A neural circuit mechanism for mechanosensory feedback control of ingestion.

Mechanosensory feedback from the digestive tract to the brain is critical for limiting excessive food and water intake, but the underlying gut-brain communication pathways and mechanisms remain poorly understood1-12. Here we show that, in mice, neurons in the parabrachial nucleus that express the prodynorphin gene (hereafter, PBPdyn neurons) monitor the intake of both fluids and solids, using mechanosensory signals that arise from the upper digestive tract. Most individual PBPdyn neurons are activated by ingestion as well as the stimulation of the mouth and stomach, which indicates the representation of integrated sensory signals across distinct parts of the digestive tract. PBPdyn neurons are anatomically connected to the digestive periphery via cranial and spinal pathways; we show that, among these pathways, the vagus nerve conveys stomach-distension signals to PBPdyn neurons. Upon receipt of these signals, these neurons produce aversive and sustained appetite-suppressing signals, which discourages the initiation of feeding and drinking (fully recapitulating the symptoms of gastric distension) in part via signalling to the paraventricular hypothalamus. By contrast, inhibiting the same population of PBPdyn neurons induces overconsumption only if a drive for ingestion exists, which confirms that these neurons mediate negative feedback signalling. Our findings reveal a neural mechanism that underlies the mechanosensory monitoring of ingestion and negative feedback control of intake behaviours upon distension of the digestive tract.

Liraglutide Effects on Upper Gastrointestinal Investigations: Implications Prior to Bariatric Surgery.

Liraglutide is a glucagon-like peptide type 1 (GLP-1) analogue that is approved for long-term obesity management in North America. While bariatric surgery remains the gold standard for weight loss, an increasing number of patients are on liraglutide in the setting of ongoing workup for bariatric surgery. The presence of gastrointestinal symptoms prior to bariatric surgery may prompt testing for dysmotility, which affects surgical decision making. Here we report six cases where treatment with liraglutide was associated with reversible reduction in gastric and esophageal motility in screening for bariatric surgery. While liraglutide is known to delay gastric emptying, there are minimal reports of how this medication affects gastrointestinal investigations used in this context. The implications of these abnormal screening investigations on candidacy for bariatric surgery are discussed.

Upper Gastrointestinal Function in Morbidly Obese Adolescents Before and 6 Months After Gastric Banding.

BACKGROUND: The effects of laparoscopic adjustable gastric band (LAGB) placement on upper gastrointestinal tract function in obese adolescents are unknown. Therefore, our aim was to determine the short-term effects of LAGB on esophageal motility, gastroesophageal reflux, gastric emptying, appetite-regulatory hormones, and perceptions of post-prandial hunger and fullness. METHODS: This study was part of a prospective cohort study (March 2009-December 2015) in one tertiary referral hospital. The study included obese adolescents (14-18 years) with a body mass index (BMI) > 40 (or ≥ 35 with comorbidities). Gastric emptying was assessed by 13C-octanoic acid breath test, pharyngeal, and esophageal motor function by high-resolution manometry with impedance (HRIM), and appetite and other perceptions using 100-mm visual analogue scales. Dysphagia symptoms were scored using a Dakkak questionnaire. Data were compared pre- and post-LAGB placement and at a 6-month follow-up. RESULTS: Based upon analysis of 15 adolescents, at the 6-month follow-up, LAGB placement: (i) led to a significant reduction in weight and BMI; (ii) increased fullness and decreased hunger post-meal; (iii) increased symptoms of dysphagia after solid food; and, despite these effects, (iv) caused little or no changes to appetite hormones, while (v) effects on gastric emptying, esophageal motility, esophageal bolus transport, and esophageal emptying were not significant. CONCLUSION: In adolescents, LAGB improved BMI and altered the sensitivity to nutrients without significant effects on upper gastrointestinal tract physiology at the 6-month follow-up.

CONSIDERATIONS ON ANATOMY AND PHYSIOLOGY OF LYMPH VESSELS OF UPPER AERO DIGESTIVE ORGANS AND CERVICAL SATELLITE LYMPH NODE GROUP.

The almost constant local regional development of the cancers of upper aero digestive organs requires the same special attention to cervical lymph node metastases, as well as to the primary neoplastic burning point. The surgical therapy alone or associated has a mutilating, damaging character, resulting in loss of an organ and function, most of the times with social implications, involving physical distortions with aesthetic consequences, which make the reintegration of the individual into society questionable. The problem of cervical lymph node metastases is vast and complex, reason why we approached several anatomical and physiological aspects of lymph vessels of the aero digestive organs. Among the available elements during treatment, the headquarters of the tumour, its histologic degree, and its infiltrative nature, each of them significantly influences the possibility of developing metastases.

Upper gastrointestinal sensitivity to meal-related signals in adult humans - relevance to appetite regulation and gut symptoms in health, obesity and functional dyspepsia.

Both the stomach and small intestine play important roles in sensing the arrival of a meal, and its physico-chemical characteristics, in the gastrointestinal lumen. The presence of a meal in the stomach provides a distension stimulus, and, as the meal empties into the small intestine, nutrients interact with small intestinal receptors, initiating the release of gut hormones, associated with feedback regulation of gastrointestinal functions, including gut motility, and signaling to the central nervous system, modulating eating behaviours, including energy intake. Lipid appears to have particularly potent effects, also in close interaction with, and modulating the effects of, gastric distension, and involving the action of gut hormones, particularly cholecystokinin (CCK). These findings have not only provided important, and novel, insights into how gastrointestinal signals interact to modulate subjective appetite perceptions, including fullness, but also laid the foundation for an increasing appreciation of the role of altered gastrointestinal sensitivities, e.g. as a consequence of excess dietary intake in obesity, or underlying the induction of gastrointestinal symptoms in functional dyspepsia (a condition characterized by symptoms, including bloating, nausea and early fullness, amongst others, after meals, particularly those high in fat, in the absence of any structural or functional abnormalities in the gastrointestinal tract). This paper will review the effects of dietary nutrients, particularly lipid, on gastrointestinal function, and associated effects on appetite perceptions and energy intake, effects of interactions of gastrointestinal stimuli, as well as the role of altered gastrointestinal sensitivities (exaggerated, or reduced) in eating-related disorders, particularly obesity and functional dyspepsia.

Caracterización de los pacientes infectados por Helicobacter pylori durante un trienio / Characterization of patients infected by Helicobacter pylori during a triennium

Se realizó una investigación descriptiva y retrospectiva de los pacientes mayores de 18 años a los que se les practicó endoscopia del tracto digestivo superior en el Servicio de Gastroenterología del Hospital Clínica Popular Simón Bolívar del Estado Carabobo, en la República Bolivariana de Venezuela, en el periodo de enero del 2010 a diciembre del 2012, con vistas a comprobar si existía infección por Helicobacter pylori en esta porción del sistema digestivo, según algunas variables clínicas, epidemiológicas y endoscópicas de interés. Entre los resultados sobresalientes de la casuística figuró la infección por dicha bacteria, que fue más frecuente en las edades de 31-60 años y en el sexo femenino; de igual modo, la epigastralgia y la pangastritis eritematosa erosiva estuvieron mayormente asociadas al microorganismo. Pudo concluirse que la endoscopia es el pilar para el diagnóstico del Helicobacter pylori(AU)

A descriptive and retrospective investigation of the patients older than 18 years to whom an endoscopy of the higher digestive duct was practiced in the Gastroenterology Service from Simón Bolívar People's Clinic Hospital, in Carabobo State, Bolivarian Republic of Venezuela was carried out in the period of January, 2010 to December, 2012, aimed at checking if there was infection due to Helicobacter pylori in this zone of the digestive system, according to some clinical, epidemiological and endoscopic variables of interest. Among the excellent results of the case material there was the infection caused by this bacteria which was more frequent in the 31-60 years age group and in the female sex; also, the epigastralgia and the erosive erythematous pangastritis were mostly associated with the microorganism. It could be concluded that the endoscopy is the key stone for the diagnosis of Helicobacter pylori(AU)

Pathophysiology of aerodigestive pulmonary disorders in the neonate.

No test can provide a definitive diagnosis of aerodigestive disease. When interpreting tests, one should weigh the benefits and weaknesses of different technologies and methods, scientific appropriateness of the testing conditions, clinicopathologic correlation, and pharmacologic approaches. Gastroesophageal reflux disease (GERD) symptoms and airway symptoms can coexist, and they cannot be distinguished without specific testing and direct observations. Important aerodigestive disorders include dysphagia, GERD, and aggravation of airway injury due to malfunctions of swallowing or airway protection mechanisms. Objective evaluation of aerodigestive reflexes and symptom correlation may provide support for evidence-based personalized management of feeding and airway protection strategies.

Impact of acid suppression on upper gastrointestinal pH and motility.

BACKGROUND: Proton pump inhibitors (PPIs), widely prescribed to patients with upper gastrointestinal symptoms, alter intragastric pH, and may affect upper gastrointestinal transit and motility parameters in addition to affecting the ability to determine Wireless Motility Capsule (WMC) gastric emptying time. AIM: To assess PPI effect on motility parameters of the upper gastrointestinal tract and to determine if PPIs confound ability of WMC to measure gastric emptying time. METHODS: Twenty healthy subjects were treated with esomeprazole 40 mg bid for 1 week. Another 50 healthy subjects underwent evaluation in absence of PPIs. All subjects underwent WMC test after meal ingestion. After a rapid, sustained luminal pH rise ≥ 0.5 pH units, marking potential gastric emptying time of WMC, an abdominal X-ray (KUB) was taken for gastric emptying time confirmation. Mean pH, pressure and transit time were compared between PPI-treated and untreated groups. RESULTS: There was no difference in gastric emptying time, small bowel transit time (SBTT), or pressure profiles between the groups. The pH in all cases rose ≥ 0.5 pH units. Distal small bowel pH was significantly lower in subjects on PPIs. Gastric emptying time was identified in all subjects treated with PPIs. Pressure and slope criteria were developed to confirm the time of emptying. CONCLUSION: PPI therapy does not have a significant impact on upper gastrointestinal transit and motility but it does decrease distal small bowel pH. The medication reduced the magnitude of pH change at gastric emptying time but using additional criteria based on slope and contraction frequency, WMC was able to measure gastric emptying time in all patients treated with PPIs.

Guinea pig ileum motility stimulation elicited by N-formyl-Met-Leu-Phe (fMLF) involves neurotransmitters and prostanoids.

In guinea-pig ileum (GPI), the chemotactic peptide N-formyl-Met-Leu-Phe-OH (fMLF) possesses spasmogenic properties through the activation of formyl peptide receptors (FPRs). Despite this, the mediators involved remain to be elucidated. fMLF (1nM-1µM) induced a dose-dependent contraction of GPI (EC(50)=24nM), that is blocked by pre-treatment with the FPRs antagonist Boc(2). The pre-treatment with tetrodotoxin (TTX) atropine or with SR140333 reduced the fMLF-induced contraction, whereas with hexamethonium, MEN10627, SB222200, mepyramine, cimetidine, thioperamide or methysergide did not produce any effect. With DuP697 pre-treatment, but not with piroxicam, reduced the fMLF-induced contraction. After stimulation with 24nM fMLF, a strong increase in the PGE(2) levels was observed. Finally, the concomitant blocking of the NK(1) receptor, the muscarinic receptors and COX-2 abolished the GPI contractions induced by fMLF. fMLF induced a concentration-dependent contraction of guinea-pig jejunum (EC(50)=11nM), proximal colon (EC(50)=3.5nM) and distal colon (EC(50)=2.2nM), with a time-course similar to that observed in GPI. In these preparations as well, the co-administration of atropine, SR140333 and DuP697 abolished the contractions induced by fMLF. Intraperitoneal injection of fMLF (0.1 or 1µmol/kg) enhanced the gastrointestinal motility in mice, abolished by the co-administration of atropine, SR140333 and DuP697. In conclusion, we showed that fMLF exerts spasmogenic actions on guinea-pig intestine both in vitro and in vivo through the release of acetylcholine and substance P from myenteric motorneurons and through prostanoids, probably from the inflammatory cells of the enteric immune system.

[Effect of prokinetic agents on the electrical activity of stomach and duodenum in rats].

OBJECTIVE: To determine the effect of prokinetic agents such as domperidone, mosapride, clarithromycin, and itopride on the electrical activity of the stomach and duodenum in SD rats,and also to explore the mechanism. METHODS: The organism functional experiment system BL-420E was used to record the myoelectrical activity in the stomach and duodenum of SD rats in all groups using domperidone, mosapride, itopride, clarithromycin, and physiological saline on the interdigestive phase. The effect of the prokinetic agents on the amplitude and frequency of gastric and duodenal electromyogram in the SD rats was compared. The antagonists such as atropine, phentolamine, and propranolol were added to investigate the mechanism of action with all prokinetic agents. RESULTS: All prokinetic agents increased the amplitude and frequency of gastric and duodenal fast waves in the SD rats(P<0.05). The effect of itopride was the most obvious among the 3 groups (P<0.05),and clarithromycin had the weakest effect(P<0.05). The amplitude and frequency of gastric and duodenal fast waves in the SD rats in the groups of clarithromycin,domperidone,mosapride, itopride, and physiological saline were inhibited by atropine(P<0.05),but not by phentolamine and propranolol. CONCLUSION: Itopride, mosapride, domperidone, and clarithromycin can increase the amplitude and frequency of gastric and duodenal fast waves in the SD rats. The mechanism may be related to cholinergic receptors, but not adrenergic receptors.

Luminal chemosensing and upper gastrointestinal mucosal defenses.

The upper gastrointestinal mucosa is exposed to endogenous and exogenous substances, including gastric acid, carbon dioxide, and foodstuffs. Physiologic processes such as secretion, digestion, absorption, and motility occur in the gastrointestinal tract in response to ingested substances, which implies the presence of mucosal sensors. We hypothesize that mucosal acid sensors and tastelike receptors are important components of the mucosal chemosensing system. We have shown that luminal acid/carbon dioxide is sensed via ecto- and cytosolic carbonic anhydrases and ion transporters in the epithelial cells and via acid sensors on the afferent nerves in the duodenum and esophagus. Furthermore, a luminal l-glutamate signal is mediated via mucosal l-glutamate receptors with activation of afferent nerves and cyclooxygenase in the duodenum, which suggests the presence of luminal l-glutamate sensing. These luminal chemosensors help to activate mucosal defense mechanisms to maintain the mucosal integrity and physiologic responses of the upper gastrointestinal tract. Because neural pathways are components of the luminal chemosensory system, investigation of these pathways may help to identify novel molecular targets in the treatment and prevention of mucosal injury and visceral sensation.

Cholecystokinin and gut-brain signalling.

Enteroendocrine cells of the gastrointestinal tract act as a luminal surveillance system responding to either the presence or absence of food in the gut lumen. Collectively, their secretory products regulate the course of digestion and determine the delivery of nutrient to the gut by controlling food intake. Afferent neurons of the vagus nerve are an important target of gut hormones, particularly for control of food intake. The intestinal hormone cholecystokinin (CCK) stimulates vagal afferent neuron discharge and also controls the expression of both G-protein coupled receptors and peptide neurotransmitters in these neurons. When plasma CCK concentrations are low, for example in fasting, vagal afferent neurons express cannabinoid CB1 and melanin concentrating hormone (MCH)-1 receptors, both of which are associated with stimulation of food intake. Post-prandial release of CCK rapidly down-regulates the expression of both receptors but stimulates the expression of Y2 receptors in neurons projecting to the stomach. In fasting, there is also increased expression in these neurons of the appetite-stimulating neuropeptide transmitter MCH, and depressed expression of the satiety-peptide cocaine and amphetamine regulated transcript (CART). Secretion of CCK decreases expression of MCH and increases expression of CART. The neurochemical phenotype of vagal afferent neurons therefore encodes whether or not there has been nutrient ingestion over the previous period. At low plasma concentrations of CCK vagal afferent neurons exhibit increased capacity for appetite-stimulation, while post-prandial concentrations of CCK lead to enhanced capacity for satiety signalling. A gatekeeper function can therefore be attributed to CCK in that its presence or absence influences the capacity of vagal afferent neurons to respond to other neurohormonal signals.

Expression of taste molecules in the upper gastrointestinal tract in humans with and without type 2 diabetes.

OBJECTIVE: Nutrient feedback from the small intestine modulates upper gastrointestinal function and energy intake; however, the molecular mechanism of nutrient detection is unknown. In the tongue, sugars are detected via taste T1R2 and T1R3 receptors and signalled via the taste G-protein alpha-gustducin (G alpha(gust)) and the transient receptor potential ion channel, TRPM5. These taste molecules are also present in the rodent small intestine, and may regulate gastrointestinal function. SUBJECTS AND METHODS: Absolute transcript levels for T1R2, T1R3, G alpha(gust) and TRPM5 were quantified in gastrointestinal mucosal biopsies from subjects with and without type 2 diabetes; immunohistochemistry was used to locate G alpha(gust). Effects of luminal glucose on jejunal expression of taste molecules were also quantified in mice. RESULTS: T1R2, T1R3, G alpha(gust) and TRPM5 were preferentially expressed in the proximal small intestine in humans, with immunolabelling for G alpha(gust) localised to solitary cells dispersed throughout the duodenal villous epithelium. Expression of T1R2, T1R3, TRPM5 (all p<0.05) and G alpha(gust) (p<0.001) inversely correlated with blood glucose concentration in type 2 diabetes subjects but, as a group, did not differ from control subjects. Transcript levels of T1R2 were reduced by 84% following jejunal glucose perfusion in mice (p<0.05). CONCLUSIONS: Taste molecules are expressed in nutrient detection regions of the proximal small intestine in humans, consistent with a role in "tasting". This taste molecule expression is decreased in diabetic subjects with elevated blood glucose concentration, and decreased by luminal glucose in mice, indicating that intestinal "taste" signalling is under dynamic metabolic and luminal control.

Anatomy and physiology of feeding and swallowing: normal and abnormal.

Eating and swallowing are complex behaviors involving volitional and reflexive activities of more than 30 nerves and muscles. They have two crucial biologic features: food passage from the oral cavity to stomach and airway protection. The swallowing process is commonly divided into oral, pharyngeal, and esophageal stages, according to the location of the bolus. The movement of the food in the oral cavity and to the oropharynx differs depending on the type of food (eating solid food versus drinking liquid). Dysphagia can result from a wide variety of functional or structural deficits of the oral cavity, pharynx, larynx, or esophagus. The goal of dysphagia rehabilitation is to identify and treat abnormalities of feeding and swallowing while maintaining safe and efficient alimentation and hydration.

Neural control of feeding and swallowing.

Eating and drinking are basic pleasures in life that most of us take for granted, yet the ease with which we perform these tasks belies their complex neurologic system of control. Recent studies of human swallowing have begun to unravel some of these complexities, evolving our understanding and thus ultimately helping to generate novel therapies for the treatment of swallowing problems after cerebral injury, such as stroke. This article provides a general overview of current knowledge of the neural control mechanisms that underlie the coordination of mastication, oral transport, swallowing, and respiration in humans.

Sweetened carbonated drinks do not alter upper digestive tract physiology in healthy subjects.

Sweetened carbonated beverages are widely consumed, which has fuelled several conflicting opinions about their effects on upper digestive tract functions. We aimed to evaluate the effect of sweetened carbonated drinks, consumed with a standard meal, on gastro-oesophageal reflux, gastric emptying and gallbladder contraction and postmeal sensations in healthy subjects. Thirteen healthy volunteers (seven women, six males; median age 22 years) were tested following the intake of 300 mL sweetened water containing increasing concentrations of carbon dioxide (seven subjects), and of 300 mL sweetened commercial flavoured drink with and without carbon dioxide (six subjects). Gastro-oesophageal reflux, gastric emptying and gallbladder contraction were studied by pH-impedance, octanoic acid breath test and ultrasound respectively. Gastro-oesophageal refluxes were significantly increased 1 h after meal with both water and commercial beverages; only sweetened water without carbon dioxide determined a persistently increasing number of refluxes 2 h postmeal. No differences were found for gastric emptying, gallbladder contraction or postmeal symptoms with any of the beverages tested. This study shows that 300 mL of sweetened carbonated beverage with different levels of carbonation or a commercial soft drink do not modify the physiology of the upper digestive tract.

Personal reminiscences about Morton Grossman and the founding of the Center for Ulcer Research and Education (CURE).

The Center for Ulcer Research and Education (CURE) from its onset was primarily the work of one man: Professor Morton Grossman, or "Mort" as he was known and called by all. Mort's legacy includes a large body of scientific publications, the first National Institutes of Health Digestive Diseases Center (CURE), and, most importantly, a group of scientists who have become academic leaders and who have made important contributions in the fields of upper gastrointestinal (GI) tract secretion, hormones and receptors, mucosal defense mechanisms, the design and conduct of randomized clinical trials, and ulcer epidemiology. Indeed, Mort is considered to be a founding father of modern academic GI research. I was fortunate to have known and worked with Mort and would like to memorialize his contributions so that his memory can inspire the next generation of academicians.

Dopaminergic control of foregut contractions in Locusta migratoria.

Tyrosine hydroxylase-like immunoreactivity is present in cell bodies and processes in the brain and optic lobes of Locusta migratoria, with processes projecting along the frontal connectives to form a neuropile within the frontal ganglion. Immunoreactive cell bodies and processes are also evident in the hypocerebral and ventricular ganglia with processes extending over the foregut. Tyrosine hydroxylase is the rate-limiting enzyme in dopamine biosynthesis, and high-performance liquid chromatography coupled to electrochemical detection was used to confirm the presence of dopamine in the innervation to the foregut. Spontaneous foregut contractions are under the control of the ventricular ganglia and are absent when these ganglia are removed. Dopamine leads to an inhibition of both the amplitude and frequency of phasic contractions of the foregut that are produced when the ventricular ganglia are left attached. Dopamine has direct effects on the foregut muscle in the absence of the ventricular ganglia, inhibiting a proctolin-induced contraction in a dose-dependent manner.

Superiority of nasal mask pressure over mouth pressure, as a surrogate of diaphragm twitch-related esophageal pressure, in healthy humans.

Assessing diaphragm function is clinically and physiologically pertinent. It can rely on the measurement of pressure responses to phrenic stimulation. Combining mouth pressure (Pm) with cervical magnetic stimulation (CMS) is painless and easy to perform, but Pm-CMS poorly reflects esophageal pressure (Pes-CMS) because of poor pressure transmission across the airway. We reasoned that the mouth opening and neck flexion that are associated with the measurement of Pm-CMS would impair upper airway dynamics and further hinder pressure transmission. Therefore, we assessed the CMS-related pressure measured in a nasal mask (Pmask; mouth closed) without neck flexion as a possible surrogate of Pes-CMS, in 14 men and 3 women, age 24.5+/-2.2. Pes-CMS was 15.7+/-4.3 cmH2O, significantly higher than Pm-CMS (13.5+/-5.6 cmH2O, P<0.0001) but not different from Pmask-CMS (15.2+/-4.9 cmH2O). The concordance correlation coefficient was low (0.6808) between Pes-CMS and Pm-CMS. It was higher between Pes-CMS and Pmask-CMS (0.8730). Pm-CMS wrongly classified five subjects as abnormal (<10 cmH2O), versus 1 for Pmask and 5 for Pm (P=0.025). Passing and Bablok regressions found no difference between Pes-CMS and Pmask-CMS, but identified a systematic difference and a proportional error between Pes-CMS and Pm-CMS. We conclude that Pmask-CMS is a better surrogate of Pes-CMS than Pm-CMS.

Proposal for the existence of a nasogastric reflex in humans, as a potential cause of upper gastrointestinal symptoms.

The nose is a gateway of air from the environment to the body and with its rich innervation from the olfactory and trigeminal nerves plays a critical role as a sensor in both human beings and primitive animals. Irritation of the nasal or paranasal mucosa may initiate a severe bradycardia, apnea, and vasoconstriction and increase the pulmonary airflow resistance. However, the interaction between nasal mucosa and the upper gastrointestinal tract is more often than not neglected in the clinical literature. We propose that a nasogastric reflex might exist with its afferent and efferent loops being the trigeminal and vagus nerves, respectively. The central connection of these loops is located at the pontomedullary level. The sensory inputs from the nasal mucosa to the general somatic afferent component of the brainstem including the pontine and medullary trigeminal nucleuses may induce the neighboring nucleus of the solitary tract and dorsal motor nucleus of the vagus. This initiates, via the efferent fibers of the vagus nerve, the manifestations of the vagal stimulation. The presence of a nasogastric reflex may warrant considerations as diseases of nose and paranasal sinuses may be the cause upper gastrointestinal symptmatology.