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Video Video 1 This video case presentation highlights a 65-year-old woman with weight regain after Roux-en-Y gastric bypass and a dilated gastrojejunal anastomosis who presented for endoscopic revision of her gastric bypass involving a plication technique, followed by gastrojejunal anastomosis stenosis dilation.

Video Video 1 Technical feasibility, safety, and efficacy of a novel endoscopic approach to treating weight regain after open vertical-banded gastroplasty using an endoscopic suturing device.

Highlights • The diagnosis of rare gastric lesions has become more frequent after the increase in bariatric surgery. • The preoperative evaluation for bariatric surgery showed two lesions suggestive of Gastric Ectopic Pancreas. • The previous identification of these lesions provides better surgical planning. • Intraoperative Upper Endoscopy was used to identify the location of these lesions. • Simultaneous laparoscopic resection of the lesions associated with Sleeve Gastrectomy was performed., Background The diagnosis of gastric lesions, such as the Ectopic Gastric Pancreas (GEP), has become more frequent after the increase in bariatric surgeries. The most frequently used surgical options are: Sleeve Gastrectomy (SG) and Roux-en-Y Gastric Bypass (RYGB). The scientific papers about GEP in Bariatric Surgery consisted of intraoperative findings, approach the lesion with gastrectomy and the need to change the initial surgical strategy of the Sleeve for others techniques which allow extended gastric resections. Presentation of case This is a report on a 21-year-old female patient with class 3 obesity whose preoperative evaluation showed two lesions suggestive of GEP. Simultaneous surgical video-laparoscopic treatment of lesions associated with SG aided by intraoperative Upper Endoscopy (UE) was performed with no perioperative complications. Conclusion It is possible to associate the treatment of rare gastric lesions with traditional surgery techniques for obesity.

Background and Aims Accessing the pancreatobiliary region in patients with a history of Roux-en-Y gastric bypass (RYGB) can be challenging. Traditionally, techniques such as percutaneous biliary drainage, enteroscopy-assisted ERCP, and laparoscopy-assisted ERCP have been used. However, each technique has its limitations. EUS–directed transgastric ERCP (EDGE) using a lumen-apposing metal stent (LAMS) has emerged as a novel endoscopic technique for ERCP in patients who have undergone RYGB. The aim of this case series was to highlight LAMS-related shortcomings and adverse events during the periprocedural period. Methods This was a retrospective review of 4 patients with RYGB anatomy who underwent EDGE for the management of pancreaticobiliary disease and experienced LAMS-related adverse events. Techniques for managing and avoiding these events are discussed. Results Four patients underwent EDGE with both technical and clinical success. Slight LAMS migration with partial mucosal overgrowth was encountered in 1 case and was managed by LAMS removal. A large, bleeding, distal marginal ulcer after the EDGE procedure was encountered in the second case and was managed with proton pump inhibitor and removal of the LAMS, with fistula treatment with argon plasma coagulation used to enhance closure. The third case was complicated by moderate intraprocedural bleeding after LAMS dilation, which was managed by applying balloon tamponade and placing a through-the-scope esophageal stent across the LAMS. Last, preferential food passage to the excluded stomach was noted in the fourth case and resulted in symptomatic distention. The symptomatic distention was managed by another de novo jejunogastrostomy using a LAMS for drainage. Conclusions Despite its feasibility and acceptable safety profile, the use of LAMSs during EDGE could be associated with several procedure-specific adverse events, which can be avoided or managed endoscopically with no further consequence.

Obesity is a metabolic disease that affects all ages; it is considered life-threatening condition as it leads to fatal complications such as; cardiovascular diseases and diabetes. The therapeutic options include; life-style modifications, pharmacotherapy intervention, and surgical intervention. Bariatric surgery (BS) is considered as the most effective option among the others for its rapid weight loss, maintaining the lost mass, and improving the quality of life of the patients. Nevertheless, BS leads to severe changes in the bioavailability of medications, especially for chronic diseases, which may reach to limit where the patient's life endangers. Recently, pharmaceutical formulations had developed several methods to improve the drug bioavailability of drugs though the implying of nanotechnology. Nonotechnology is responsible for reducing the size of the drugs to the nano range (

Highlights • Development of a triad of intussusception, volvulus, and internal hernia after RYGB surgery is rare. • In patients with history of RYGB and acute abdomen, high suspicion for obstructive complications is required to allow for timely diagnosis and early surgical intervention. • Early surgical intervention of SBO secondary to RYGB was sufficient for preventing bowel necrosis and subsequent bowel resection., Introduction The Roux-en-y gastric bypass (RYGB) surgery is one of the most common and successful weight loss procedures. Procedure mortality is low, but intestinal complications account for a high percentage of associated morbidity. Internal hernias remain one of the most common complications while volvulus and intussusception are rare. Presentation of case A 22-year-old woman with a past surgical history of laparoscopic RYGB six years prior presented with a 12 -h history of abdominal pain. Exploratory laparotomy revealed concomitant volvulus, internal hernia and intussusception at the J-J anastomosis which was reduced without need for bowel resection. Her post-operative course was unremarkable and she was discharged home five days later. Discussion Many previous cases of intussusception related to RYGB surgery have required treatment with bowel resection secondary to delayed surgical intervention. Due to high variability in clinical presentation of post-RYGB obstruction, a high index of suspicion is necessary for prompt recognition. Early surgical intervention may prevent the need for bowel resection and improve patient outcomes. Conclusion This case represents an unusual complication of RYGB involving intussusception, internal hernia and volvulus that was successfully managed without need for bowel resection due to early identification and surgical intervention.

Objective Post–bariatric surgery hypoglycemia (PBH) is defined as the presence of neuroglycopenic symptoms accompanied by postprandial hypoglycemia in bariatric surgery patients. Recent clinical studies using continuous glucose monitoring (CGM) technology revealed that PBH is more frequently observed in vertical sleeve gastrectomy (VSG) patients than previously recognized. PBH cannot be alleviated by current medication. Therefore, a model system to investigate the mechanism and treatment is required. Methods We used CGM in a rat model of VSG and monitored the occurrence of glycemic variability and hypoglycemia in various meal conditions for 4 weeks after surgery. Another cohort of VSG rats with CGM was used to investigate whether the blockade of glucagon-like peptide-1 receptor (GLP-1R) signaling alleviates these symptoms. A mouse VSG model was used to investigate whether the impaired glucose counterregulatory system causes postprandial hypoglycemia. Results Like in humans, rats have increased glycemic variability and hypoglycemia after VSG. Postprandial hypoglycemia was specifically detected after liquid versus solid meals. Further, the blockade of GLP-1R signaling raises the glucose nadir but does not affect glycemic variability. Conclusions Rat bariatric surgery duplicates many features of human post–bariatric surgery hypoglycemia including postprandial hypoglycemia and glycemic variability, while blockade of GLP-1R signaling prevents hypoglycemia but not the variability., Highlights • VSG causes glycemic variability during ad lib feeding condition. • Single liquid meal ingestion causes post-VSG hypoglycemia. • Blockade of GLP-1 receptor prevents post-VSG hypoglycemia.

Video Video 1 Demonstration of deploying lumen-apposing metal stents for gastrogastrostomy and choledochoduodenostomy in a patient with Roux-en-Y gastric bypass anatomy, as well as EUS-guided fine needle biopsy for pancreatic mass.

Background and Aims Therapeutic endoscopy plays a major role in the management of postbariatric anastomotic leaks, offering an effective treatment alternative to repeated surgery. In recent years, management has been moving from bridging and closing the leak’s orifice toward an approach that uses vacuum therapy or internal drainage. Our aim was to demonstrate different treatment options for the management of postbariatric leaks. Methods We describe 3 different endoscopic techniques for postbariatric leaks in 2 patients who had undergone Roux-en-Y gastric bypass (RYGB) and 1 patient who had undergone sleeve gastrectomy. Results The first patient had a 20-mm early post-RYGB leak with an intra-abdominal associated collection treated with 5 sessions of endoscopic vacuum therapy (EVT). The second patient had a 12-mm acute postgastric sleeve leak with an associated collection, in whom therapy with EVT had failed, and who was then treated with endoscopic internal drainage (EID). The last patient had a chronic intra-abdominal collection after RYGB, despite reoperation, in whom therapy with EID and esophageal stent had failed, and who was treated with a diabolo-shaped lumen-apposing metal stent placed between the gastric pouch and the gastric remnant. Weight-loss intention was not compromised in any patient. All patients remain well. Conclusions Staple-line or anastomotic leaks are an important cause of morbidity and mortality after surgery. There are myriad endoscopic techniques, with varying reported efficacy. Often, more than one endoscopic approach can be used concomitantly, whereas in other cases, therapies are applied sequentially depending on the initial clinical response. Multiple therapeutic options should be considered before endoscopic failure.

Bariatric surgery is the most effective and durable treatment for morbid obesity, with an unexplained yet beneficial side effect of restoring insulin sensitivity and improving glycemia, often before weight loss is observed. Among the many contributing mechanisms often cited, the altered handling of intestinal bile acids is of considerable therapeutic interest. Here, we review a growing body of literature examining the metabolic effects of bile acids ranging from their physical roles in dietary fat handling within the intestine to their functions as endocrine and paracrine hormones in potentiating responses to bariatric surgery. The roles of 2 important bile acid receptors, Takeda G-protein coupled receptor (also known as G-protein coupled bile acid receptor) and farnesoid X receptor, are highlighted as is downstream signaling through glucagon-like polypeptide 1 and its cognate receptor. Additional improvements in other phenotypes and potential contributions of commensal gut bacteria, such as Akkermansia muciniphila, which are manifest after Roux-en-Y gastric bypass and other emulations, such as gallbladder bile diversion to the ileum, are also discussed. Keywords: Bariatric Surgery, Bile Acids, Type 2 Diabetes, Roux-en Y Gastric Bypass, Glucagon-Like Polypeptide 1 (GLP-1)

Roux-en-Y gastric bypass (RYGB) is one of the most commonly performed weight-loss procedures, but how severe obesity and RYGB affect circulating HDL-associated microRNAs (miRNAs) remains unclear. Here, we aim to investigate how HDL-associated miRNAs are regulated in severe obesity and how weight loss after RYGB surgery affects HDL-miRNAs. Plasma HDLs were isolated from patients with severe obesity (n = 53) before and 6 and 12 months after RYGB by immunoprecipitation using goat anti-human apoA-I microbeads. HDLs were also isolated from 18 healthy participants. miRNAs were extracted from isolated HDL and levels of miR-24, miR-126, miR-222, and miR-223 were determined by TaqMan miRNA assays. We found that HDL-associated miR-126, miR-222, and miR-223 levels, but not miR-24 levels, were significantly higher in patients with severe obesity when compared with healthy controls. There were significant increases in HDL-associated miR-24, miR-222, and miR-223 at 12 months after RYGB. Additionally, cholesterol efflux capacity and paraoxonase activity were increased and intercellular adhesion molecule-1 (ICAM-1) levels decreased. The increases in HDL-associated miR-24 and miR-223 were positively correlated with an increase in cholesterol efflux capacity (r = 0.326, P = 0.027 and r = 0.349, P = 0.017, respectively). An inverse correlation was observed between HDL-associated miR-223 and ICAM-1 at baseline. Together, these findings show that HDL-associated miRNAs are differentially regulated in healthy participants versus patients with severe obesity and are altered after RYGB. These findings provide insights into how miRNAs are regulated in obesity before and after weight reduction and may lead to the development of novel treatment strategies for obesity and related metabolic disorders.

Bariatric surgery has proven to be a valuable treatment option for morbid obesity. However, these procedures can lead to impaired intestinal absorption of calcium and vitamin D, thereby challenging calcium homeostasis and possibly contributing to bone loss leading to an increased fracture risk. Besides calcium and vitamin D malabsorption, hormonal changes occurring after surgery can also be the source of observed bone loss. In this review, first, a case report will be discussed, highlighting the relevance of this topic. Afterwards, changes in bone density and fracture risk, after the two most performed types of bariatric surgery, Sleeve Gastrectomy (SG) and Roux-en-Y Gastric Bypass (RYGB) will be discussed. In addition, we discuss the putative underlying mechanisms leading to bone changes based on both preclinical and clinical observations. Nonetheless, it is clear further research is needed to further elucidate the exact mechanisms of bone loss following bariatric surgery and subsequently identify potential treatment options for bone preservation., Highlights • Bariatric surgery induces bone loss and leads to increased fracture risk. • Bone resorption increases after both SG and, more strongly, after RYGB. • Malabsorption and adipose tissue-related hormones likely contribute to bone loss.

The absorption of oral drugs is frequently plagued by significant variability with potentially serious therapeutic consequences. The source of variability can be traced back to interindividual variability in physiology, differences in special populations (age- and disease-dependent), drug and formulation properties, or food-drug interactions. Clinical evidence for the impact of some of these factors on drug pharmacokinetic variability is mounting: e.g. gastric pH and emptying time, small intestinal fluid properties, differences in pediatrics and the elderly, and surgical changes in gastrointestinal anatomy. However, the link of colonic factors variability (transit time, fluid composition, microbiome), sex differences (male vs. female) and gut-related diseases (chronic constipation, anorexia and cachexia) to drug absorption variability has not been firmly established yet. At the same time, a way to decrease oral drug pharmacokinetic variability is provided by the pharmaceutical industry: clinical evidence suggests that formulation approaches employed during drug development can decrease the variability in oral exposure. This review outlines the main drivers of oral drug exposure variability and potential approaches to overcome them, while highlighting existing knowledge gaps and guiding future studies in this area. ispartof: EUROPEAN JOURNAL OF PHARMACEUTICAL SCIENCES vol:162 ispartof: location:Netherlands status: published

Highlights • Performance of MGB with a 200 cm bypassed limb in a morbidly obese female. • Presentation of anemia, low albumin, elevated LFT at 8th month despite good intake. • NAFLD activity score progressed from 2/8 to 7/8, leading to revisional surgery. • Rapid course of weight loss after BS and/or long bypassed limb could be responsible. • Bowel length measurement is recommended to avoid a short common intestinal channel., Introduction Mini-gastric bypass (MGB) is a popular bariatric procedure. Its effect on non-alcoholic fatty liver disease (NAFLD), however, has not yet been comprehensively studied. Presentation of case A 57 year-old non-alcoholic female with a body mass index of 42.8 kg/m2 underwent MGB without any incident. A concurrent liver biopsy showed an NAFLD activity score (NAS) of 2/8 without fibrosis. She presented at postoperative month eight with edema, vague abdominal pain, nausea, and vomiting and was hospitalized. Her BMI had dropped to 25.7 kg/m2. Her blood workup revealed mild anemia, mildly elevated liver enzymes, and hypoalbuminemia (2.5 g/dL). Liver ultrasound revealed grade-2 fatty liver. She received parenteral nutrition and intensive nutrient supplementation. Nevertheless, with regard to unsuccessful supportive measures and rising liver enzymes, revisional surgery −gastrogastrostomy- was performed. Her liver biopsy demonstrated a NAS of 7/8 at the time of revisional surgery. Her postoperative course was uneventful and she was discharged after one week. Discussion Bariatric surgery has shown favorable results regarding improvement of NAFLD in morbid obesity. This beneficial effect has been linked to the amount of weight loss. However, case reports have shown deteriorating liver function and NAFLD even after significant weight loss. They all have in common significant weight loss in a relatively short period of time. There may also be a connection between specific bariatric surgery procedures and this phenomenon. Conclusion Future studies comparing the effect of various bariatric procedures, including MGB, are necessary to help clinicians decide the optimal procedure for patients with this liver condition.

Highlights • Revisional bariatric surgery will rise in the future. • The established single-anastomosis-duodeno-ileal bypass with sleeve gastrectomy (SADI-S) as the restrictive part of the procedure. Due to preserved pylorus, SG has the disadvantage of a high-pressure system with de-novo or worsening of existing gastroesophageal reflux disease in the long-term. • One anastomosis gastric bypass/Mini-gastric bypass (OAGB/MGB) reduces the high-pressure system of SG in a low-pressure system of OAGB/MGB. • OAGB/MGB might be a simple method to rescue failed SADI-S patients., Introduction The established single-anastomosis-duodeno-ileal bypass with sleeve gastrectomy (SADI-S) is based on a sleeve gastrectomy (SG) as the restrictive part of the procedure. Due to preserved pylorus, SG has the disadvantage of a high-pressure system with de novo or worsening of existing gastroesophageal reflux disease (GERD). Case presentation A female patient presented herself due to protracted GERD and weight regain after multiple bariatric surgeries. At an initial weight of 158 kg (BMI 62.5 kg/m2) the patient underwent adjustable gastric banding in 2009. After band removal in slippage, the patient underwent SG at a weight of 135 kg in 2012. Nine months after SG, SADI-S was performed as a malabsorptive second step procedure. After 32 months the patient suffered from severe GERD under proton pump inhibitor therapy. Actual weight was 107.9 kg (BMI 42.7 kg/m2). Upper endoscopy showed a hiatal hernia and esophagitis B and dorsal hiatoplasty was performed. After 6 months in still existing severe GERD and weight regain indication for laparoscopic conversion to One anastomosis gastric bypass/Mini-gastric bypass (OAGB/MGB) was given, aiming to reduce the high-pressure system of SG in a low-pressure system of OAGB/MGB. One year after revisional surgery reflux was reported to be only occasionally. Further weight loss was seen (91 kg, BMI 36 kg/m2, EWL 67.7%). Conclusion SG as the restrictive part of SADI-S may lead to GERD and consequently to pathologic eating of “soft” calories, that defeats the operation and results in weight regain. OAGB/MGB might be a simple method to rescue such failed SADI-S patients.

Objective Postprandial hypoglycemia is an infrequent but disabling complication of Roux-en-Y gastric bypass (RYGB) surgery. Controversy still exists as to whether the postprandial hyperinsulinemia observed is due to inherent changes in pancreatic β-cell mass or function or to reversible alterations caused by RYGB anatomy. We aimed to determine if gastric feeding or reversal of RYGB would normalize postprandial glucose and hormone excursions in patients with symptomatic hypoglycemia. Methods We completed a prospective study of six patients with severe symptomatic RYGB hypoglycemia who underwent RYGB reversal. An additional subject without hypoglycemia who underwent RYGB reversal was also studied prospectively. Mixed meal tolerance testing (MTT) was done orally (RYGB anatomy), via gastrostomy tube in the excluded stomach in the setting of RYGB, and several months after RYGB reversal. Results All subjects reported symptomatic improvement of hypoglycemia after reversal of RYGB. Weight gain after reversal was moderate and variable. Postprandial glucose, insulin, and GLP-1 excursions were significantly diminished with gastric feeding and after reversal. Insulin secretion changed proportional to glucose levels and insulin clearance increased after reversal. Glucagon/insulin ratios were similar throughout study. We further compared the impact of modified sleeve gastrectomy reversal surgery to those with restoration of complete stomach and found no significant differences in weight regain or in postprandial glucose or hormone levels. Conclusions Reversal of RYGB is an effective treatment option for severe postprandial hypoglycemia. The pathophysiology of this disorder is primarily due to RYGB anatomy resulting in altered glucose, gut, and pancreatic hormone levels and decreased insulin clearance, rather than inherent β-cell hyperplasia or hyperfunction., Graphical abstract, Highlights • Prospective study of gastric feeding and bypass reversal in hypoglycemic subjects. • Altered gut anatomy is the main driver of postmeal glucose and hormone excursions. • Beta-cell function is not inherently altered in gastric-bypass related hypoglycemia. • Bypass reversal is effective therapy for gastric-bypass related hypoglycemia.

Objective Roux-en-Y gastric surgery (RYGB) promotes a rapid and sustained weight loss and amelioration of glucose control in obese patients. A high number of molecular hypotheses were previously tested using duodenal-jejunal bypass (DJB) performed in various genetic models of mice with knockouts for various hormones or receptors. The data were globally negative or inconsistent. Therefore, the mechanisms remained elusive. Intestinal gluconeogenesis is a gut function that has been suggested to contribute to the metabolic benefits of RYGB in obese patients. Methods We studied the effects of DJB on body weight and glucose control in obese mice fed a high fat-high sucrose diet. Wild type mice and mice with a genetic suppression of intestinal gluconeogenesis were studied in parallel using glucose- and insulin-tolerance tests. Fecal losses, including excretion of lipids, were studied from the feces recovered in metabolic cages. Results DJB induced a dramatic decrease in body weight and improvement in glucose control (glucose- and insulin-tolerance) in obese wild type mice fed a high calorie diet, for 25 days after the surgery. The DJB-induced decrease in food intake was transient and resumed to normal in 7–8 days, suggesting that decreased food intake could not account for the benefits. Total fecal losses were about 5 times and lipid losses 7 times higher in DJB-mice than in control (sham-operated and pair-fed) mice, and could account for the weight loss of mice. The results were comparable in mice with suppression of intestinal gluconeogenesis. There was no effect of DJB on food intake, body weight or fecal loss in lean mice fed a normal chow diet. Conclusions DJB in obese mice fed a high calorie diet promotes dramatic fecal loss, which could account for the dramatic weight loss and metabolic benefits observed. This could dominate the effects of the mouse genotype/phenotype. Thus, fecal energy loss should be considered as an essential process contributing to the metabolic benefits of DJB in obese mice., Highlights • Duodenal-jejunal bypass (DJB) promotes weight loss in mice fed a high calorie diet. • DJB induces dramatic fecal energy losses in mice fed a high calorie diet. • DJB has no effect in mice fed a control (starch-based) diet. • There is no fecal losses in DJB-mice fed a control diet. • Fecal energy loss is a cause of body weight loss in DJB-mice fed high calorie diet.

Highlights • Choledocholithiasis in Roux-en-Y patients is a therapeutic challenge for both surgeons and endoscopists. • Prophylactic cholecystectomy is not recommended in bariatric surgery. • Laparoscopic assisted-ERCP is a safe and feasible intervention. • B-ERCP and EDGE are two valid alternatives B-ERCP and EDGE are two valid alternatives., Introduction Choledocholithiasis in Roux-en-Y patients is a therapeutic challenge for both surgeons and endoscopists. In fact, typical procedures, such as ERCP, can’t be performed due to the altered anatomy of the patient. Nowadays, procedures on this kind of patient are performed not only in specialized bariatric centers, but, due to the increasing number of patients undergoing bariatric surgery, are starting to become more common even in smaller and non-specialized centers that don’t possess the same expertise and technology. Case presentation We present the case of a 33-year-old patient, who had already undergone bariatric surgery, and presented to our department with a diagnosis of choledocholithiasis. Due to the altered anatomy the patient was treated through a laparoscopic assisted ERCP. Discussion A review of the need and proper timing for a cholecystectomy in this kind of patient, in order to prevent choledocholithiasis, is discussed. Moreover, a review of the literature regarding the possible treatments of this pathology in bariatric patients underlines the presence of other treatments, beyond the one performed in our department, that can be performed even in small non-specialized centers. Conclusions Prophylactic cholecystectomy is not recommended in bariatric surgery. Laparoscopic assisted-ERCP is a safe and feasible intervention which is to be preferred, even if B-ERCP and EDGE are two valid alternatives.

Highlights • Obese patients with end-stage renal disease on hemodialysis, decreases the access to kidney transplantation. • Bariatric surgery has proven to be safe and effective for weight loss. • Dialysis-dependency does not independently increase the risk for adverse outcomes after bariatric surgery. • The estimation of DW through BIA is an effective method for avoiding complications generated by excessive or deficient ultrafiltration., Introduction Morbid obesity in chronic kidney disease patients on hemodialysis limits access to renal transplantation. We report here a case of a surgical procedure for weight reduction in a hemodialysis patient and adjustment of dry weight through bioelectrical impedance. Case presentation A 44-year-old male with CKD on hemodialysis for 26 years. After 3 years on dialysis, he underwent a cadaveric kidney transplant. However, after 8 years of transplant, he loses the kidney graft and returns to dialysis treatment. The patient’s BMI increased to 42 kg/m2 and he had difficult-to-control hypertension and severe sleep apnea. Behavioral, nutritional and pharmacologic measures were not sufficient to achieve an adequate weight control. Thus, a surgical procedure for weight reduction was considered. The patient underwent a laparoscopic gastric sleeve without any complications. Dry weight was adjusted through bioelectrical impedance before each hemodialysis session. The patient did not display hypotension, cramps, or fluid overload. After a 30 kg weight loss, the patient’s BMI was 28.3 kg/m2, allowing registration on the kidney transplant waitlist. Discussion Obesity in CKD restricts access to kidney transplant waitlist. Bariatric surgery has proven to be safe and effective for sustained weight loss and it seems that the fact that a patient is dialysis dependent does not independently increase post-operatory complications. Conclusion Surgical procedures for weight reduction in dialysis patients does not independently increase the risk for adverse outcomes after bariatric surgery. The estimation of DW through BIA is an effective method for avoiding complications generated by excessive or deficient ultrafiltration.

Background Bariatric surgery leads to early and long-lasting remission of type 2 diabetes (T2D). However, the mechanisms behind this phenomenon remain unclear. Among several factors, gut hormones are thought to be crucial mediators of this effect. Unlike GLP-1, the role of the hormone peptide tyrosine tyrosine (PYY) in bariatric surgery in humans has been limited to appetite regulation and its impact on pancreatic islet secretory function and glucose metabolism remains under-studied. Methods Changes in PYY concentrations were examined in obese patients after bariatric surgery and compared to healthy controls. Human pancreatic islet function was tested upon treatment with sera from patients before and after the surgery, in presence or absence of PYY. Alterations in intra-islet PYY release and insulin secretion were analysed after stimulation with short chain fatty acids (SCFAs), bile acids and the cytokine IL-22. Findings We demonstrate that PYY is a key effector of the early recovery of impaired glucose-mediated insulin and glucagon secretion in bariatric surgery. We establish that the short chain fatty acid propionate and bile acids, which are elevated after surgery, can trigger PYY release not only from enteroendocrine cells but also from human pancreatic islets. In addition, we identify IL-22 as a new factor which is modulated by bariatric surgery in humans and which directly regulates PYY expression and release. Interpretation This study shows that some major metabolic benefits of bariatric surgery can be emulated ex vivo. Our findings are expected to have a direct impact on the development of new non-surgical therapy for T2D correction.

Background The mechanism by which Roux-en-Y Gastric Bypass (RYGB) increases the secretion of glucagon-like peptide-1 (GLP-1) remains incompletely defined. Here we investigated whether TGR5-mTORC1 signaling mediates the RYGB-induced alteration in GLP-1 production in mice and human beings. Methods Circulating bile acids, TGR5-mTORC1 signaling, GLP-1 synthesis and secretion were determined in lean or obese male C57BL/6 mice with or without RYGB operation, as well as in normal glycemic subjects, obese patients with type 2 diabetes before and after RYGB. Results Positive relationships were observed among circulating bile acids, ileal mechanistic target of rapamycin complex 1 (mTORC1) signaling and GLP-1 during changes in energy status in the present study. RYGB increased circulating bile acids, ileal Takeda G protein-coupled receptor 5 (TGR5) and mTORC1 signaling activity, as well as GLP-1 production in both mice and human subjects. Inhibition of ileal mTORC1 signaling by rapamycin significantly attenuated the stimulation of bile acid secretion, TGR5 expression and GLP-1 synthesis induced by RYGB in lean and diet-induced obese mice. GLP-1 production and ileal TGR5-mTORC1 signaling were positively correlated with plasma deoxycholic acid (DCA) in mice. Treatment of STC-1 cells with DCA stimulated the production of GLP-1. This effect was associated with a significant enhancement of TGR5-mTORC1 signaling. siRNA knockdown of mTORC1 or TGR5 abolished the enhancement of GLP-1 synthesis induced by DCA. DCA increased interaction between mTOR-regulatory-associated protein of mechanistic target of rapamycin (Raptor) and TGR5 in STC-1 cells. Interpretation Deoxycholic acid-TGR5-mTORC1 signaling contributes to the up-regulation of GLP-1 production after RYGB., Highlights • Ileal mTORC1 signaling activity and GLP-1 production are up-regulated by RYGB in both rodents and human subjects. • Manipulation of intestinal mTORC1 signaling alters the up-regulation of GLP-1 induced by RYGB. • Ileal TGR5-mTORC1 signaling and GLP-1 production are positively correlative with plasma deoxycholic acid in mice. • Deoxycholic acid enhances synthesis and secretion of GLP-1 through TGR5-mTORC1 pathway in STC-1 cells. Diabetes resolves rapidly after RYGB. GLP-1 improves glycemic control in rodents and patients. Although literature has documented that postprandial secretion of GLP-1 is enhanced after RYGB, its underlying molecular mechanisms remain poorly understood. We have identified the deoxycholic acid-TGR5-mTORC1 signaling pathway as a potential mechanism by which RYGB increases GLP-1 production, thus expanding its interest as a target for the treatment of type 2 diabetes mellitus.

Highlights • The association between obesity surgery (OS) and cancer risk remains unclear. • Colorectal cancer (CRC) risk is increased in obese individuals. • No evidence of increased CRC risk after OS in this English population study. • Reduced breast cancer risk was apparent after OS. • Renal and endometrial cancer risk is elevated in obese patients., Background The association between obesity surgery (OS) and cancer risk remains unclear. We investigated this association across the English National Health Service. A population-based Swedish study has previously suggested that OS may increase the risk of developing colorectal cancer (CRC). Methods A retrospective observational study of individuals who underwent OS (surgery cohort) or diagnosed with obesity, but had no OS (no-surgery cohort) (1997–2013) were identified using Hospital Episode Statistics. Subsequent diagnosis of CRC, breast, endometrial, kidney and lung cancer, as well as time ‘at risk’, were determined by linkage to National Cancer Registration & Analysis Service and Office of National Statistics data, respectively. Standardised incidence ratios (SIR) in relation to OS were calculated. Results 1 002 607 obese patients were identified, of whom 3.9% (n = 39 747) underwent OS. In the no-surgery obese population, 3 237 developed CRC (SIR 1.12 [95% CI 1.08–1.16]). In those who underwent OS, 43 developed CRC (SIR 1.26 [95% CI 0.92–1.71]). The OS cohort demonstrated decreased breast cancer risk (SIR 0.76 [95% CI 0.62–0.92]), unlike the no surgery cohort (SIR 1.08 [95% CI 1.04–1.11]). Increased risk of endometrial and kidney cancer was observed in surgery and no-surgery cohorts. Conclusions CRC risk is increased in individuals diagnosed as obese. Prior obesity surgery was not associated with an increased CRC risk. However, the OS population was small, with limited follow-up. Risk of breast cancer after OS is reduced compared with the obese no-surgery population, while the risk of endometrial and kidney cancers remained elevated after OS.

Background: Like all healthy ecosystems, richness of microbiota species characterizes the GI microbiome in healthy individuals. Conversely, a loss in species diversity is a common finding in several disease states. This biome is flooded with energy in the form of undigested and partially digested foods, and in some cases drugs and dietary supplements. Each microbiotic species in the biome transforms that energy into new molecules, which may signal messages to physiological systems of the host. Scope of review: Dietary choices select substrates for species, providing a competitive advantage over other GI microbiota. The more diverse the diet, the more diverse the microbiome and the more adaptable it will be to perturbations. Unfortunately, dietary diversity has been lost during the past 50 years and dietary choices that exclude food products from animals or plants will narrow the GI microbiome further. Major conclusion: Additional research into expanding gut microbial richness by dietary diversity is likely to expand concepts in healthy nutrition, stimulate discovery of new diagnostics, and open up novel therapeutic possibilities. Keywords: Microbiome, Microbiota, Gastrointestinal, Dietary diversity, Agrobiodiversity, Microbiota richness