Hyperphagia is prominent in adult patients with short bowel syndrome: A role for the colon?

RATIONALE: Short Bowel Syndrome (SBS) is the major cause of chronic intestinal failure (IF) and requires parenteral nutrition (PN). After bowel resection, some patients develop spontaneous intestinal adaptations and hyperphagia. Since promoting oral energy intake contributes to PN weaning, this study aims to characterize hyperphagia in patients with SBS and identify its determinants. METHODS: This observational retrospective study included adult patients with SBS who were followed at an expert PN center between 2006 and 2019, with at least 2 separate nutritional assessments. Exclusion criteria were: active neoplasia, alternative treatment for IF or appetite-affecting medication. Resting energy expenditure (REE) was calculated for each patient using the Harris-Benedict equation. Food Intake Ratio (FIR) was calculated by dividing the highest caloric oral intake by REE and hyperphagia was defined as FIR >1.5. RESULTS: Among the 59 patients with SBS included in this study, 82.6% had a FIR >1.5, including 15.5% with a FIR >3. Protein supplied approximately 16% of total energy intake while fat and carbohydrates provided 36% and 48%, respectively. The FIR was independent of gender and whether patients received oral nutrition alone (n = 28) or combined with PN (n = 31). The FIR was also not associated with residual small bowel length, nor the proportion of preserved colon. However, it was negatively correlated with the body mass index (BMI) of these patients (r = -0.533, p < 0.001), whether they had PN support or not. Patients with either a jejuno-colonic (n = 31) or a jejuno-ileal anastomosis (n = 9), had a significantly higher FIR compared to those with an end-jejunostomy (n = 18) (p < 0.05). However, no difference was found in the proportion of calories provided by protein, fat and carbohydrate between the 3 patients groups divided according to the SBS anatomical type. CONCLUSION: A large majority of patients with SBS exhibited a hyperphagia regardless of PN dependence or bowel length, which was inversely correlated with BMI. The presence of the colon in continuity, thus in contact with the nutritional flow, seems to favor a higher oral intake which is beneficial for the nutritional autonomy of patients. This raises the question of a role of colonic microbiota and hormones in this behavior. Finally, this study also revealed an unexpected discrepancy between recommended energy intakes from protein, fat and carbohydrate and the actual intake of patients with SBS.

Unexpected upper gastrointestinal polyps in patients with short bowel syndrome treated with teduglutide: need for close monitoring.

BACKGROUND: Teduglutide is a GLP-2 analog indicated for the treatment of short bowel syndrome (SBS) since 2015. Its efficacy in reducing parenteral nutrition (PN) has been shown in patients with SBS. OBJECTIVES: Because teduglutide is a trophic factor, the aim of this study was to assess risk of developing polypoid intestinal lesions during treatment. METHODS: A retrospective study was conducted in 35 patients with SBS treated with teduglutide for ≥1 y in a home PN expert center. All patients underwent ≥1 follow-up intestinal endoscopy during treatment. RESULTS: In the 35 patients, the small bowel length was 74 cm (IQR: 25-100), and 23 patients (66%) had a colon in continuity. Upper and lower gastrointestinal endoscopy was performed after a mean treatment duration of 23 mo (IQR: 13-27), and polypoid lesions were found in 10 patients (6 with a colon in continuity, 4 with an end jejunostomy) and no lesion in 25 patients. In 8 out of the 10 patients, the lesion was found in the small bowel. Five of these lesions presented an aspect of hyperplastic polyp without dysplasia, and 3 of a traditional adenoma with low-grade dysplasia. CONCLUSIONS: Our study highlights the importance of performing follow-up upper and lower gastrointestinal endoscopy in SBS patients treated with teduglutide and the potential need to make changes to the recommendations with respect to treatment initiation and follow-up.

No Long-Term Mucosal Lesions in the Esophagus but More Gastric Mucosal Lesions after Sleeve Gastrectomy in Obese Rats.

Sleeve gastrectomy (SG) often induces gastroesophageal reflux, with few and discordant long-term data on the risk of Barrett's esophagus (BE) in operated patients. The aim of this study was to analyze the impact of SG on esogastric mucosa in a rat model at 24 weeks postoperatively, which corresponds to approximately 18 years in humans. After 3 months of a high-fat diet, obese male Wistar rats were subjected to SG (n = 7) or sham surgery (n = 9). Esophageal and gastric bile acid (BA) concentrations were measured at sacrifice, at 24 weeks postoperatively. Esophageal and gastric tissues were analyzed by routine histology. The esophageal mucosa of the SG rats (n = 6) was not significantly different in comparison to that of the sham rats (n = 8), with no esophagitis or BE. However, there was more antral and fundic foveolar hyperplasia in the mucosa of the residual stomach 24 weeks after SG than in the sham group (p < 0.001). Luminal esogastric BA concentrations did not differ between the two groups. In our study, SG induced gastric foveolar hyperplasia but no esophageal lesions at 24 weeks postoperatively in obese rats. Therefore, long-term endoscopic esophageal follow-up that is recommended in humans after SG to detect BE may also be useful for detecting gastric lesions.

Fecal microbiota transplantation in a rodent model of short bowel syndrome: A therapeutic approach?

Extensive intestinal resection leads to Short Bowel Syndrome (SBS), the main cause of chronic intestinal failure. Colon preservation is crucial for spontaneous adaptation, to improve absorption and reduce parenteral nutrition dependence. Fecal microbiota transplantation (FMT), a promising approach in pathologies with dysbiosis as the one observed in SBS patients, was assessed in SBS rats with jejuno-colonic anastomosis. The evolution of weight and food intake, the lenght of intestinal villi and crypts and the composition of fecal microbiota of Sham and SBS rats, transplanted or not with high fat diet rat microbiota, were analyzed. All SBS rats lost weight, increased their food intake and exhibited jejunal and colonic hyperplasia. Microbiota composition of SBS rats, transplanted or not, was largely enriched with Lactobacillaceae, and α- and ß-diversity were significantly different from Sham. The FMT altered microbiota composition and α- and ß-diversity in Sham but not SBS rats. FMT from high fat diet rats was successfully engrafted in Sham, but failed to take hold in SBS rats, probably because of the specific luminal environment in colon of SBS subjects favoring aero-tolerant over anaerobic bacteria. Finally, the level of food intake in SBS rats was positively correlated with their Lactobacillaceae abundance. Microbiota transfer must be optimized and adapted to this specific SBS environment.

Analysis of the Efficacy and the Long-term Metabolic and Nutritional Status of Sleeve Gastrectomy with Transit Bipartition Compared to Roux-en-Y Gastric Bypass in Obese Rats.

PURPOSE: Sleeve gastrectomy with transit bipartition (SG-TB) could be an attractive alternative to Roux-en-Y gastric bypass (RYGB) on weight loss and improvement of comorbidities in patients with obesity. However, there is little long-term data. Translational research on a rat model could allow long-term projection to assess efficacy and safety of SG-TB. The aim of this research was to evaluate the long-term efficacy and safety of SG-TB compared to RYGB and SHAM in rat model. MATERIALS AND METHODS: Ninety-four male obese Wistar rats were distributed into 3 groups: SG-TB (n = 34), RYGB (n = 32), and SHAM (control group, n = 28). The percentage of total weight loss (%TWL), coprocalorimetry, glucose and insulin tolerance test, insulin, GLP-1, PYY, and GIP before and after surgery were assessed. The animals were followed over 6 months (equivalent to 16 years in humans). RESULTS: At 6 months, %TWL was significantly greater(p = 0.025) in the SG-TB group compared to the RYGB group. There was no difference between the groups (p = 0.86) in malabsorption 15 and 120 days postoperatively. Glucose tolerance was significantly improved (p = 0.03) in the SG-TB and RYGB groups compared to the preoperative state. Insulin secretion, at 3 months, was significantly more important in the SG-TB group (p = 0.0003), compared to the RYGB and SHAM groups. GLP-1 secretion was significantly increased in the SG-TB and RYGB groups compared to the preoperative state (p = 0.001) but similar between SG-TB and RYGB animals (p = 0.72). CONCLUSION: In a rat model, at long term compared to RYGB, SG-TB provides greater and better-maintained weight loss and an increased insulin secretion without impairing nutritional status.

Shortening the Biliopancreatic Limb Length of One Anastomosis Gastric Bypass Maintains Glucose Homeostasis Improvement with Limited Weight Loss.

One anastomosis gastric bypass (OAGB) is associated with similar metabolic improvements and weight loss as Roux-en-Y gastric bypass (RYGB). However, this bariatric procedure is still controversial as it is suspected to result in undernutrition. Reducing the size of the biliopancreatic limb of OAGB could be essential to maintain positive outcomes while preventing side effects. The objective of this study was to compare and contrast outcomes of OAGB with two different biliopancreatic limb lengths to RYGB and Sham surgery in obese and non-obese rats. Lean and diet-induced obese Wistar rats were operated on RYGB, OAGB with a short (15 cm OAGB-15) or a long (35 cm OAGB-35) biliopancreatic limb or Sham surgery. Body weight and food intake were monitored over 30 weeks, and rats underwent oral glucose and insulin tolerance tests with a pancreatic and gut hormone secretion assay. Macronutrient absorption was determined by fecal analyses. Statistical analyses used non-parametric one-way or two-way ANOVA tests. Compared to Sham rats, RYGB, OAGB-15 and OAGB-35 rats displayed a significant reduced weight. Weight loss was greater after OAGB-35 than after OAGB-15 or Sham surgery because of transient malabsorption. All OAGB- and RYGB-operated rats displayed an improved pancreatic and gut hormone secretion in response to a meal compared to Sham rats, these effects were independent of limb length, rat weight, and maintained overtime. In conclusion, glucose homeostasis was similarly improved in obese and non-obese OAGB-15 and OAGB-35 rats suggesting that shortening the biliopancreatic limb can improve the metabolic parameters without a major influence on weight.

[Nutritionnal complications and patients follow-up after bariatric surgery]. / Complications nutritionnelles de la chirurgie bariatrique et surveillance des patients opérés.

NUTRITIONNAL COMPLICATIONS AND PATIENTS FOLLOW-UP AFTER BARIATRIC SURGERYBariatric surgery is the most consistently effective method for sustained weight reduction and can result in a substantial improvement in overall survival in patients with severe obesity. Complex mechanisms underlying metabolic benefits could also drive preventable, but potentially life-threatening, long-term nutritional complications. Consequently, physicians should be familiar with the lifelong monitoring of patients after bariatric surgery and the potential long-term complications in this paradoxical situation where the long-awaited weight loss can lead to severe nutritional complications.

COMPLICATIONS NUTRITIONNELLES DE LA CHIRURGIE BARIATRIQUE ET SURVEILLANCE DES PATIENTS OPÉRÉS La chirurgie bariatrique est le traitement le plus efficace en termes de perte pondérale durable et de réduction de la morbi-mortalité en cas d'obésité sévère. Cependant, les modifications profondes de la physiologie digestive qui sous-tendent ces bénéfices métaboliques peuvent entraîner des carences nutritionnelles qui peuvent induire des complications sévères et irréversibles. La population des patients bariatriques étant en constante augmentation, tout médecin peut être amené à prendre un charge un patient opéré. Il devrait donc connaître les principes de la surveillance à vie et les possibles complications à long terme dans cette situation si paradoxale où la perte de poids tant attendue peut aussi s'associer à des carences potentiellement sévères.

Circulating bile acids concentration is predictive of coronary artery disease in human.

Synthetized by the liver and metabolized by the gut microbiota, BA are involved in metabolic liver diseases that are associated with cardiovascular disorders. Animal models of atheroma documented a powerful anti-atherosclerotic effect of bile acids (BA). This prospective study examined whether variations in circulating BA are predictive of coronary artery disease (CAD) in human. Consecutive patients undergoing coronary angiography were enrolled. Circulating and fecal BA were measured by high pressure liquid chromatography and tandem mass spectrometry. Of 406 screened patients, 80 were prospectively included and divided in two groups with (n = 45) and without (n = 35) CAD. The mean serum concentration of total BA was twice lower in patients with, versus without CAD (P = 0.005). Adjusted for gender and age, this decrease was an independent predictor of CAD. In a subgroup of 17 patients, statin therapy doubled the serum BA concentration. Decreased serum concentrations of BA were predictors of CAD in humans. A subgroup analysis showed a possible correction by statins. With respect to the anti-atherosclerotic effect of BA in animal models, and their role in human lipid metabolism, this study describe a new metabolic disturbance associated to CAD in human.

Hepcidin and Iron Deficiency in Women One Year after Sleeve Gastrectomy: A Prospective Cohort Study.

Iron deficiency with or without anemia, needing continuous iron supplementation, is very common in obese patients, particularly those requiring bariatric surgery. The aim of this study was to address the impact of weight loss on the rescue of iron balance in patients who underwent sleeve gastrectomy (SG), a procedure that preserves the duodenum, the main site of iron absorption. The cohort included 88 obese women; sampling of blood and duodenal biopsies of 35 patients were performed before and one year after SG. An analysis of the 35 patients consisted in evaluating iron homeostasis including hepcidin, markers of erythroid iron deficiency (soluble transferrin receptor (sTfR) and erythrocyte protoporphyrin (PPIX)), expression of duodenal iron transporters (DMT1 and ferroportin) and inflammatory markers. After surgery, sTfR and PPIX were decreased. Serum hepcidin levels were increased despite the significant reduction in inflammation. DMT1 abundance was negatively correlated with higher level of serum hepcidin. Ferroportin abundance was not modified. This study shed a new light in effective iron recovery pathways after SG involving suppression of inflammation, improvement of iron absorption, iron supply and efficiency of erythropoiesis, and finally beneficial control of iron homeostasis by hepcidin. Thus, recommendations for iron supplementation of patients after SG should take into account these new parameters of iron status assessment.

Do Preoperative Esophageal pH Monitoring and High-Resolution Manometry Predict Symptoms of GERD After Sleeve Gastrectomy?

BACKGROUND: Predictive factors of evolution or appearance of gastroesophageal reflux disease (GERD) after sleeve gastrectomy (SG) have not been identified to date. We aimed to assess the evolution of GERD symptoms 1 year after SG and to determine preoperative predictive factors using high-resolution manometry (HRM) and ambulatory 24-h esophageal pH monitoring (APM). METHODS: We included 160 patients who underwent SG between 2013 and 2017 and performed preoperative APM and HRM. Positive APM was defined according to the Lyon consensus. Symptoms of GERD, proton pump inhibitors (PPI) use, weight loss (WL), and diet were recorded in all patients before and 1 year after surgery. RESULTS: One year after surgery, 58 patients (36.3%) complained of GERD symptoms compared to 52 patients (32.5%) preoperatively (p=0.48). Among patients with preoperative GERD symptoms, only 26/52 patients (50%) still had symptoms, whereas 32/108 (29.6%) asymptomatic patients developed de novo GERD symptoms after surgery. PPI use increased after surgery reaching 36.9% of patients against 15.0% before (p<0.0001). Only preoperative symptoms of GERD were predictive of postoperative symptoms (OR= 2.47 [1.14-5.45]; p=0.023) in multivariate analysis. Preoperative manometric parameters, postoperative diet, and WL were not related to postoperative symptoms. In asymptomatic patients before surgery, silent GERD (positive APM without symptom) was predictive of postoperative GERD symptoms (OR=2.69 [1.00-7.25]; p=0.049). CONCLUSION: Evolution of GERD symptoms after SG reveals improvement for half of the patients and de novo GERD symptoms in one-third of patients. Predictive factors of postoperative symptoms are preoperative symptoms and positive preoperative APM in asymptomatic patients.

Prevention and treatment of nutritional complications after bariatric surgery.

Obesity and the corresponding burden of related diseases is a major public health issue worldwide that is reaching pandemic proportions. Bariatric surgery is the only intervention that has been shown to result in substantial and lasting weight loss, and a decrease in overall mortality for patients with severe obesity. Consequently, the population of patients having undergone this procedure is increasing. Multifactorial weight-dependent and independent mechanisms underlying metabolic diseases could also drive preventable, but potentially life-threatening, long-term nutritional complications. However, given post-bariatric patients are prone to functional gastrointestinal symptoms and substantial weight loss, nutritional complications might be challenging. This Review is focused on the prevention and treatment of nutritional complications after bariatric surgery in the clinical setting.

Bariatric surgery induces a new gastric mucosa phenotype with increased functional glucagon-like peptide-1 expressing cells.

Glucagon-Like Peptide-1 (GLP-1) undergoes rapid inactivation by dipeptidyl peptidase-4 (DPP4) suggesting that target receptors may be activated by locally produced GLP-1. Here we describe GLP-1 positive cells in the rat and human stomach and found these cells co-expressing ghrelin or somatostatin and able to secrete active GLP-1 in the rats. In lean rats, a gastric load of glucose induces a rapid and parallel rise in GLP-1 levels in both the gastric and the portal veins. This rise in portal GLP-1 levels was abrogated in HFD obese rats but restored after vertical sleeve gastrectomy (VSG) surgery. Finally, obese rats and individuals operated on Roux-en-Y gastric bypass and SG display a new gastric mucosa phenotype with hyperplasia of the mucus neck cells concomitant with increased density of GLP-1 positive cells. This report brings to light the contribution of gastric GLP-1 expressing cells that undergo plasticity changes after bariatric surgeries, to circulating GLP-1 levels.

Endocannabinoid Receptor-1 and Sympathetic Nervous System Mediate the Beneficial Metabolic Effects of Gastric Bypass.

The exact mechanisms underlying the metabolic effects of bariatric surgery remain unclear. Here, we demonstrate, using a combination of direct and indirect calorimetry, an increase in total resting metabolic rate (RMR) and specifically anaerobic RMR after Roux-en-Y gastric bypass (RYGB), but not sleeve gastrectomy (SG). We also show an RYGB-specific increase in splanchnic sympathetic nerve activity and "browning" of visceral mesenteric fat. Consequently, selective splanchnic denervation abolishes all beneficial metabolic outcomes of gastric bypass that involve changes in the endocannabinoid signaling within the small intestine. Furthermore, we demonstrate that administration of rimonabant, an endocannabinoid receptor-1 (CB1) inverse agonist, to obese mice mimics RYGB-specific effects on energy balance and splanchnic nerve activity. On the other hand, arachidonoylethanolamide (AEA), a CB1 agonist, attenuates the weight loss and metabolic signature of this procedure. These findings identify CB1 as a key player in energy regulation post-RYGB via a pathway involving the sympathetic nervous system.

Short Bowel Syndrome: A Paradigm for Intestinal Adaptation to Nutrition?

Short bowel syndrome (SBS) is a rare disease that results from extensive resection of the intestine. When the remaining absorption surface of the intestine cannot absorb enough macronutrients, micronutrients, and water, SBS results in intestinal failure (IF). Patients with SBS who suffer from IF require parenteral nutrition for survival, but long-term parenteral nutrition may lead to complications such as catheter sepsis and metabolic diseases. Spontaneous intestinal adaptation occurs weeks to months after resection, resulting in hyperplasia of the remnant gut, modification of gut hormone levels, dysbiosis, and hyperphagia. Oral nutrition and presence of the colon are two major positive drivers for this adaptation. This review aims to summarize the current knowledge of the mechanisms underlying spontaneous intestinal adaptation, particularly in response to modifications of luminal content, including nutrients. In the future, dietary manipulations could be used to treat SBS.

Long-term consequences of one anastomosis gastric bypass on esogastric mucosa in a preclinical rat model.

Although bariatric surgery is proven to sustain weight loss in morbidly obese patients, long-term adverse effects have yet to be fully characterized. This study compared the long-term consequences of two common forms of bariatric surgery: one-anastomosis gastric bypass (OAGB) and Roux-en-Y Gastric Bypass (RYGB) in a preclinical rat model. We evaluated the influence of biliopancreatic limb (BPL) length, malabsorption, and bile acid (BA) reflux on esogastric mucosa. After 30 weeks of follow-up, Wistar rats operated on RYGB, OAGB with a short BPL (15 cm, OAGB-15), or a long BPL (35 cm, OAGB-35), and unoperated rats exhibit no cases of esogastric cancer, metaplasia, dysplasia, or Barrett's esophagus. Compared to RYGB, OAGB-35 rats presented higher rate of esophagitis, fundic gastritis and perianastomotic foveolar hyperplasia. OAGB-35 rats also revealed the greatest weight loss and malabsorption. On the contrary, BA concentrations were the highest in the residual gastric pouch of OAGB-15 rats. Yet, no association could be established between the esogastric lesions and malabsorption, weight loss, or gastric bile acid concentrations. In conclusion, RYGB results in a better long-term outcome than OAGB, as chronic signs of biliary reflux or reactional gastritis were reported post-OAGB even after reducing the BPL length in a preclinical rat model.

Effect of different bariatric surgeries on dietary protein bioavailability in rats.

Bariatric surgery may induce protein malabsorption, although data are scarce. This study aims at evaluating dietary protein bioavailability after different bariatric surgeries in rats. Diet-induced obese Wistar rats were operated for vertical sleeve gastrectomy (VSG) or Roux-en-Y gastric bypass (RYGB). The control group was composed of pair-fed, sham-operated rats (Sham). Two weeks after surgery, rats were fed a 15N protein meal. Protein bioavailability was assessed by determination of 15N recovery in the gastrointestinal tract and organs 6 h after the meal. Fractional protein synthesis rate (FSR) was assessed using a flooding dose of 13C valine. Weight loss was the highest in RYGB rats and the lowest in Sham rats. Surprisingly, RYGB (95.6 ± 0.7%) improved protein digestibility (P = 0.045) compared with Sham (93.5 ± 0.5%) and VSG (93.8 ± 0.6%). In contrast, 15N retained in the liver (P = 0.001) and plasma protein (P = 0.037) was lower than in Sham, with a similar trend in muscle (P = 0.052). FSR was little altered by bariatric surgery, except for a decrease in the kidney of RYGB (P = 0.02). The 15N distribution along the small intestinal tissue suggests that dietary nitrogen was considerably retained in the remodeled mucosa of RYGB compared with Sham. This study revealed that in contrast to VSG, RYGB slightly improved protein digestibility but altered peripheral protein bioavailability. This effect may be ascribed to a higher uptake of dietary amino acids by the remodeled intestine.NEW & NOTEWORTHY Using a sensitive 15N meal test, we found that gastric bypass slightly improved protein digestibility compared with sleeve gastrectomy or control but, in contrast, lowered protein retention in the liver and muscles. This paradox can be due to a higher uptake of dietary nitrogen by the intestinal mucosa that was hypertrophied. This study provides new insight on the digestive and metabolic fate of dietary protein in different models of bariatric surgery in rats.

Saccharomyces boulardii CNCM I-745 Modulates the Fecal Bile Acids Metabolism During Antimicrobial Therapy in Healthy Volunteers.

Saccharomyces boulardii CNCM I-745 (SB) is a probiotic yeast used to lower the incidence of antibiotic-associated Clostridium difficile (C. difficile) infection, though its mechanism of action remains unclear. Cholic acid is a primary bile acid, which triggers the germination and promotes the growth of C. difficile. The intestinal microbiota transforms primary into secondary bile acids. This study examined (1) the antimicrobial-induced alteration of fecal bile acid content, and (2) whether the concomitant administration of SB influences this transformation. This is an ancillary work from a randomized study, which revealed that SB modulates fecal microbiota dysbiosis during antibiotic treatment. Healthy subjects were randomly assigned to (1) SB only, (2) amoxicillin-clavulanate (AC), (3) SB plus AC, or (4) no treatment. We analyzed fecal concentrations of BA by high performance liquid chromatography/tandem mass spectrometry. Compared to the untreated or the SB-treated groups, AC decreased the percentage of fecal secondary BA significantly (days 3 and 7). When SB and AC were administered concomitantly, this decrease in secondary BA was no longer significant. Following treatment with AC, a significant peak of fecal CA was measured on days 3 and 7, which was prevented by the concomitant administration of SB. AC administered to healthy volunteers altered the microbial transformation of primary BA, decreased secondary BA, and increased CA. The latter was prevented by the concomitant administration of SB and AC, suggesting a potent mechanism protection conferred by SB against post-antimicrobial C. difficile infection. Clinical Trial Registration: www.ClinicalTrials.gov, identifier NCT01473368.

Neuromedin U is a gut peptide that alters oral glucose tolerance by delaying gastric emptying via direct contraction of the pylorus and vagal-dependent mechanisms.

The gut-brain peptide neuromedin U (NMU) decreases food intake and body weight and improves glucose tolerance. Here, we characterized NMU as an enteropeptide and determined how it impacts glucose excursion. NMU was expressed predominantly in the proximal small intestine, and its secretion was triggered by ingestion of a mixed meal. Although a single peripheral injection of NMU in C57BL/6NRj mice prevented the rise of glycemia upon an oral but not an intraperitoneal load of glucose, it unexpectedly prevented insulin secretion, only slightly improved peripheral insulin sensitivity, and barely reduced intestinal glucose absorption. Interestingly, peripheral administration of NMU abrogated gastric emptying. NMU receptors 1 and 2 were detected in pyloric muscles and NMU was able to directly induce pyloric contraction in a dose-dependent manner ex vivo in isometric chambers. Using a modified glucose tolerance test, we demonstrate that improvement of oral glucose tolerance by NMU was essentially, if not exclusively, because of its impact on gastric emptying. Part of this effect was abolished in vagotomized (VagoX) mice, suggesting implication of the vagus tone. Accordingly, peripheral injection of NMU was associated with increased number of c-FOS-positive neurons in the nucleus of the solitary tract, which was partly prevented in VagoX mice. Finally, NMU kept its ability to improve oral glucose tolerance in obese and diabetic murine models. Together, these data demonstrate that NMU is an enteropeptide that prevents gastric emptying directly by triggering pylorus contraction and indirectly through vagal afferent neurons. This blockade consequently reduces intestinal nutrient absorption and thereby results in an apparent improved tolerance to oral glucose challenge.-Jarry, A.-C., Merah, N., Cisse, F., Cayetanot, F., Fiamma, M.-N., Willemetz, A., Gueddouri, D., Barka, B., Valet, P., Guilmeau, S., Bado, A., Le Beyec, J., Bodineau, L., Le Gall, M. Neuromedin U is a gut peptide that alters oral glucose tolerance by delaying gastric emptying via direct contraction of the pylorus and vagal-dependent mechanisms.

Roux-en-Y Gastric-Bypass and sleeve gastrectomy induces specific shifts of the gut microbiota without altering the metabolism of bile acids in the intestinal lumen.

Some shifts in the gut microbiota composition and its metabolic fingerprints have been associated to Sleeve gastrectomy (SG) and Roux-en-Y Gastric Bypass (RYGB). So far, plasma bile acids have been associated with post-operative glucose improvement and weight loss, but nothing is known about their metabolism in the gut lumen. As bile acids are physiologically transformed by the microbiota into various species, the aim of this work was to study how SG and RYGB-associated dysbiosis impact the bioconversion of bile acids in the intestinal lumen. Comparing SHAM (n = 9) with our validated rat models of SG (n = 5) and RYGB (n = 6), we quantified luminal bile acids along the gut and found that the metabolic transformation of bile acids (deconjugation, dehydroxylation, and epimerization) is not different from the duodenum to the colon. However, in the cecum where the biotransformation mainly takes place, we observed deep alterations of the microbiota composition, which were specific of each type of surgery. In conclusion, despite specific dysbiosis after surgery, the bile acids metabolism in the gut lumen is highly preserved, suggesting that a resilience of the gut microbiota occurs after these procedures.