Review on the Regional Effects of Gastrointestinal Luminal Stimulation on Appetite and Energy Intake: (Pre)clinical Observations.

Macronutrients in the gastrointestinal (GI) lumen are able to activate "intestinal brakes", feedback mechanisms on proximal GI motility and secretion including appetite and energy intake. In this review, we provide a detailed overview of the current evidence with respect to four questions: (1) are regional differences (duodenum, jejunum, ileum) present in the intestinal luminal nutrient modulation of appetite and energy intake? (2) is this "intestinal brake" effect macronutrient specific? (3) is this "intestinal brake" effect maintained during repetitive activation? (4) can the "intestinal brake" effect be activated via non-caloric tastants? Recent evidence indicates that: (1) regional differences exist in the intestinal modulation of appetite and energy intake with a proximal to distal gradient for inhibition of energy intake: ileum and jejunum > duodenum at low but not at high caloric infusion rates. (2) the "intestinal brake" effect on appetite and energy appears not to be macronutrient specific. At equi-caloric amounts, the inhibition on energy intake and appetite is in the same range for fat, protein and carbohydrate. (3) data on repetitive ileal brake activation are scarce because of the need for prolonged intestinal intubation. During repetitive activation of the ileal brake for up to 4 days, no adaptation was observed but overall the inhibitory effect on energy intake was small. (4) the concept of influencing energy intake by intra-intestinal delivery of non-caloric tastants is intriguing. Among tastants, the bitter compounds appear to be more effective in influencing energy intake. Energy intake decreases modestly after post-oral delivery of bitter tastants or a combination of tastants (bitter, sweet and umami). Intestinal brake activation provides an interesting concept for preventive and therapeutic approaches in weight management strategies.

Preliminary evidence that endoscopic gastroplication reduces food reward.

Morbidly obese patients are most successfully treated with bariatric surgery. Although restrictive gastric surgery physically limits food intake, it is also suggested that eating behavior and food-reward mechanisms are affected. Therefore, eating behavior and food-reward were assessed in ten patients that underwent gastric volume reduction by endoscopic gastroplication. Patients participated in test days before and one, three and twelve months after the procedure. Weight loss, food intake, appetite, gastric emptying rate, food-reward (i.e. liking and wanting) and eating behavior were assessed. Body mass index decreased from 38.3 (37.6-42.6) to 33.9 (31.0-35.9) kg/m2 after one year. Ad libitum food intake decreased significantly after one month, but not after one year. Gastric emptying rate did not change. AUC of VAS scores for desire to eat, quantity, fullness, hunger, snacking and satiety changed after one month, but not all remained significantly changed after one year. Thirst did not change. Liking scores of food items decreased significantly in the fasted as well as the satiated state after the procedure. Wanting scores did not change. Uncontrolled eating decreased significantly after three and twelve months; emotional eating was only significantly decreased after three months. The results show that food intake decreases, while VAS scores for appetite and eating behavior change accordingly. Liking, but not wanting of food items changed to benefit the weight losing patient. The effects were stronger at one-month follow-up than at 12 months, which may be a risk of relapse after initial successful weight loss. The effects of new bariatric procedures on food-reward should be studied in future randomized trials to further elucidate their impact. REGISTERED AT CLINICALTRIALS. GOV: NCT02381340.

Intestinal barrier function in morbid obesity: results of a prospective study on the effect of sleeve gastrectomy.

BACKGROUND: Obesity has been associated with impaired intestinal barrier function. It is not known whether bariatric surgery leads to changes in intestinal barrier function. We hypothesized that obesity is associated with disturbances in gastrointestinal barrier function, and that after bariatric surgery barrier function will improve. METHODS: Prospective single center study in which we assessed segmental gut permeability by urinary recovery of a multisugar drink in 27 morbidly obese (BMI 43.3 ± 1.1 kg/m2) and 27 age and gender matched lean subjects (BMI 22.9 ± 0.43 kg/m2). Fecal calprotectin, SCFAs, plasma cytokines, and hsCRP were assessed as inflammatory and metabolic markers. Comparisons: (a) morbidly obese subjects vs. controls and (b) 2 and 6 months postsleeve vs. presleeve gastrectomy (n = 14). In another group of 10 morbidly obese and 11 matched lean subjects colonic and ileal biopsies were obtained in order to measure gene transcription of tight junction proteins. RESULTS: Gastroduodenal permeability (urinary sucrose recovery) was significantly increased in obese vs. lean controls (p < 0.05). Small intestinal and colonic permeability (urinary recovery of lactulose/L-rhamnose and sucralose/erythritol, respectively) in obese subjects were not significantly different from controls. Morbidly obese subjects had a proinflammatory systemic and intestinal profile compared with lean subjects. After sleeve gastrectomy BMI decreased significantly (p < 0.001). Postsleeve gastroduodenal permeability normalized to values that do not differ from lean controls. CONCLUSIONS: Gastroduodenal permeability, but not small intestinal or colonic permeability, is significantly increased in morbidly obese patients. After sleeve gastrectomy, gastroduodenal permeability normalized to values in the range of lean controls. Thus, the proximal gastrointestinal barrier is compromised in morbid obesity and is associated with a proinflammatory intestinal and systemic profile.

Normal colonic transit time predicts the outcome of colonic manometry in patients with chronic constipation-an exploratory study.

PURPOSE: Colonic manometry (CM) can be of additive value in the diagnostic workup of colonic motility in chronic constipated patients. However, it is claimed that colonic motor disturbances occur in normal-transit constipation (NTC) and slow-transit (STC) constipation, as measured using a radio-opaque marker study, and therefore, the relationship between colonic motor disturbances on CM and colonic transit time (CTT) remains unclear. Our aim was to compare results from colonic marker study with the outcome of CM in patients with treatment-refractory chronic constipation (CC). METHOD: Eighty-seven CC patients and 12 healthy volunteers, undergoing both a CTT study and a 24-h CM in a Dutch tertiary referral center, were included. CTT was measured using radio-opaque markers (X-ray at day 4 after ingestion of 20 markers at day 0). CM was performed using a catheter with 6 solid-state pressure sensors, endoscopically clipped to the mucosa in the right colon. CM was defined as normal when at least three high-amplitude propagating contractions (HAPCs), i.e., propagating waves with amplitude ≥ 80 mmHg over at least three sensors, were identified. RESULTS: In total, 70 patients showed STC on CTT, of which 21 (30%) showed normal CM. All 17 NTC patients and healthy volunteers showed normal CM. The negative predictive value of CTT for normal CM was 100%. CONCLUSION: Colonic manometry should be considered in therapy-refractory STC patients in order to further delineate colonic motility. However, in this exploratory study, for patients presenting with NTC on a radio-opaque marker study, colonic manometry does not appear to have added value.

Intraintestinal Delivery of Tastants Using a Naso-Duodenal-Ileal Catheter Does Not Influence Food Intake or Satiety.

Intraduodenal activity of taste receptors reduces food intake. Taste receptors are expressed throughout the entire gastrointestinal tract. Currently, there are no data available on the effects of distal taste receptor activation. In this study, we investigate the effect of intraduodenal and/or intraileal activation of taste receptors on food intake and satiety. In a single-blind randomized crossover trial, fourteen participants were intubated with a naso-duodenal-ileal catheter and received four infusion regimens: duodenal placebo and ileal placebo (DPIP), duodenal tastants and ileal placebo (DTIP), duodenal placebo and ileal tastants (DPIT), duodenal tastants and ileal tastants (DTIT). Fifteen minutes after cessation of infusion, subjects received an ad libitum meal to measure food intake. Visual analog scale scores for satiety feelings were collected at regular intervals. No differences in food intake were observed between the various interventions (DPIP: 786.6 ± 79.2 Kcal, DTIP: 803.3 ± 69.0 Kcal, DPIT: 814.7 ± 77.3 Kcal, DTIT: 834.8 ± 59.2 Kcal, p = 0.59). No differences in satiety feelings were observed. Intestinal infusion of tastants using a naso-duodenal-ileal catheter did not influence food intake or satiety feelings. Possibly, the burden of the four-day naso-duodenal-ileal intubation masked a small effect that tastants might have on food intake and satiety.

The Effect of an Encapsulated Nutrient Mixture on Food Intake and Satiety: A Double-Blind Randomized Cross-Over Proof of Concept Study.

Activation of the intestinal brake by infusing nutrients into the distal small intestine with catheters inhibits food intake and enhances satiety. Encapsulation of macronutrients, which protects against digestion in the proximal gastrointestinal tract, can be a non-invasive alternative to activate this brake. In this study, we investigate the effect of oral ingestion of an encapsulated casein and sucrose mixture (active) targeting the distal small intestine versus a control product designed to be released in the stomach on food intake, satiety, and plasma glucose concentrations. Fifty-nine volunteers received the active and control product on two separate test days. Food intake was determined during an ad libitum meal 90 min after ingestion of the test product. Visual analogue scale scores for satiety and blood samples for glucose analysis were collected at regular intervals. Ingestion of the active product decreased food intake compared to the control product (655 kcal compared with 699 kcal, respectively, p < 0.05). The area under the curve (AUC) for hunger was decreased (p < 0.05) and AUC for satiety was increased (p < 0.01) after ingestion of the active product compared to the control product. Ingestion of an encapsulated protein-carbohydrate mixture resulted in inhibition of food intake compared to a non-encapsulated control product.

Intraileal casein infusion increases plasma concentrations of amino acids in humans: A randomized cross over trial.

BACKGROUND: Activation of the ileal brake by casein induces satiety signals and reduces energy intake. However, adverse effects of intraileal casein administration have not been studied before. These adverse effects may include impaired amino acid digestion, absorption and immune activation. OBJECTIVE: To investigate the effects of intraileal infusion of native casein on plasma amino acid appearance, immune activation and gastrointestinal (GI) symptoms. DESIGN: A randomized single-blind cross over study was performed in 13 healthy subjects (6 male; mean age 26 ± 2.9 years; mean body mass index 22.8 ± 0.4 kg/m-2), who were intubated with a naso-ileal feeding catheter. Thirty minutes after intake of a standardized breakfast, participants received an ileal infusion, containing either control (C) consisting of saline, a low-dose (17.2 kcal) casein (LP) or a high-dose (51.7 kcal) of casein (HP) over a period of 90 min. Blood samples were collected for analysis of amino acids (AAs), C-reactive protein (CRP), pro-inflammatory cytokines and oxylipins at regular intervals. Furthermore, GI symptom questionnaires were collected before, during and after ileal infusion. RESULTS: None of the subjects reported any GI symptoms before, during or after ileal infusion of C, LP and HP. Plasma concentrations of all AAs analyzed were significantly increased after infusion of HP as compared to C (p < 0.001), and most AAs were increased after infusion of LP (p < 0.001). In total, 12.49 ± 1.73 and 3.18 ± 0.87 g AAs were found in plasma after intraileal infusion of HP and LP, corresponding to 93 ± 13% (HP) and 72 ± 20% (LP) of AAs infused as casein, respectively. Ileal casein infusion did not affect plasma concentrations of CRP, IL-6, IL-8, IL-1ß and TNF-α. Infusion of HP resulted in a decreased concentration of 11,12-dihydroxyeicosatrienoic acid whereas none of the other oxylipins analyzed were affected. CONCLUSIONS: A single intraileal infusion of native casein results in a concentration and time dependent increase of AAs in plasma, suggesting an effective digestion and absorption of AAs present in casein. Also, ileal infusion did not result in immune activation nor in GI symptoms. CLINICALTRIALS.GOV: NCT01509469.

Effect of Endoscopic Gastroplication on the Genome-Wide Transcriptome in the Upper Gastrointestinal Tract.

BACKGROUND: Bariatric surgery is an effective intervention strategy in obesity, resulting in sustained weight loss and a reduction of comorbidities. Gastroplication, using the articulating circular endoscopic stapler, was recently introduced as a transoral bariatric technique. This procedure reduces gastric volume and induced 34.9 % of excess weight loss in the first year (Paulus et al. Gastrointest Endosc. 81(2):312-20, 3). The aim of the present study was to gain insight in the long-term effects and underlying mechanisms of gastroplication by investigating differences in the genome-wide gastric and duodenal transcriptome before and 1 year after intervention. METHODS: Ten morbidly obese patients (BMI 39.8 ± 0.9 kg/m2 (mean ± SEM)) underwent gastroplication. Previous to the procedure and after 1 year, blood samples were taken, and mucosal biopsies were collected from the fundus, antrum and duodenum. Gene expression was measured using microarray analysis. Plasma adiponectin, HbA1c, IL-1ß, IL-6, IL-7, TNF-α, IFN-γ, MCP-1, IL-8, TGF-1 and CRP levels were determined. RESULTS: Downregulation of inflammatory genes and gene sets was observed in the fundus and duodenum 1 year after surgery. Gene expression of ghrelin and its activating enzyme GOAT were downregulated in the upper gastrointestinal tract. Patients showed a reduction in plasma HbA1c levels (from 6.17 ± 0.51 to 5.32 ± 0.14 %, p = 0.004) and an increase of plasma adiponectin (from 16.87 ± 3.67 to 27.67 ± 5.92 µg/ml, p = 0.002). CONCLUSIONS: Individuals undergoing gastroplication displayed a downregulation of inflammatory tone in the stomach and duodenum, which coincided with improved HbA1c and adiponectin levels. The reduction of inflammatory tone in the upper gastrointestinal tract may be a consequence of an improved metabolic health status or alternatively caused by the procedure itself.

Translational Difficulties in Studying the TRPA1 Receptor.

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Gastrointestinal Nutrient Infusion Site and Eating Behavior: Evidence for A Proximal to Distal Gradient within the Small Intestine?

The rapidly increasing prevalence of overweight and obesity demands new strategies focusing on prevention and treatment of this significant health care problem. In the search for new and effective therapeutic modalities for overweight subjects, the gastrointestinal (GI) tract is increasingly considered as an attractive target for medical and food-based strategies. The entry of nutrients into the small intestine activates so-called intestinal "brakes", negative feedback mechanisms that influence not only functions of more proximal parts of the GI tract but also satiety and food intake. Recent evidence suggests that all three macronutrients (protein, fat, and carbohydrates) are able to activate the intestinal brake, although to a different extent and by different mechanisms of action. This review provides a detailed overview of the current evidence for intestinal brake activation of the three macronutrients and their effects on GI function, satiety, and food intake. In addition, these effects appear to depend on region and length of infusion in the small intestine. A recommendation for a therapeutic approach is provided, based on the observed differences between intestinal brake activation.

Capsaicin-induced satiety is associated with gastrointestinal distress but not with the release of satiety hormones.

BACKGROUND: Capsaicin, which is the major pungent principle in chili peppers, is able to induce satiety and reduce caloric intake. The exact mechanism behind this satiating effect is still unknown. We hypothesized that capsaicin induces satiety through the release of gastrointestinal peptides, such as glucagon-like peptide-1 (GLP-1) and peptide YY (PYY), from enteroendocrine cells in the small intestine. OBJECTIVE: We investigate the effects of an intraduodenal capsaicin infusion (1.5 mg pure capsaicin) in healthy volunteers on hunger, satiety, and gastrointestinal symptoms and the release of GLP-1 and PYY. DESIGN: Thirteen participants (7 women) [mean ± SEM age: 21.5 ± 0.6 y; body mass index (in kg/m(2)): 22.8 ± 0.6] participated in this single-blind, randomized, placebo-controlled crossover study with 2 different treatments. During test days, an intraduodenal infusion of either capsaicin or a placebo (physiologic saline) was performed with the use of a nasoduodenal catheter over a period of 30 min. Visual analog scale scores were used to measure hunger, satiety, and gastrointestinal symptoms. Blood samples were drawn at regular intervals for GLP-1 and PYY. Gallbladder volumes were measured with the use of real-time ultrasonography. RESULTS: The intraduodenal capsaicin infusion significantly increased satiety (P-treatment effect < 0.05) but also resulted in an increase in the gastrointestinal symptoms pain (P-treatment × time interaction < 0.0005), burning sensation (P-treatment × time interaction < 0.0001), nausea (P-treatment × time interaction < 0.05), and bloating (P-treatment × time interaction < 0.001) compared with the effects of the placebo infusion. Satiety scores had a positive correlation with all gastrointestinal symptoms. No differences in GLP-1 and PYY concentrations and gallbladder volumes were observed after the capsaicin infusion compared with after the placebo infusion. CONCLUSIONS: An intraduodenal infusion of capsaicin significantly increases satiety but does not affect plasma concentrations of GLP-1 and PYY. Rather, the effect on satiety seems related to gastrointestinal stress as shown by the associations with pain, burning sensation, nausea, and bloating scores. This trial was registered at clinicaltrials.gov as NCT01667523.

Intraduodenal infusion of a combination of tastants decreases food intake in humans.

BACKGROUND: Taste receptors are expressed not only in taste buds but also in the gastrointestinal tract. It has been hypothesized that these receptors may play a role in satiety and food intake. OBJECTIVE: This study investigated the effect of intraduodenal tastant infusions (bitter, sweet, and umami) on food intake, hunger and fullness, gastrointestinal symptoms, and gastrointestinal peptide release. DESIGN: Fifteen healthy volunteers [6 male; mean ± SEM age: 23.9 ± 2.0 y; mean ± SEM body mass index (in kg/m(2)): 22.4 ± 0.3] received 5 treatments in a double-blind, randomized, placebo-controlled crossover design. Test days started with the insertion of a nasoduodenal catheter followed by a standardized liquid breakfast. Participants received an intraduodenal infusion 150 min after breakfast, containing quinine (bitter), rebaudioside A (sweet), monosodium glutamate (umami), a combination of the 3 tastants, or placebo (tap water) over a period of 60 min. Food intake was measured during an ad libitum meal, and visual analog scales were used to monitor gastrointestinal complaints and hunger and fullness scores. Blood samples were drawn at regular intervals for cholecystokinin, glucagon-like peptide 1 (GLP-1), and peptide YY (PYY) analysis. RESULTS: Infusion of the combination of tastants substantially decreased food intake (422 ± 97 compared with 486 ± 104 kcal for placebo, P < 0.05), whereas both a combination of tastants and umami decreased hunger scores compared with placebo. No change in cholecystokinin, GLP-1, or PYY concentrations was observed during the infusions. Intraduodenal infusions of the tastants did not result in gastrointestinal symptoms. CONCLUSIONS: Intraduodenal infusion of umami and a combination of tastants inhibits feelings of hunger, but only the latter also reduces food intake. However, these alterations were not accompanied by changes in the plasma concentrations of the gut-derived peptides cholecystokinin, GLP-1, or PYY. This trial was registered at clinicaltrials.gov as NCT01956838.

Cross-species comparison of genes related to nutrient sensing mechanisms expressed along the intestine.

INTRODUCTION: Intestinal chemosensory receptors and transporters are able to detect food-derived molecules and are involved in the modulation of gut hormone release. Gut hormones play an important role in the regulation of food intake and the control of gastrointestinal functioning. This mechanism is often referred to as "nutrient sensing". Knowledge of the distribution of chemosensors along the intestinal tract is important to gain insight in nutrient detection and sensing, both pivotal processes for the regulation of food intake. However, most knowledge is derived from rodents, whereas studies in man and pig are limited, and cross-species comparisons are lacking. AIM: To characterize and compare intestinal expression patterns of genes related to nutrient sensing in mice, pigs and humans. METHODS: Mucosal biopsy samples taken at six locations in human intestine (n = 40) were analyzed by qPCR. Intestinal scrapings from 14 locations in pigs (n = 6) and from 10 locations in mice (n = 4) were analyzed by qPCR and microarray, respectively. The gene expression of glucagon, cholecystokinin, peptide YY, glucagon-like peptide-1 receptor, taste receptor T1R3, sodium/glucose cotransporter, peptide transporter-1, GPR120, taste receptor T1R1, GPR119 and GPR93 was investigated. Partial least squares (PLS) modeling was used to compare the intestinal expression pattern between the three species. RESULTS AND CONCLUSION: The studied genes were found to display specific expression patterns along the intestinal tract. PLS analysis showed a high similarity between human, pig and mouse in the expression of genes related to nutrient sensing in the distal ileum, and between human and pig in the colon. The gene expression pattern was most deviating between the species in the proximal intestine. Our results give new insights in interspecies similarities and provide new leads for translational research and models aiming to modulate food intake processes in man.

A new flexible plug and play scheme for modeling, simulating, and predicting gastric emptying.

BACKGROUND: In-silico models that attempt to capture and describe the physiological behavior of biological organisms, including humans, are intrinsically complex and time consuming to build and simulate in a computing environment. The level of detail of description incorporated in the model depends on the knowledge of the system's behavior at that level. This knowledge is gathered from the literature and/or improved by knowledge obtained from new experiments. Thus model development is an iterative developmental procedure. The objective of this paper is to describe a new plug and play scheme that offers increased flexibility and ease-of-use for modeling and simulating physiological behavior of biological organisms. METHODS: This scheme requires the modeler (user) first to supply the structure of the interacting components and experimental data in a tabular format. The behavior of the components described in a mathematical form, also provided by the modeler, is externally linked during simulation. The advantage of the plug and play scheme for modeling is that it requires less programming effort and can be quickly adapted to newer modeling requirements while also paving the way for dynamic model building. RESULTS: As an illustration, the paper models the dynamics of gastric emptying behavior experienced by humans. The flexibility to adapt the model to predict the gastric emptying behavior under varying types of nutrient infusion in the intestine (ileum) is demonstrated. The predictions were verified with a human intervention study. The error in predicting the half emptying time was found to be less than 6%. CONCLUSIONS: A new plug-and-play scheme for biological systems modeling was developed that allows changes to the modeled structure and behavior with reduced programming effort, by abstracting the biological system into a network of smaller sub-systems with independent behavior. In the new scheme, the modeling and simulation becomes an automatic machine readable and executable task.