-inflammatory effects of cellular molecules such as nitric oxide and hemeoxygenase-1. Therefore, therapies that induce cyclic GMP and cyclic AMP levels by inhibiting their degradation (phosphodiesterase inhibitors) exhibit good efficacy in murine models of ulcerative colitis. Activation of guanylate cyclase C (GC-C) by uroguanylin (UG), a peptide hormone produced in the GI tract lumen, results in enhanced production of cyclic GMP. Earlier we reported that UG expression is suppressed in human colon tumors and that the oral treatment with UG inhibited polyps formation in ApcMin/+ mice via a cGMP-mediated mechanism. Subsequently, we also reported that GC-C agonists (plecanatide and SP-333), highly potent analogs of UG, ameliorated GI inflammation in murine colitis models via downregulation of certain pro-inflammatory cytokines. Thus, we reasoned that GC-C agonists might also retard progression of colitis into colorectal tumors. Apc Min/+ mice were randomized to receive either powdered diet supplemented with or without plecanatide. DSS (4%) was administered in the drinking water for two cycles. Cycle 1 consisted of 4 days of DSS plus 17 days of water. Cycle 2 consisted of 3 days of DSS plus 18 days of water. Mice were sacrificed at 15 wks of age. The number of tumors per animal was counted for each segment of the colon. The mRNA levels of UG, GC-C, Ki-67 and protein levels of β-catenin within the colon were measured. Expression of cytokines was examined in explant cultures of colon. Both plecanatide and SP-333 were as effective as sulfasalazine or 5-ASA to inhibit DSS-induced inflammation in mice. Treatment with plecanatide reduced multiplicity of tumors within the colon, increased expression of protein kinase G-II (PKG-II) and decreased levels of Ki-67 and β-catenin. Expression of UG was reduced following DSS treatment but it was partially restored following treatment with plecanatide. In explant cultures, plecanatide reduced production of the pro-inflammatory cytokines such as IL-6, IL-17 and IL-23. These results suggest that anti-inflammatory and anti-carcinogenesis activities of plecanatide were mediated through downregulation of pro-inflammatory cytokines. This study opens a novel avenue for development of GC-C agonists as a new class of orally delivered, mucosally active, drug candidates for treatment of GI inflammatory diseases and IBD-associated colon cancer. Supported by NIH grant R21 CA133689 to KS. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1636. doi:1538-7445.AM2012-1636