13C-octanoic Acid Breath Test Research Articles

Macronutrients effects on satiety and food intake in older and younger adults: A randomised controlled trial

Older adults are advised to increase their protein intake to maintain their muscle mass. However, protein is considered the most satiating macronutrient and this recommendation may cause a decrease in total energy intake. To date, satiety studies comparing all three macronutrients have been undertaken in young adults, and it is unclear if the same response is seen in older adults. The objective of this study was to compare the effect of preloads high in protein, fat, and carbohydrate but equal in energy (∼300 kcal) and volume (250 ml) on energy intake, perceived appetite, and gastric emptying in younger and older adults. Twenty older and 20 younger adults completed a single-blinded randomised crossover trial involving three study visits. Participants consumed a standard breakfast, followed by a preload milkshake high in either carbohydrate, fat, or protein. Three hours after the preload, participants were offered an ad libitum meal to assess food intake. Visual analogue scales were used to measure perceived appetite and gastric emptying was measured via the 13C-octanoic acid breath test. There was no significant effect of preload type or age on energy intake either at the ad libitum meal, self-recorded food intake for the rest of the test day or subjective appetite ratings. There was a significant effect of preload type on gastric emptying latency phase and ascension time, and an effect of age on gastric emptying latency and lag phase such that older adults had faster emptying. In conclusion, energy intake, and perceived appetite were not affected by macronutrient content of the preloads in both younger and older adults, but gastric emptying times differed.

IN VIVO MONITORING STRATEGIES FOR EVALUATION OF FLOATING DRUG DELIVERY SYSTEMS

In recent years, various advancements have been introduced in the development of controlled drug release devices for resolving different physiological problems for example, gastric retention inconsistency along with erratic gastric emptying time. Gastroretentive delivery formulations receive considerable attention to overcome these drawbacks and in optimizing the absorption of different medicaments. Gastroretentive technologies considerably extend the stomach retention time of dosage forms with increased bioavailability as well as therapeutic efficacy. Gastroretention can be successfully achieved utilizing gastric floating system. The rationale of the present manuscript focuses on current advancements of gastric floating systems so as to accomplish appropriate drug bioavailability and, subsequently drug targeting to the stomach. In vivo evaluation parameters, especially pivotal imaging techniques including roentgenography, gamma scintigraphy, gastroscopy, magnetic marker monitoring, magnetic resonance imaging, ultrasonography, 13C octanoic acid breath test etc. have been emphasized in this manuscript for monitoring drug formulation behavior which extensively revolutionized thorough understanding in the avenue of improved bioavailability of gastroretentive systems.

Measurement of Gastric Emptying Using a 13C-octanoic Acid Breath Test with Wagner-Nelson Analysis and Scintigraphy in Type 2 Diabetes.

Breath tests utilising 13C-labelled substrates for the assessment of gastric emptying have been applied widely. Wagner-Nelson analysis is a pharmacokinetic model that can be utilised to generate a gastric emptying curve from the % 13CO2 measured in breath samples. We compared Wagner-Nelson analysis with (i) scintigraphy and (ii) conventional breath test modelling to quantify gastric emptying in type 2 diabetes. Thirteen patients (age 68.1±1.5 years, body mass index 31.0±0.9 kg/m2, HbA1c 6.3±0.2%) consumed a mashed potato meal comprising 65 g powdered potato, 20 g glucose, 250 ml water, an egg yolk labelled with 100 μL 13C-octanoic acid and 20MBq 99mTc-calcium phytate. Scintigraphic data were acquired and breath samples collected for 4 hours after the meal. Gastric emptying curves were derived based on each technique; the 50% emptying time and intragastric retention at 60 min were also calculated. With Wagner-Nelson analysis, a Kel=0.60 (the elimination constant) best approximated the scintigraphic gastric emptying curve. There was a relationship between the T50 calculated with scintigraphy and by both Wagner-Nelson Kel=0.60 (r2=0.45, P<0.05) and conventional analysis (r2=0.44, P<0.05). There was no significant difference in the 50% gastric emptying time for scintigraphy (68.5±4.8 min) and Wagner-Nelson Kel=0.60 (71.3±4.5 min), however, the 50% gastric emptying time calculated by conventional analysis was much greater at 164.7±6.0 min (P<0.001). In type 2 diabetes, gastric emptying of a mashed potato meal measured using a 13C-octanoic acid breath test analysed with Wagner-Nelson Kel=0.60 closely reflects measurements obtained with scintigraphy, whereas, in absolute terms, the conventional breath test analysis does not.

Matched whole grain wheat and refined wheat milled products do not differ in glycemic response or gastric emptying in a randomized, crossover trial

Epidemiologic and some clinical studies support the view that whole grain foods have lower glycemic response than refined grain foods. However, from the perspective of food material properties, it is not clear why whole grain cereals containing mostly insoluble and nonviscous dietary fibers (e.g., wheat) would reduce postprandial glycemia. We hypothesized that glycemic response for whole grain wheat milled products would not differ from that of refined wheat when potentially confounding variables (wheat source, food form, particle size, viscosity) were matched. Our objective was to study the effect of whole grain wheat compared with refined wheat milled products on postprandial glycemia, gastric emptying, and subjective appetite. Using a randomized crossover design, healthy participants (n=16) consumed 6 different medium-viscosity porridges made from whole grain wheat or refined wheat milled products, all from the same grain source and mill: whole wheat flour, refined wheat flour, cracked wheat, semolina, reconstituted wheat flour with fine bran, and reconstituted wheat flour with coarse bran. Postprandial glycemia, gastric emptying, and appetitive response were measured using continuous glucose monitors, the 13C-octanoic acid (8:0) breath test, and visual analog scale (VAS) ratings. Bayes factors were implemented to draw inferences about null effects. Little-to-no differences were observed in glycemic responses, with lower incremental AUC between 0 and 120min glycemic responses only for semolina [mean difference (MD): -966mg min/dL; 95% CI: -1775, -156mg min/dL; P = 0.02) and cracked wheat (MD: -721mg min/dL; 95% CI: -1426, -16mg min/dL; P = 0.04) than for whole wheat flour porridge. Bayes factors suggested weak to strong evidence for a null effect (i.e., no effect of treatment type) in glycemic response, gastric emptying, and VAS ratings. Although whole grain wheat foods provide other health benefits, they did not in their natural composition confer lower postprandial glycemia or gastric emptying than their refined wheat counterparts.This trial was registered at clinicaltrials.gov as NCT03467659.

Iron tablets delay gastric emptying, which is ameliorated by 5-HT&lt;sub&gt;3&lt;/sub&gt; receptor antagonist.

Gastrointestinal symptoms, including nausea and vomiting, are common adverse effects of oral iron tablets, but the mechanism of iron-induced nausea and vomiting is not yet known. Studies have shown that there are close relationships between gastrointestinal motility and gastrointestinal symptoms such as nausea, vomiting, and diarrhea, with more than 90% of patients with delayed gastric emptying experiencing nausea and vomiting. However, the effect of iron on gastrointestinal motility has not yet been investigated. In the present study, we aimed to elucidate the effects of iron on gastrointestinal motility using sodium ferrous citrate (SFC), the most commonly used iron tablets. Gastric emptying in mice was assessed by 13C-octanoic acid breath test to examine the effect of SFC (3-30 mg Fe/kg, p.o.) with or without the 5-HT3 receptor antagonist, palonosetron hydrochloride (5 mg/kg. s.c.). Colon transit was also measured by the beads method. The results showed that SFC delayed the gastric emptying, which was ameliorated by administration of palonosetron hydrochloride. It was also confirmed that ingredients of the tablets had no effect on gastric emptying. SFC also had no effect on the colon transit in vivo. These results lead the possibility that the iron-induced delayed gastric emptying may be mediated through nausea and vomiting.

Effect of Combined Interval and Continuous Exercise Training on Gastric Emptying, Appetite, and Adaptive Responses in Men With Overweight and Obesity.

Background/Objectives: Characterizing compensatory and adaptive responses to exercise assists in understanding changes in energy balance and health outcomes with exercise interventions. This study investigated the effects of a short-term exercise intervention (combining high intensity interval (HII) and continuous exercise) on (1) gastric emptying, appetite and energy intake; and (2) other adaptive responses including cardiorespiratory fitness, in inactive men with overweight/obesity.Methods: Fifteen men (BMI: 29.7 ± 3.3 kg/m−2) completed a 4-wk supervised exercise intervention, consisting of 5 exercise sessions per week alternating between HII (30 s at 100% VO2max followed by 30 s recovery) and continuous (at 50% VO2max) training on a cycle ergometer, progressing from 30 to 45 min session duration. Gastric emptying (13C-octanoic acid breath test), appetite (visual analog scale), energy intake (ad libitum lunch meal), body composition (air displacement plethysmography), non-exercise activity (accelerometery) VO2max, blood pressure, and fasting concentrations of glucose, insulin, and ghrelin were measured before and after (≥48 h) the intervention.Results: Gastric emptying, glucose, insulin and ghrelin were unchanged, but energy intake at the ad libitum lunch test meal significantly increased at post-intervention (+171 ± 116 kcal, p < 0.01). Body weight (−0.9 ± 1.1 kg), waist circumference (−2.3 ± 3.5 cm) and percent body fat (−0.9 ± 1.1%) were modestly reduced (P < 0.05). VO2max increased (+4.4 ± 2.1 ml.kg.min−1) by 13% and systolic (−6.2 ± 8.4 mmHg) and diastolic (−5.8 ± 2.2 mmHg) blood pressure were significantly reduced (P ≤ 0.01 for all).Conclusions: Four weeks of exercise training did not alter gastric emptying, indicating gastric emptying may only adapt to a higher volume/longer duration of exercise or changes in other characteristics associated with regular exercise. The combination of HII and continuous exercise training had beneficial effects on body composition, cardiorespiratory fitness, and blood pressure and warrants further investigation in larger randomized controlled trials.

Astroglial Regulation of Caloric Intake Following Acute High‐Fat Diet Exposure

Chronic high fat diet (HFD) exposure results in hyperphagia and the development of obesity. Caloric intake during acute (3-5 days) HFD exposure, however, is regulated. We have previously shown that increased activation of NMDA receptors on the motoneurons of the dorsal motor nucleus of the vagus (DMV) contributes to the regulation of caloric intake during acute HFD exposure (Clyburn, et. al. 2018). The mechanism that is responsible for altered excitatory drive to DMV neurons is unknown. HFD exposure is associated with inflammation. Neuroinflammation and astroglial activation have been shown to modulate neural activity and glutamatergic signaling. The purpose of this study is to test the hypothesis that during acute HFD exposure, astrocyte activation increases the glutamatergic drive to DMV neurons and regulates caloric intake. Male and female Sprague-Dawley rats were transfected with the astrocyte inhibitory DREADD, pAAV-GFAP-hM4D(Gi)-mCherry, (“hM4Di”; Addgene #50479-AAV5; titer 1x1013 diluted 1:10) or AAV-GFAP104-mCherry, (“empty vector”; UNC vector core, titer 2.7x1012 diluted 1:10). Microinjections were made into the dorsal vagal complex. After recovery, rats were fed a control or HFD (14% and 60% kcal from fat, respectively) for 3-5 days. Whole-cell patch clamp recordings were made of gastric-projecting DMV neurons in thin brainstem slices of transfected rats. The effects of the NMDA receptor antagonist, AP5 (25μM), in the presence of clozapine (10μM) or the DREADD agonist, clozapine-N-oxide (CNO; 10μM) on miniature excitatory postsynaptic current (mEPSC) kinetics and action potential (AP) firing rate were examined. The effects of CNO and clozapine on caloric intake and gastric emptying rates using the 13C octanoic acid breath test were also assessed. As shown previously, following acute HFD, AP5 decreases mEPSC frequency and AP firing rate. This AP5-mediated decrease was unaffected by clozapine or CNO application to empty vector control groups. CNO in the hM4Di group attenuated the AP5-mediated decrease in mEPSC frequency and AP firing rate (mEPSC frequency: 54±5.0% vs. 53±9.5% vs. 100±1.5% of baseline, respectively; AP firing rate: 8±5.3% vs. 41±14.9% vs. 111±3.5%; P<0.05 with two-way ANOVA and post-hoc Bonferroni; N=7-9 cells from 3-5 rats). In addition, the delay in gastric emptying rates observed 4 days following HFD exposure was attenuated by CNO administration to hM4Di rats, while empty vector or clozapine controls were uneffected (119±7.9% vs. 166±7.4% vs. 144±6.7% of baseline, respectively; P<0.05 with two-way ANOVA and post-hoc Bonferroni; N=6-7 rats). CNO administration to hM4Di rats also prevented the regulation of caloric intake normally observed 3-5 days of HFD exposure, compared to clozapine and empty vector controls (AUC: 964±34.4a.u. vs. 843±14.3a.u. vs. 815±17.9a.u., respectively; P<0.05 from Student's unpaired t-test; N=6). These data suggest that astrocyte activation is involved in the alteration of glutamatergic currents and the homeostatic regulation of food intake following acute HFD. Understanding the mechanism responsible for the regulation of caloric intake is critical in identifying potential therapeutic targets for the treatment of obesity when such neuroplasticity may be absent.

Pyloric dilation with the esophageal functional lumen imaging probe in gastroparesis improves gastric emptying, pyloric distensibility, and symptoms

The role of decreased pyloric distensibility in gastroparesis as measured by the endolumenal functional luminal imaging probe (EndoFLIP) has been receiving increasing attention. In this study, we present clinical outcomes to pyloric dilation with the esophageal FLIP (EsoFLIP) in regard to gastric emptying, symptom evolution, and FLIP metrics. Patients evaluated for gastroparesis (gastric emptying studies of t1/2≥180 minutes during 13C-octanoic acid breath test and/or gastric remnants during gastroscopy after a sufficient fasting period) were scheduled for EsoFLIP controlled pyloric dilation. Pre- and postprocedural gastric emptying studies, questionnaires (Patient Assessment of Upper GI Symptoms Severity Index [PAGI-SYM; including the Gastroparesis Cardinal Symptom Index] and Patient Assessment of Quality of Life Index [PAGI-QOL]), and FLIP metrics were documented. Dilation was conducted according to a self-developed algorithm. Forty-six patients were analyzed (72% women; median age, 39 years [range, 18-88]). Etiologies of gastroparesis were diabetic in 10 patients (22%), idiopathic in 33 (72%), and postoperative in 3 (6%). Postprocedural gastric emptying time decreased from a median of 211 minutes to 179 minutes (P= .001). In accordance, pyloric distensibility, PAGI-SYM, PAGI-QOL, and Gastroparesis Cardinal Symptom Index values improved significantly. After a median follow-up of 3.9 months, 57% of all treated patients with returned questionnaires reported improved symptoms. Pyloric EsoFLIP controlled dilation shows value in the treatment of gastroparesis, both subjectively and objectively. Long-term follow-up to assess efficacy and comparative trials are warranted.

Resistance of postprandial gastric functions and autonomic balance to taste stimulation.

Exposure to unpleasant tastes leads to disturbances of interdigestive gastric myoelectrical activity (GMA) and may affect sympathetic/parasympathetic balance (SPB). We made a careful study to determine whether taste stimulation modulates the postprandial GMA, SPB, and gastric emptying (GE) of a solid meal. Eighteen healthy volunteers (9F/9M) entered the study. On six separate days, we recorded a four-channel electrogastrogram from each volunteer during a 35-min fasting period, then for 90 min after ingestion of a solid test meal of 300 kcal. GE was measured using a 13C-octanoic acid breath test. Heart rate variability (HRV) analysis was simultaneously performed. At the start of the 21st min after the test meal, subjects received an agar cube delivering either a sweet, salty, sour, or bitter taste, which they kept in the mouth for 35 min. Control procedures involved sessions performed with a tasteless agar cube, and without any stimulation. There was no effect of the experimental intervention upon the relative power share of particular GMA rhythms. Stimulation with the salty and the bitter taste evoked a statistically significant increase in the dominant frequency, whereas the sweet and sour taste did not affect it. Taste stimulation did not interfere with the meal-induced rise in the dominant power, nor affect slow wave coupling. The kinetics of the solid GE remained unchanged by the intervention. None of the taste stimulations affected the postprandial SPB. Taste stimulation elicited after ingestion of a meal, in contrast to that during a fast, did not adversely modify the postprandial pattern of either the GMA or SPB, nor affect the GE of solids.

Some pearl millet-based foods promote satiety or reduce glycaemic response in a crossover trial.

In a previous trial in Mali, we showed that traditional pearl millet couscous and thick porridge delayed gastric emptying (about 5 h half-emptying times) in a normal-weight population compared with non-traditional carbohydrate-based foods (pasta, potatoes, white rice; about 3 h half-emptying times), and in a gastric simulator we showed millet couscous had slower digestion than wheat couscous. In light of these findings, we tested the hypothesis in a normal-weight US population (n 14) that millet foods would reduce glycaemic response (continuous glucose monitor), improve appetitive sensations (visual analogue scale ratings), as well as reduce gastric emptying rate (13C-octanoic acid breath test). Five carbohydrate-based foods (millet couscous - commercial and self-made, millet thick porridge, wheat couscous, white rice) were fed in a crossover trial matched on available carbohydrate basis. Significantly lower overall glycaemic response was observed for all millet-based foods and wheat couscous compared with white rice (P≤0·05). Millet couscous (self-made) had significantly higher glycaemic response than millet couscous (commercial) and wheat couscous (P<0·0001), but as there were no differences in peak glucose values an extended glycaemic response was indicated for self-made couscous. Millet couscous (self-made) had significantly lower hunger ratings and higher fullness ratings (P<0·05) than white rice, millet thick porridge and millet couscous (commercial). A normal gastric emptying rate (<3 h half-emptying times) was observed for all foods, with no significant differences among them. In conclusion, some traditionally prepared pearl millet foods show the potential to reduce glycaemic response and promote satiety.

A Close Relationship Between Networks of Interstitial Cells of Cajal and Gastrointestinal Transit In Vivo.

The interstitial cells of Cajal associated with the myenteric plexus (ICC-MP) are located in the same area as the myenteric plexus. ICC-MP networks are linked to the generation of electrical pacemaker activity that causes spontaneous gastrointestinal (GI) contractions; however, its role in GI transit is not clear. The aim of this study was to comprehensively investigate the effect of ICC-MP disruption on GI transit in vivo using W/W v mice, partially ICC-deficient model mice. In this study, we measured GI transit using a 13C-octanoic acid breath test, an orally administered dye and a bead expulsion assay. ICC were detected by immunohistochemical staining for c-Kit, a specific marker for ICC. Interestingly, we found that gastric emptying in W/W v mice was normal. We also found that the ability of small intestinal and colonic transit was significantly reduced in W/W v mice. Immunohistochemical staining using whole-mount muscularis samples revealed that c-Kit-positive ICC-MP networks were formed in wild-type mice. In contrast, ICC-MP networks in W/W v mice were maintained only in the gastric antrum and were significantly reduced in the ileum and colon. No significant changes were observed in the nerve structures of the myenteric plexus in W/W v mice. These findings suggest that ICC-MP contribute to GI transit as a powerful driving function in vivo.

Plasma dosage of ghrelin, IGF-1, GLP-1 and leptin related to gastric emptying and esophageal pH-impedance in children with obesity.

The main aim of the study was to assess the relationship between leptin, ghrelin, insulin-like growth factor 1 (IGF-1), and glucagon-like peptide 1 (GLP-1) blood levels and gastric motility in children with obesity compared to healthy children. Secondary aims were to assess the possible association between these hormones and obesity, reflux impedance parameters, reflux symptoms, other GI disorders, and quality-of-life scores within the same groups. Children with obesity plus GERD symptoms and 2 control groups of children with obesity without GERD and healthy lean children aged 4-17years underwent an auxological evaluation, an assessment of gastro-intestinal symptoms and quality of life, hormonal dosages, and an evaluation of gastric emptying time (GET) through 13C-octanoic acid breath test. No significant association was found between hormones and gastric motility. Leptin and ghrelin levels were significantly associated with obesity parameters. No significant differences were found between GET and hormones of the patients with obesity, either with or without GERD. Although we found an association between auxological parameters and both leptin and ghrelin levels, this association did not imply an effect on the upper GI motility. Therefore, our hypothesis that alterations of these hormones in children with obesity could affect gastric emptying, triggering GERD, was not supported by our data.

Contribution of Serotonin 3A Receptor to Motor Function and Its Expression in the Gastrointestinal Tract

Introduction: The serotonin 3A receptor (5-HT_3AR) is involved in vomiting and gastrointestinal motility. However, it is not well understood the expression pattern of 5-HT_3AR in the gut immunohistochemically and how much contribution of 5-HT_3AR to upper or lower intestinal motility. Objectives: We investigated the contribution of 5-HT_3AR to gastrointestinal motor function by using 5-HT_3AR KO mice and sought to identify 5-HT_3AR-expressing cells via immunohistochemical staining using 5-HT_3AR-GFP reporter mice. Methods: The expression of 5-HT_3AR was measured in each section of the gut through real-time PCR. The motor function of the stomach and colon was assessed via the ¹³C-octanoic acid breath test and colonic bead expulsion test, respectively, using 5-HT_3AR KO mice. 5-HT_3AR-expressing cells in the muscle layer of the gut were identified by immunohistochemical staining using 5-HT_3AR-GFP reporter mice. Results: 5-HT_3AR was expressed throughout the digestive tract, and 5-HT_3AR expression in the stomach and lower digestive tract was higher than that in the other sections. Motor function in the stomach and colon was lower in 5-HT_3AR KO mice than in WT mice. As a result of immunohistochemical staining using GFP reporter mice, cholinergic neurons and PDGFRα⁺ cells were shown to express 5-HT_3AR. In contrast, 5-HT_3AR indicated by GFP fluorescence was rarely detected in ICC and smooth muscle cells. Conclusions: These results show that 5-HT_3AR is highly expressed in the stomach and large intestine and that the activation of 5-HT_3AR accelerates gastric emptying and large intestine transit. Additionally, 5-HT_3AR is highly expressed in cholinergic neurons and some interstitial cells, such as PDGFRα⁺ cells.

Food Intake is Influenced by Gastric Emptying, Motility, and Compliance

Obesity, which results from an increase in caloric intake relative to energy expenditure, is often associated with an alterations in gastric emptying. The exact relationship between gastric emptying and food intake, however, is unclear. Some reports have suggested that obesity is associated with an accelerated liquid but a delayed solid gastric emptying rate, while more recent studies have suggested that there may be no significant correlation between BMI and gastric emptying. The purpose of the present study is to test the hypothesis that food intake in rodents is influenced by a combination of gastric emptying, gastric tone and motility, and compliance.Male and female Sprague‐Dawley rats (4–8 weeks of age) were fed a control or HFD (14% or 60% kcal from fat, respectively) for 3–5 days prior to experimentation (acute HFD). Food intake and body weight were measured twice daily prior to, and throughout, HFD exposure. The 13C octanoic acid breath test was used to measure gastric emptying rates in rats repeatedly throughout exposure to the high fat diet. Miniature strain gauges were sewn onto the ventral surface of the corpus and the antrum of the stomach in anesthetized rats to allow measurement of basal gastric motility and tone. Gastric compliance was measured via a latex balloon inserted into the stomach via the pylorus in anesthetized rats. Following placement, the balloon was maximally inflated (2mL; 1min) before deflation. After 10min recovery, the balloon was then inflated in 0.2mL increments for 1 minute each, and the balloon pressure measured continuously.Acute high fat diet exposure induced a brief (24hr) period of hyperphagia before rats regulate their food intake and restore caloric balance within a 3–5 day period (74.7±4.0 kcal/day at day 1 vs. 59±3.7 kcal/day at days 3–5, P&lt;0.05, N=16), as described previously (PMID: 29368945). While gastric emptying rate was not significantly different during the hyperphagic period following high fat diet exposure (120±14.1% of baseline, P&gt;0.05, N=6), emptying was significantly delayed after 4 days HFD exposure (144±15.8% of baseline, P&gt;0.05, N=6), when caloric intake is restored to baseline levels. Neither gastric compliance (total AUC throughout distention volume range: 37±1.7 vs. 38±1.1, P&gt;0.05, N=6–8) nor basal gastric motility (104±12.2 vs. 110±16.3mg/min P&gt;0.05, N=10–13) was altered during this time period.These data suggest that i) gastric emptying rates are more closely associated with the regulation of caloric intake and energy balance than either basal gastric motility or compliance, and ii) gastric emptying may be disrupted without any observed alterations in local gastric functions. We have shown previously, that restoration of caloric balance is associated with neuroplasticity within central vagal neurocircuits (PMID: 29368945). These data suggest that dysregulation of gastric emptying may be important in the central control of food intake, even under conditions where alterations in peripheral gastric functions, including motility and compliance, are not observed.Support or Funding InformationNIH DK111667 to KNB NIH F31 118833 to CC

Astroglial Regulation of Caloric Intake Following Acute High‐Fat Diet Exposure

Obesity and long‐term exposure to high fat diet (HFD) are both associated with peripheral and central inflammation. Acute HFD exposure, however, is also associated with neuroinflammation in brainstem areas responsible for control of gastric functions and energy homeostasis prior to the development of obesity. Neuroinflammation and astroglial activation are known to modulate neuronal activity and physiological outcomes, such as gastric motility, emptying, and food intake. Following initial HFD exposure and a brief (24hr) period of hyperphagia, both humans and rodent models regulate their caloric intake within 3–5 days. The neuroinflammation observed within the brainstem during acute HFD exposure may, therefore, contribute to the homeostatic regulation of caloric intake. The aim of this study is to test the hypothesis that restoration of energy balance during acute HFD exposure requires brainstem astroglial activation.Sprague‐Dawley rats, 6–8 weeks of age, were fed a control or HFD (14% or 60% kcal from fat, respectively) throughout the study. Immunohistochemical techniques were used to examine astrocyte (GFAP and S100β) and microglia (Iba1 and CD11b) morphology and activity state within the dorsal vagal complex (DVC) after 1,3,5, and 14 days of HFD exposure. Confocal microscopy was used to quantify astrocyte and microglial density, staining intensity, and morphology. Chronic 4th ventricular cannulae were implanted for the administration the astrocyte metabolism inhibitor, fluoroacetate, the microglial activation inhibitor, minocycline (5 and 10mg/mL in 5μL, respectively), or vehicle (PBS) to assess the role of astrocytes and microglia in the regulation of caloric intake. Food intake and body weight were measured twice daily for 10 days prior to, and throughout, HFD exposure. The effects of 4th ventricular administration of fluoroacetate on gastric emptying rates were additionally assessed using the 13C octanoic acid breath test technique.Immunohistochemical characterization of DVC microglia and astrocytes demonstrated an increase in Iba1 and GFAP staining intensity on days 3 and 5 of HFD exposure, which recovered by day 14 (3 Day: 225%, 210%, 5 Day: 195%, 280%, 14 Day: 124%, 92% of control total fluorescence (CTF), respectively, N=2). 4th ventricular application of fluoroacetate and minocycline attenuated the homeostatic regulation of caloric intake observed following acute HFD exposure, compared to vehicle controls (AUC: 242±11.4 vs. 264±2.8 vs. 187±10.6, P&lt;0.05 F=10.35, N=3–5) and preliminary data suggest that fluoroacetate also attenuates the homeostatic delay in gastric emptying observed in control conditions (t1/2: 102.5% vs 150.3% of baseline, respectively, N=1–2).The results from this study indicate that astrocyte and microglial activation occurs within 3–5 days of HFD exposure and is required for the homeostatic regulation of caloric intake and gastric emptying following acute HFD exposure. Understanding the physiological mechanisms responsible for energy homeostasis, and importantly, how this mechanism is lost, is critically important for the development of novel therapeutic targets for the treatment of obesity.Support or Funding InformationAPS UGSRF to CSNIH DK111667 to KNB NIH F31 118833 to CC

Neural Mechanisms Responsible for the Regulation of Caloric Intake Following Acute High Fat Diet are Developmentally Regulated

Previous studies have shown that, in adulthood, acute high fat diet (HFD) exposure is associated with an initial period of hyperphagia before caloric intake is restored within 3–5 days. This period of homeostasis is accompanied by activation of NMDA receptors (NMDA‐R) and increased excitability of identified vagal efferent motoneurons regulating gastric motility. The mechanisms responsible regulation of caloric intake, as well as how and why these mechanisms are lost, are critical to understanding the development of obesity. Alterations in vagal neurocircuit maturation following perinatal (p)HFD exposure, has profound effects on neural control of gastric motility in adulthood, including the failure to regulate caloric intake, which may increase the predisposition to develop obesity. Our previous studies have shown that, following pHFD, inhibitory synaptic inputs to vagal efferent motoneurons are increased, which may prevent the voltage‐dependent activation of synaptic NMDA‐Rs. The purpose of this study was to test the hypothesis that pHFD exposure attenuates the homeostatic activation of DMV NMDA‐Rs following acute HFD exposure in adulthood, leading to dysregulated gastric motility.Sprague Dawley rats were exposed to a control or HFD (14% or 60% kcal from fat, respectively) during postnatal (P) days 1–10. In adulthood, (&gt;P28) rats were re‐exposed to a HFD for 3–5 days prior to experimentation. Whole‐cell patch clamp recordings were made from DMV neurons and the effects of the NMDA‐R antagonist, AP5 (25μM) was tested on miniature excitatory postsynaptic current (mEPSC) amplitude and action potential (AP) firing rates. The 13C octanoic acid breath test was used to determine the effects of pHFD (P1–10) exposure on basal gastric emptying rates. Food intake and body weight was measured twice daily for 10 days prior to, and throughout, adult exposure to HFD.pHFD (P1–10) exposure attenuated the actions of AP5 to inhibit DMV NMDA‐R activation (mEPSC amplitude: 103±5.7% vs. 35±9.4%, P&lt;0.05, N=4–6), and to decrease neuronal excitability (AP firing rate: 102±7.7% vs. 21±13.7% of baseline, P&lt;0.05; N=4–7) observed previously following acute HFD exposure in adulthood. Measurement of gastric emptying rates suggest that pHFD exposure itself significantly delayed baseline gastric emptying (73±1.4 vs. 63±4.3min, P&lt;0.05 N=8–12), and, unlike control rats, gastric emptying was not delayed further by adult dietary challenge (102±13.0% vs. 144±15.8% of baseline, respectively, P&gt;0.05, N=4–6). Additionally, rats that were exposed to a pHFD (P1–10) did not regulate their caloric intake within 3–5 days of adult HFD exposure, as observed control rats (AUC: 215±28.0 vs. 393±34.7, P&lt;0.05, N=9–16).These data suggest that pHFD (P1–10) exposure disrupts central vagal neurocircuit development, increasing the inhibitory drive to DMV neurons, delaying gastric emptying, and preventing the homeostatic regulation of gastric emptying and caloric intake in response to acute adult HFD exposure. Understanding how diet affects the development of vagal neurocircuits is critical for identifying therapeutic targets for the development of obesity.Support or Funding InformationNIH DK111667 to KNB NIH F31 118833 to CC

Transcutaneous vagal nerve stimulation improves gastroenteric complaints in Parkinson's disease patients.

Gastrointestinal dysfunctions are common in Parkinson's disease. Their management is still challenging and new treatment options are needed. To test whether transcutaneous vagal nerve stimulation can improve gastrointestinal dysfunction in patients with Parkinson's disease. We performed a randomized double-blind pilot study enrolling patients suffering from Parkinson's disease with gastroenteric complaints. Patients were randomized to use either a sham-device or to stimulate the vagal nerve with an electric device over the course of four weeks with four stimulations per day. Ten patients (aged 69.6±4.6 years) were randomized for the intervention group, and nine patients (aged 67.2±6.3 years) used a sham-device. Clinical outcome was evaluated using the Gastrointestinal Symptom Rating Scale whereas gastrointestinal motility was measured with the 13C-octanoic acid breath test. In the treatment group, vagal nerve stimulation improved the Gastrointestinal Symptom Rating Scale comparing before and after stimulation (before, 8.7±6.09; after 5.67±3.08; p-value 0.48). This improvement was not observed in the sham group (before, 7.44±4.85; after, 5.67±3.08; p-value 0.16). In the 13C-octanoic acid breath test no significant changes were detectable. Vagal nerve stimulation is well tolerated with no side effects and may be a promising non-invasive therapy option to improve gastroenteric symptoms in Parkinson's disease.

Hyperglycemia in the early stages of type 1 diabetes accelerates gastric emptying through increased networks of interstitial cells of Cajal.

Gastric emptying (GE) can be either delayed or accelerated in diabetes mellitus (DM). However, most research has focused on delayed GE mediated by a chronic hyperglycemic condition in DM. As such, the function of GE in the early stages of DM is not well understood. Interstitial cells of Cajal (ICC) are pacemaker cells in the gastrointestinal tract. In the present study, we investigated changes in GE and ICC networks in the early stages of DM using a streptozotocin-induced type 1 diabetic mouse model. The changes in GE were measured by the 13C-octanoic acid breath test. ICC networks were immunohistochemically detected by an antibody for c-Kit, a specific marker for ICC. Our results showed that GE in type 1 DM was significantly accelerated in the early stages of DM (2–4 weeks after onset). In addition, acute normalization of blood glucose levels by a single administration of insulin did not recover normal GE. ICC networks of the gastric antrum were significantly increased in DM and were not affected by the acute normalization of blood glucose. In conclusion, our results suggest that GE is accelerated in the early stages of DM, and it is associated with increased ICC networks. This mechanism may help to clarify a link between the onset of DM and GE disorders.

Prucalopride in Gastroparesis: A Randomized Placebo-Controlled Crossover Study.

Prokinetics are considered the preferred treatment option for gastroparesis, but evidence of their efficacy is scarce. Prucalopride, a selective 5-hydroxytryptamine 4 receptor agonist used in the treatment of constipation, is able to enhance the gastric emptying rate. In a double-blind, randomized, placebo-controlled crossover study, we evaluated the efficacy of prucalopride to improve the gastric emptying rate and symptoms in patients with gastroparesis. Thirty-four patients with gastroparesis (28 idiopathic, 7 men, mean age 42 ± 13 years) were evaluated in a double-blind crossover trial of 4-week treatment periods with placebo or prucalopride 2 mg q.d., separated by 2 weeks of washout. The primary end point was the change in symptom severity, assessed by the Gastroparesis Cardinal Symptom Index; secondary end points comprised the Patient Assessment of Upper Gastrointestinal Disorders-Symptom Severity Index, the Patient Assessment of Upper Gastrointestinal Disorders-Quality of Life, and daily diaries, and the gastric emptying rate was assessed by the C-octanoic acid breath test. Three patients were lost to follow-up. One serious adverse event occurred (small bowel volvulus in the prucalopride group), and 3 patients dropped out because of adverse events of nausea and headache (all prucalopride). For the entire patient group, compared with placebo, prucalopride significantly improved the total Gastroparesis Cardinal Symptom Index (1.65 ± 0.19 vs 2.28 ± 0.20, P < 0.0001) and the subscales of fullness/satiety, nausea/vomiting, and bloating/distention. Prucalopride significantly improved the overall Patient Assessment of Upper Gastrointestinal Disorders-Quality of Life score (1.15 ± 0.16 vs 1.44 ± 0.16, P < 0.05) and the domains of clothing and diet. The gastric half emptying time was significantly enhanced by prucalopride compared with placebo and baseline (98 ± 10 vs 143 ± 11 and 126 ± 13 minutes, P = 0.005 and <0.001, respectively). These significant improvements were also found when considering only the idiopathic gastroparesis subgroup. In a cohort of patients with predominantly idiopathic gastroparesis, 4 weeks of prucalopride treatment significantly improved symptoms and quality of life and enhanced gastric emptying compared with placebo.

DOZ047.02: Effect of prokinetics on gastric function in children with esophageal atresia and tracheoesophageal fistula (EA-TEF)

Abstract Background To the aim of this study was to determine the effect of domperidone on gastric function in the EA-TEF cohort. Methods Five participants with previously demonstrated abnormal gastric myoelectrical activity and/or delayed gastric emptying on electrogastrography (EGG) and 13C-octanoic acid breath test (OBT), respectively, were recruited. These participants were treated with domperidone (0.2 mg/kg/dose twice a day), for a minimum of 2 weeks, and EGG and OBT investigations were repeated along with a validated PedsQL gastrointestinal symptom questionnaire. A baseline and follow-up ECG was done to check for potential QT interval prolongation. Results Mean gastric emptying half-time was135.4 minutes off therapy and 277.01 minutes on therapy (p = NS) while the mean gastric emptying coefficients were 3.34 and 3.25, respectively (p = NS). All five participants’ gastric myoelectrical activity on EGG remained abnormal. Although the mean percentage of gastric slow waves spent in normal frequency decreased by 1.65%, the post- prandial-to-resting power ratio increased by 8.452 (p = NS). Both parent- and child-reported overall PedsQL scores increased as did the child-reported PedsQL scores based on symptoms related to gastric function (p = NS). Conclusions Domperidone in standard doses did not result in significant change in gastric emptying in EA-TEF children with delayed gastric emptying. This may be due to abnormalities in gastric innervation, in children with EA-TEF. There was however an improvement in the power ratio on EGG. There was also improvement in the PedsQL scores. The lack of statistical significance may be due to our small sample size.