GI Motility Research Articles

The response of vagal motoneurons to brainstem oxytocin stimulation depends on sex and stress levels.

Stress maladaptation plays a pivotal role in the development and exacerbation of functional gastrointestinal disorders (FGID), including impaired gastric emptying and decreased gastric motility, both of which are more prevalent in women. The prototypical anti‐stress hormone, oxytocin (OXY), has been shown to modulate GI tone and motility via vagal pathways. We have shown previously that in naïve male rats, OXY modulates the critical GABAergic synapse projecting to gastric‐projecting preganglionic vagal (DMV) neurons only after pharmacological increase of cAMP levels by forskolin or CRF pretreatment, suggesting a stress‐induced plasticity of brainstem vagal neurocircuits.The aim of this study was to test the hypothesis that the response of vagal motoneurons to brainstem oxytocin application depends on sex and stress adaptation or resilience. Age‐matched male and female SD rats were subdivided in the following groups: i) control; ii) chronic repetitive homotypic (restraint) stress, rats in this group show adaptation to stress; iii) chronic repetitive heterotypic (restraint, forced swim, water avoidance and cold) stress, rats in this group do not show adaptation to stress. Female rats were further subdivided according to their estrogen levels (high: pro‐estrus and estrus; low: meta‐ and di‐estrus). Following 5‐days of stress, whole cell patch clamp recordings were made from thin brainstem slices to examine GABAergic miniature inhibitory postsynaptic currents (mIPSCs) in medial, presumably gastric‐projecting, DMV neurons.Our results, see table, indicate that 1) in male rats OXY modulated inhibitory neurotransmission only in stressed rats; 2) in female rats, OXY modulated inhibitory neurotransmission independently of estrogen or stress load. 3) OXY effects on mIPSC frequency, however, is different when rats are exposed to heterotypic stress load. Taken together, our data support the hypothesis that the response of vagal motoneurons to brainstem oxytocin stimulation depends on sex and stress levels and suggest that, independently of estrogen or stress, female rats have a response similar to that of stressed males.Support or Funding InformationNIH DK 55530This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Loss of HCN2 leads to delayed gastrointestinal motility and reduced energy intake in mice.

Hyperpolarization-activated Cyclic Nucleotide-gated (HCN) channels are important regulators of excitability in neural, cardiac, and other pacemaking cells, which are often altered in disease. In mice, loss of HCN2 leads to cardiac dysrhythmias, persistent spike-wave discharges similar to those seen in absence epilepsy, ataxia, tremor, reduced neuropathic and inflammatory pain, antidepressant-like behavior, infertility, and severely restricted growth. While many of these phenotypes have tissue-specific mechanisms, the cause of restricted growth in HCN2 knockout animals remains unknown. Here, we characterize a novel, 3kb insertion mutation of Hcn2 in the Tremor and Reduced Lifespan 2 (TRLS/2J) mouse that leads to complete loss of HCN2 protein, and we show that this mutation causes many phenotypes similar to other mice lacking HCN2 expression. We then demonstrate that while TRLS/2J mice have low blood glucose levels and impaired growth, dysfunction in hormonal secretion from the pancreas, pituitary, and thyroid are unlikely to lead to this phenotype. Instead, we find that homozygous TRLS/2J mice have abnormal gastrointestinal function that is characterized by less food consumption and delayed gastrointestinal transit as compared to wildtype mice. In summary, a novel mutation in HCN2 likely leads to impaired GI motility, causing the severe growth restriction seen in mice with mutations that eliminate HCN2 expression.

Further investigation of the effects of 5-hydroxytryptamine, 8-OH-DPAT and DOI to mediate contraction and relaxation responses in the intestine and emesis in Suncus murinus

5-HT receptors are implicated in many gastrointestinal disorders. However, the precise role of 5-HT in mediating GI responses in Suncus murnius is still unclear. Therefore in this study, the effects of 5-HT and its agonists were investigated in Suncus. The involvement of 5-HT2C receptors in mediating emesis was also investigated. The ability of 5-HT and its agonists/antagonists at 5-HT1A and 5-HT2 to modify GI motility was investigated in vitro and in vivo.WAY100635 (a 5-HT1A antagonist) inhibited the contraction response to 5-HT in the proximal segments without affecting the maximum response; whilst enhancing the contraction to 5-HT (>30.0nM) in the distal intestine. The selective 5-HT2A and 5-HT2B receptor antagonists MDL-100907 and RS-127445 attenuated 5-HT-induced contractions (<10.0µM) in the distal segments. RS-127445 also attenuated 5-HT-induced contractions in the central segments. The selective 5-HT2C receptor antagonist SB-242084, attenuated the responses to 5-HT (> 3.0nM) in the proximal and central but not the distal regions. 8-OH-DPAT-induced relaxation was resistant to the antagonism by 5-HT1A/7 antagonists. DOI in the presence of 5-HT1A/2A/2B/2C antagonists induced greater contraction responses (>1.0µM) in most tissues, whilst RS-127445, or SB-242084, reduced the responses to DOI (< 1.0µM) in some tissues. SB-242084 also suppressed emesis-induced by motion and intragastric CuSO4.In conclusion, within different regions of intestine, 5-HT2 receptors are differently involved in contraction and emetic responses and that 8-OH-DPAT induces relaxation via non-5-HT1A/7 receptors. Suncus could provide a model to investigate these diverse actions of 5-HT.

Anti‐inflammatory Effects of Enhanced Recovery Programs on Early‐Stage Colorectal Cancer Surgery

Postoperative ileus (POI) is observed in 20-30% of patients undergoing colorectal cancer surgery, despite enhanced recovery programs (ERPs). Cyclooxygenase (COX)-2 is identified as a key enzyme in POI, but other arachidonic acid pathway enzymes have received little attention despite their potential as selective targets to prevent POI. The objectives were to compare the expression of arachidonic acid metabolism (AAM) enzymes (1) between patients who underwent colorectal cancer surgery and followed an ERP or not (NERP), (2) and between ERP patients who experimented POI or not and (3) to determine the ability of antagonists of these pathways to modulate contractile activity of colonic muscle. This was a translational study. Main outcome measures were gastrointestinal motility recovery data, mRNA expressions of key enzymes involved in AAM (RT-qPCR) and ex vivo motility values of the circular colon muscle. Twenty-eight prospectively included ERP patients were compared to eleven retrospectively included NERP patients that underwent colorectal cancer surgery. ERP reduced colonic mucosal COX-2, microsomal prostaglandin E synthase (mPGES1) and hematopoietic prostaglandin D synthase (HPGDS) mRNA expression. mPGES1 and HPGDS mRNA expression were significantly associated with ERP compliance (respectively, r2=0.25, p=0.002 and r2=0.6, p<0.001). In muscularis propria, HPGDS mRNA expression was correlated with GI motility recovery (p=0.002). The pharmacological inhibition of mPGES1 increased spontaneous ex vivo contractile activity in circular muscle (p=0.03). The effects of ERP on GI recovery are correlated with the compliance of ERP and could be mediated at least in part by mPGES1, HPGDS and COX-2. Furthermore, mPGES1 shows promise as a therapeutic target to further reduce POI duration among ERP patients.

Carthami flos regulates gastrointestinal motility functions

BackgroundGastrointestinal (GI) symptoms are common in the general population. This investigation studied the effects of Carthami flos (CF), a natural product, on GI motility. MethodsWe checked the intestinal transit rates (ITRs) or gastric emptying in normal and in GI-motility-dysfunction (GMD) mice in vivo. The GMD mice were made by acetic acid or streptozotocin. ResultsBoth ITRs and gastric emptying were increased by CF (0.0025–0.25g/kg) dose dependently. Also, in the GMD mice models, acetic-acid-induced peritoneal irritation, and streptozotocin-induced diabetic mice, the ITRs were decreased compared to normal mice, and these decreases were inhibited by CF. ConclusionThese results suggest that CF is one of the good candidates for the development of a prokinetic agent that may regulate GI-motility functions.

Relamorelin for the treatment of gastrointestinal motility disorders

ABSTRACTIntroduction: Current treatments for gastroparesis are limited. Chronic idiopathic constipation (CIC) has more treatment options, but none are efficacious for severe cases.Areas covered: Molecular targets to accelerate GI motility are being identified, and relamorelin, a synthetic ghrelin analog, has been promising. In humans, relamorelin increases growth hormone levels and accelerates gastric emptying. Relamorelin was superior to placebo for symptom relief in phase IIA studies for diabetic gastroparesis (DG) and CIC. In phase IIB studies in DG, relamorelin did not significantly reduce vomiting frequency when compared to placebo, but it reduced four symptoms of DG (nausea, fullness, bloating and abdominal pain) and accelerated gastric emptying. To date, relamorelin has been well tolerated and safe in humans without cardiac or neurologic adverse effects. It is still in clinical trial stages and not yet approved by the Food and Drug Administration. Phase III studies are underway.Expert opinion: Relamorelin shows promise in treating DG, with a reduction in core symptoms. Relative to available treatments, it appears to be efficacious and well tolerated. The absence of neurological or cardiovascular adverse effects places it at an advantage over other available therapies. Once approved, it will likely become the drug of first choice for DG.

Prostanoid EP3 receptor agonist sulprostone enhances pacemaker activity of colonic interstitial cells of Cajal.

EP receptor activation by PGE2 regulates gastrointestinal motility by modulating smooth muscle contractility. Interstitial cells of Cajal (ICCs) are pacemaker cells that regulate smooth muscle activity. We aimed to determine effects of the EP3 receptor agonist sulprostone on pacemaker potentials in colonic ICCs. We performed a whole cell patch clamp, RT-PCR, and Ca2+ imaging in cultured ICCs from mouse colon. Sulprostone depolarized the membrane and increased pacemaker frequency. EP3 receptor antagonist blocked these sulprostone-induced effects. EP3 receptors were expressed in ANO1-positive ICCs. Phospholipase C inhibitor or Ca2+-ATPase inhibitor from the endoplasmic reticulum blocked the sulprostone-induced effects and sulprostone increased intracellular Ca2+ ([Ca2+]i) oscillations. Hyperpolarization-activated cyclic nucleotide-gated (HCN) channel blockers also suppressed the sulprostone-induced effects. Sulprostone enhanced pacemaker activity through EP3 receptors by activating HCN channels via the [Ca2+]i release pathway. Therefore, EP3 receptor activation in ICCs may modulate colonic motility and could be a therapeutic target for enhancing colonic GI motility.

Examination of the effects of breath hydrogen and methane levels on the EC/IR II

ABSTRACTFifty patients undergoing hydrogen and methane breath testing at Cedars-Sinai GI Motility Lab were recruited, and consented to having their breath tested for alcohol using the EC/IR II (Intoximeters, Inc., St. Louis). The subjects gave multiple breath samples for alcohol analysis during this controlled study. All subjects had hydrogen in their breath ranging from 1 to 176 parts per million (ppm). Methane was also present in some patients’ breath samples (0–107 ppm). In all cases, except for one subject that admitted to heavy drinking the night before, breath alcohol results were 0.000 g/210 L. Based on these findings, breath hydrogen and methane do not have any impact on breath alcohol results with the EC/IR II.

The 5-HT4 receptor agonist prucalopride does not facilitate cholinergic neurotransmission in circular and longitudinal smooth muscle preparations of equine mid-jejunum

BackgroundPostoperative ileus (POI) remains an important cause of death in horses. The recently developed selective 5-HT4 receptor agonists such as prucalopride target 5-HT4 receptors on myenteric cholinergic neurons to enhance acetylcholine release and GI motility. No clearcut in vitro evaluation whether highly selective 5-HT4 receptor agonists enhance submaximal cholinergic neurotransmission towards the muscle layer has been performed in horses. ObjectivesTo identify functional 5-HT4 receptors in equine jejunum. Study designIn vitro experimental study. MethodsCircular and longitudinal smooth muscle strips (mid-jejunum) were mounted in organ baths between 2 platinum electrodes allowing electrical field stimulation (EFS). To delineate the conditions to obtain purely cholinergic responses, voltage-response curves were studied. To investigate the influence of prucalopride and 5-HT, submaximal cholinergic contractions at a single voltage were induced. ResultsIn circular and longitudinal strips, EFS induced voltage-dependent neurogenic on-contractions when the bathing medium contained a NO-synthesis inhibitor and apamin to prevent inhibitory responses to NO and ATP. Contractions at a voltage inducing 50% of maximal amplitude were cholinergic, as they were blocked by atropine. These contractions were not influenced by prucalopride (up to 3μM), even in the presence of the phosphodiesterase inhibitor isobutyl-methyl-xanthine to inhibit breakdown of the second messenger of 5-HT4 receptors, cAMP. Also the full 5-HT4 receptor agonist 5-HT did not influence the EFS-induced submaximal cholinergic contractions. Moreover, prucalopride did not influence muscle tone continuously enhanced with KCl. ConclusionsThere are no functional 5-HT4 receptors on myenteric cholinergic neurons nor muscular 5-HT4 receptors in equine jejunum.

Rice Bran Extract Inhibits TMEM16A-Involved Activity in the Neonatal Rat Cochlea.

TMEM16A is a Ca²⁺-activated Cl⁻ channel found in secretory glands, GI and respiratory tracts, and sensory organs, playing a major physiological role in fluid secretion, autonomous GI motility, and sensory transduction. In addition, overexpression of TMEM16A has been associated with cancer cell proliferation and invasion. Suppression of upregulated TMEM16A has been proposed as an effective anti-cancer strategy. While searching for a potential TMEM16A inhibitor, components of rice bran attracted our attention due to their anti-cancer potential in colon cancer cells, a type of cells known to overexpressing TMEM16A. Here, it was tested whether rice bran extract exhibits anti-TMEM16A activity. Rice bran extract was tested in the neonatal rat cochlear tissues where TMEM16A-involved spontaneous activity is generated as a part of normal development of the auditory pathway. Rice bran extract readily inhibited the TMEM16A-involved activity in the cochlear tissues and the effect was reversible upon washout. Taken together, rice bran extract appears to contain a putative TMEM16A inhibitor and the rice byproduct might serve as a source of a new anti-cancer agent.

Age-dependent shift in macrophage polarisation causes inflammation-mediated degeneration of enteric nervous system

ObjectiveThe enteric nervous system (ENS) undergoes neuronal loss and degenerative changes with age. The cause of this neurodegeneration is poorly understood. Muscularis macrophages residing in close proximity to enteric ganglia...

Fatty acid and mineral receptors as drug targets for gastrointestinal disorders.

Nutrient-sensing receptors, including fatty acid receptors (FFA1-FFA4), Ca2+-sensing receptors and Zn2+-sensing receptors, are involved in several biological processes. These receptors are abundantly expressed in the GI tract, where they have been shown to play crucial roles in regulating GI function. This review provides an overview of the GI functions of fatty acid and mineral receptors, including the regulation of gastric and enteroendocrine functions, GI motility, ion transport and cell growth. Recently, several lines of evidence have implicated these receptors as promising therapeutic targets for the treatment of GI disorders, for example, inflammatory bowel disease, colorectal cancer, metabolic syndrome and diarrheal diseases. A future perspective on drug discovery research targeting these receptors is discussed.

Cell therapy for GI motility disorders: comparison of cell sources and proposed steps for treating Hirschsprung disease

Cell therapeutic approaches to treat a range of congenital and degenerative neuropathies are under intense investigation. There have been recent significant advancements in the development of cell therapy to treat disorders of the enteric nervous system (ENS), enteric neuropathies. These advances include the efficient generation of enteric neural progenitors from pluripotent stem cells and the rescue of a Hirschsprung disease model mouse following their transplantation into the bowel. Furthermore, a recent study provides evidence of functional innervation of the bowel muscle by neurons derived from transplanted ENS-derived neural progenitors. This mini-review discusses these recent findings, compares endogenous ENS-derived progenitors and pluripotent stem cell-derived progenitors as a cell source for therapy, and proposes the key steps for cell therapy to treat Hirschsprung disease.

AB310. SPR-37 Cholinergic excitatory motor responses in the colon are mediated through the calcium-activated chloride conductance Ano1

ObjectiveThere is a growing body of evidence that gastrointestinal smooth muscle excitability is regulated by several different classes of interstitial cells [interstitial cells of Cajal (ICC) and PDGFRα(+) cells] that are electrically coupled to SMC. Thus, ‘myogenic’ activity results from the integrated behavior of the SMC/ICC/PDGFRα(+) cell (SIP) syncytium. Inputs from excitatory and inhibitory motor neurons are required to produce the complex motor patterns of the gut and coordinate GI motility. Motor neurons innervate these three cell types in the SIP syncytium, and receptors, second messenger pathways, and ion channels in these cells mediate postjunctional responses. Cholinergic neurotransmission in GI muscles from several species has long been thought to be dependent upon activation of a non-selective cation conductance in smooth muscle cells and the molecular candidates for mediating cholinergic excitation have been reported to be the transient receptor protein channels Trpc4 and Trpc6. However, we have shown that cholinergic responses in the GI tract involve ICC and in their absence these motor responses are greatly diminished or absent. We sought to determine the conductance(s) responsible for cholinergic motor responses in the colon.MethodsCre-LoxP recombinase technology was utilized to determine the role of the calcium-activated chloride conductance, Ano1 in post-junctional motor responses in the mouse colon in a cell-specific manner (Kit+ ICC). c-KitCreERT2/+ (Kit-Cre) mice and Ano f/f mice were crossed to generate c-KitCreERT2/+; Ano1f/f (mutants) and c-KitCreERT2/+; Ano1f/+ (controls) animals that were subsequently treated with tamoxifen to induce Cre recombinase expression in ICC. Confocal microscopy was used to determine the cell type Cre expression was switched on. Intracellular microelectrode recordings were performed to determine changes in post-junctional neural responses to nerve stimulation in c-KitCreERT2/+ (Kit-Cre) mice and Anof/f mice to generate c-KitCreERT2/+; Ano1f/f and c-KitCreERT2/+; Ano1f/+ animals mice treated with tamoxifen using electrical field stimulation (EFS).ResultsKnock down of Ano1 in Kit+ ICC using the Cre/Lox P technology caused a marked reduction or loss of excitatory junction potentials (EJPs) in colonic muscles of c-KitCreERT2/+; Ano1f/f in response to EFS compared to c-KitCreERT2/+; Ano1f/+ controls. These EJPs were atropine sensitive providing evidence that cholinergic muscarinic receptors were responsible for these excitatory responses.ConclusionsThese data provide evidence that Ano1 expressed in ICC and not smooth muscle cells is critically important for cholinergic excitatory post-junctional neural responses in colonic muscles.Funding SourcesNIH PO1 41315 and RO1 DK57236

Simultaneous Pseudo-achalasia and Renal Failure: A Rare Presentation of Amyloidosis

49 years old Pakistani male with no significant past medical history presented with 2 weeks history of low grade fever and diarrhea. He also reported almost 12 years history of dysphagia for both solids and liquids for which he was never worked up before. On examination, he was thin lean individual with normal vitals. Apart from signs of wasting he had no significant sign of wasting. Investigations revealed WBC of 13500, Hb 13.3 and platelets 250,000. LFTs were normal, ESR 115mm in 1st hour. Stool examination was unremarkable. BMP showed Creatinine of 3.09 with no significant electrolyte abnormality. Nephrology and gastroenterology were consulted. Further investigation showed 3+ proteinuria, Phosphorous 7.7, Uric Acid 12.9 and Albumin 1.5 and normal complement ANCA and ANA panel. Barium Swallow recommended by GI showed findings of dilated mid and lower esophagus with narrowing of GI junction. Endoscopic dilatation of LES was done successfully. Renal biopsy showed glomeruli with eosinophilic deposits, apple green birefringence on congo red stain, findings consistent with amyloidosis. Test to rule out Multiple Myeloma were performed and they were negative. Patient was discharged with diagnosis of amyloidosis with renal and gastrointestinal involvement. He is regularly followed up by GI and Renal and reports improvement in symptoms. Discussion: Although amyloidosis involve pretty much every system of the body including renal and GI, but achalasia is very rarely presenting symptom of amyloidosis. GI tract is usually involved in 60% of cases of amyloidosis, however the more frequent presentations are GI bleeding, diarrhea and motility disorder depending on the site of involvement. Esophageal involvement is seen in just 13% of the cases. However in most cases the symptoms are usually those of reflux. Ours is a rare case where dysphagia is the presenting symptom and patient also had advanced renal disease with it. Therapy is usually aimed at treatment of underlying disease and relieving symptoms. Although gastrointestinal symptoms are rarely cause of death, renal failure frequently is. Renal failure is treated with dialysis or transplant. Recurrent amyloid deposition in the transplant occurs in 20 to 33 percent of cases due to continued activity of the underlying disease, but graft loss due to recurrence is uncommon.Figure 1

Adult Cyclic Vomiting Syndrome Is Treatable and Curable

Introduction: Cyclic Vomiting Syndrome (CVS) in adults is underdiagnosed because it is not well recognized by physicians although it accounts for up to 20% of patients referred to a GI practice for evaluation of unexplained vomiting and abdominal pain. Goals of therapy are to induce remission while also addressing the predisposing “trigger” factors. The purposes of this study are to provide an analysis of the clinical profile, treatment responses, and outcomes based on managing adult CVS at a GI motility center. Methods: Our adult CVS database identified 18 patients, 10 female, of ages ranging from 22-60, who were initially diagnosed at our center, received treatment, and had long term follow up of 1 to 4 years by one of the authors. Results: Onset of symptoms ranged from 1-15 years prior to diagnosis (mean of 4). The mean number of yearly ER visits or hospitalizations was 5.8. Weight loss ranged from 5-50 pounds. Ten patients underwent a 4 hour standardized radionuclide gastric emptying test: 6 had rapid emptying and. Six major “triggers” were identified (some patients having >1): anxiety in 17, post-traumatic stress disorder in 2, migraines in 5, chronic marijuana use in 5, poorly controlled diabetes in 5, and menses in 4. All patients were treated with tricyclic antidepressants. Amitriptyline was the first choice, starting at 10mg at night, increasing by 10mg every 2-3 weeks until CVS improved. Two patients were switched to doxepin due to side effects; their max doses were 100mg and 200mg. At the same time the “trigger” factors were aggressively addressed. With this treatment strategy 4 patients (22%) were able to stop their CVS medications and have remained asymptomatic for over 1 year. In addition, 11 patients (61%) responded remarkably with a reduction in the mean number of annual ER visits or hospitalizations from 5.8 to 0.6 and were fully functional. Three patients (17%) reported ongoing, approximately monthly, episodes and had unresolved trigger factors and medication noncompliance. Conclusion: 1) Adult CVS is a treatable and reversible entity; 2) The treatment consisting of high dose TCA & addressing the “trigger factors” was able to prevent cycles in 83% of patients, including 22% that were effectively cured and able to taper off medications without recurrence; 3) The approximately 17% of patients who have ongoing cycles require better control of the predisposing factors as well as reinforcing compliance with the treatment regimen.

Feeding Difficulties and Gastrointestinal Tract Morphology and Innervation in ‘Charge’ Syndrome

Abstract BACKGROUND: CHARGE syndrome has been linked to mutations in the CHD7 gene and results in a number of physiological and structural abnormalities. The estimated incidence in the Atlantic Provinces is 1 in 8500 births. Challenges include eating problems, which have a profound impact throughout a child’s life and can lead to complications and even death. OBJECTIVES: To investigate feeding difficulties and model the morphology and innervation of the gastrointestinal tract in CHARGE syndrome. DESIGN/METHODS: Three research studies (two clinical, one basic science) were conducted to assess feeding difficulties in CHARGE syndrome. The first study conducted a qualitative analysis of parent interviews to understand packing and problematic feeding behaviors. The second study investigated general eating and GI motility problems by having parents complete a series of feeding questionnaires. The third study modeled CHARGE syndrome in zebrafish by using a morpholino to knock down the expression of CHD7. RESULTS: Study 1: Twenty parents completed a phone interview, describing their child/adult’s (2-32 years) adverse feeding behaviors. Parents reported food packing most commonly with bread and pasta (33%), and reported that food was held in cheeks for hours after a meal had ended (35%). Packing was reported to prolong mealtimes for over an hour (30%). Parents were worried about choking during eating (30%).Study 2: Sixty-nine parents of children (age 1-18 years) completed the questionnaires. Those who were tube fed had significantly more gastrointestinal symptoms (stomach pain, nausea, etc.) and worse feeding difficulties than those who were orally fed. The CHARGE characteristics of choanal atre-sia/stenosis and cranial nerve IX/X dysfunction were associated with significantly more gastrointestinal symptoms. Parents identified constipation as a major challenge. Study 3: Immunohistochemistry demonstrated changes in the enteric innervation of the gastrointestinal tract in the CHARGE syndrome zebrafish models. There was decreased branching of the gastrointestinal nerve network surrounding the stomach. Use of fluorescent microbeads demonstrated reduced motility and delayed passage of the microbeads through the gastrointestinal tract. CONCLUSION: These three studies provided a comprehensive analysis of feeding and gastrointestinal difficulties, from mouth to anus, in CHARGE syndrome. They provide a deeper understanding of adverse feeding behaviors, feeding difficulties, and the abnormal morphology of the gastrointestinal system. The information from this study can be useful for general pediatricians and feeding therapy teams who are involved in the care of these individuals starting in infancy. The team-based approach of conducting multiple research projects investigating a common issue may be useful in other genetic disorders.

Beneficial Effects of Anti-Interleukin-6 Antibodies on Impaired Gastrointestinal Motility, Inflammation and Increased Colonic Permeability in a Murine Model of Sepsis Are Most Pronounced When Administered in a Preventive Setup.

Background and ObjectivesDuring sepsis, gastrointestinal ileus, mucosal barrier dysfunction and bacterial translocation are accepted to be important triggers that can maintain or exacerbate the septic state. In the caecal ligation and puncture animal model of sepsis, we demonstrated that systemic and colonic interleukin-6 levels are significantly increased coinciding with an impaired colonic barrier function. We therefore aimed to study the effect of therapeutic or curative administration of anti-IL6 antibodies on overall GI motility, colonic permeability and translocation of intestinal bacteria in blood and mesenteric lymph nodes in the mouse caecal ligation and puncture model.MethodsOF-1 mice were randomized to either the preventive or curative protocol, in which they received 1 mg/kg of antibodies to interleukin-6, or its IgG isotype control solution. They subsequently underwent either the caecal ligation and puncture procedure, or sham-surgery. GI motility was assessed 48h following the procedure, as well as colonic permeability, serum and colon cytokines, colonic tight junction proteins at the mRNA level; cultures of blood and mesenteric lymph nodes were performed.ResultsPreventive administration of anti-interleukin-6 antibodies successfully counteracted the gastrointestinal motility disturbances and impaired colonic barrier function that could be observed in vehicle-treated septic animals. Serum and colonic levels of proinflammatory cytokines were significantly lower when animals were preventively treated with anti-interleukin-6 antibodies. A repetitive injection 24h later resulted in the most pronounced effects. Curative treatment significantly lowered systemic and colonic inflammation markers while the effects on transit and permeability were unfortunately no longer significant.ConclusionsCaecal ligation and puncture resulted in septic ileus with an increased colonic permeability. Antibodies to interleukin-6 were able to ameliorate gastro-intestinal motility, suppress inflammation and normalize the permeability of the colonic wall, with the preventive administration combined with a repeat injection being far more efficacious than the sole preventive or curative one.

985 Training in Neurogastroenterology and GI motility in USA: Preliminary Results of a Survey of Gastroenterology Fellowship Program Directors

985 Training in Neurogastroenterology and GI motility in USA: Preliminary Results of a Survey of Gastroenterology Fellowship Program Directors

Tu1113 The Development of a GI Motility Curriculum Using an Entrustable Professional Activity (EPA): A Novel Process Template for Creating Competency-Based Medical Education Driven Curricula

Tu1113 The Development of a GI Motility Curriculum Using an Entrustable Professional Activity (EPA): A Novel Process Template for Creating Competency-Based Medical Education Driven Curricula