Exercise training and DNA methylation profile in post-bariatric women: Results from an exploratory study.

Exercise training and bariatric surgery have been shown to independently modulate DNA methylation profile in clusters of genes related to metabolic and inflammatory pathways. This study aimed to investigate the effects of a 6-month exercise training program on DNA methylation profile in women who underwent bariatric surgery. In this exploratory, quasi-experimental study, we analyzed DNA methylation levels by array technology in eleven women who underwent Roux-en-Y Gastric Bypass and a 6-month, three-times-a-week, supervised exercise training program. Epigenome Wide Association Analysis showed 722 CpG sites with different methylation level equal to or greater than 5% (P < 0.01) after exercise training. Some of these CpGs sites were related to pathophysiological mechanisms of inflammation, specially Th17 cell differentiation (FDR value < 0.05 and P < 0.001). Our data showed epigenetic modification in specific CpG sites related to Th17 cell differentiation pathway in post-bariatric women following a 6-months exercise training program.

Exercise modifies hypothalamic connectivity and brain functional networks in women after bariatric surgery: a randomized clinical trial.

BACKGROUND: Obesity is a disease that may involve disrupted connectivity of brain networks. Bariatric surgery is an effective treatment for obesity, and the positive effects on obesity-related conditions may be enhanced by exercise. Herein, we aimed to investigate the possible synergistic effects of Roux-en-Y Gastric Bypass (RYGB) and exercise training on brain functional networks. METHODS: Thirty women eligible for bariatric surgery were randomly assigned to a Roux-en-Y gastric bypass (RYGB: n = 15, age = 41.0 ± 7.3 years) or RYGB plus Exercise Training (RYGB + ET: n = 15, age = 41.9 ± 7.2 years). Clinical, laboratory, and brain functional connectivity parameters were assessed at baseline, and 3 (POST3) and 9 months (POST9) after surgery. The 6-month, three-times-a-week, exercise intervention (resistance plus aerobic exercise) was initiated 3 months post-surgery (for RYGB + ET). RESULTS: Exercise superimposed on bariatric surgery (RYGB + ET) increased connectivity between hypothalamus and sensorial regions (seed-to-voxel analyses of hypothalamic connectivity), and decreased default mode network (DMN) and posterior salience (pSAL) network connectivity (ROI-to-ROI analyses of brain networks connectivity) when compared to RYGB alone (all p-FDR < 0.05). Increases in basal ganglia (BG) network connectivity were only observed in the exercised training group (within-group analyses). CONCLUSION: Exercise training is an important component in the management of post-bariatric patients and may improve the hypothalamic connectivity and brain functional networks that are involved in controlling food intake. TRIAL REGISTRATION: Clinicaltrial.gov: NCT02441361.

Influence of Adherence to Social Distancing Due to the COVID-19 Pandemic on Physical Activity Level in Post-bariatric Patients.

We assessed physical activity using accelerometers and a questionnaire in 33 post-bariatric patients who reported to be adherent (n = 15) or not (n = 18) to social distancing due to the COVID-19 pandemic. Patients adherent to social distancing spent more time in sedentary behavior (1.1 h/day, 0.1, 2.2; p = 0.045) and less time in moderate-to-vigorous physical activity (- 12.2 min/day, - 23.8, - 0.6; p = 0.040) vs. non-adherent ones. Bland-Altman analysis comparing objective and subjective physical activity estimates showed a bias for time spent in sedentary behavior and moderate-to-vigorous activity of 2.8 h/day and 8.5 min/day. In conclusion, post-bariatric patients who were adherent to social distancing measures were more inactive and sedentary than non-adherent ones. Strategies to increase physical activity in post-bariatric patients exposed to social distancing are necessary during the COVID-19 pandemic.

Exercise-Induced Increases in Insulin Sensitivity After Bariatric Surgery Are Mediated By Muscle Extracellular Matrix Remodeling.

Exercise seems to enhance the beneficial effect of bariatric (Roux-en-Y gastric bypass [RYGB]) surgery on insulin resistance. We hypothesized that skeletal muscle extracellular matrix (ECM) remodeling may underlie these benefits. Women were randomized to either a combined aerobic and resistance exercise training program following RYGB (RYGB + ET) or standard of care (RYGB). Insulin sensitivity was assessed by oral glucose tolerance test. Muscle biopsy specimens were obtained at baseline and 3 and 9 months after surgery and subjected to comprehensive phenotyping, transcriptome profiling, molecular pathway identification, and validation in vitro. Exercise training improved insulin sensitivity beyond surgery alone (e.g., Matsuda index: RYGB 123% vs. RYGB + ET 325%; P ≤ 0.0001). ECM remodeling was reduced by surgery alone, with an additive benefit of surgery and exercise training (e.g., collagen I: RYGB -41% vs. RYGB + ET -76%; P ≤ 0.0001). Exercise and RYGB had an additive effect on enhancing insulin sensitivity, but surgery alone did not resolve insulin resistance and ECM remodeling. We identified candidates modulated by exercise training that may become therapeutic targets for treating insulin resistance, in particular, the transforming growth factor-ß1/SMAD 2/3 pathway and its antagonist follistatin. Exercise-induced increases in insulin sensitivity after bariatric surgery are at least partially mediated by muscle ECM remodeling.

Gut Microbiota Profile of Obese Diabetic Women Submitted to Roux-en-Y Gastric Bypass and Its Association with Food Intake and Postoperative Diabetes Remission.

Gut microbiota composition is influenced by environmental factors and has been shown to impact body metabolism. OBJECTIVE: To assess the gut microbiota profile before and after Roux-en-Y gastric bypass (RYGB) and the correlation with food intake and postoperative type 2 diabetes remission (T2Dr). DESIGN: Gut microbiota profile from obese diabetic women was evaluated before (n = 25) and 3 (n = 20) and 12 months (n = 14) after RYGB, using MiSeq Illumina-based V4 bacterial 16S rRNA gene profiling. Data on food intake (7-day record) and T2Dr (American Diabetes Association (ADA) criteria) were recorded. RESULTS: Preoperatively, the abundance of five bacteria genera differed between patients with (57%) and without T2Dr (p < 0.050). Preoperative gut bacteria genus signature was able to predict the T2Dr status with 0.94 accuracy ROC curve (receiver operating characteristic curve). Postoperatively (vs. preoperative), the relative abundance of some gut bacteria genera changed, the gut microbial richness increased, and the Firmicutes to Bacteroidetes ratio (rFB) decreased (p < 0.05) regardless of T2Dr. Richness levels was correlated with dietary profile pre and postoperatively, mainly displaying positive and inverse correlations with fiber and lipid intakes, respectively (p < 0.05). CONCLUSIONS: Gut microbiota profile was influenced by RYGB and correlated with diet and T2Dr preoperatively, suggesting the possibility to assess its composition to predict postoperative T2Dr.

Exercise Mitigates Bone Loss in Women With Severe Obesity After Roux-en-Y Gastric Bypass: A Randomized Controlled Trial.

CONTEXT: Bone loss after bariatric surgery potentially could be mitigated by exercise. OBJECTIVE: To investigate the role of exercise training (ET) in attenuating bariatric surgery-induced bone loss. DESIGN: Randomized, controlled trial. SETTING: Referral center for bariatric surgery. PATIENTS: Seventy women with severe obesity, aged 25 to 55 years, who underwent Roux-en-Y gastric bypass (RYGB). INTERVENTION: Supervised, 6-month, ET program after RYGB vs. standard of care (RYGB only). OUTCOMES: Areal bone mineral density (aBMD) was the primary outcome. Bone microarchitecture, bone turnover, and biochemical markers were secondary outcomes. RESULTS: Surgery significantly decreased femoral neck, total hip, distal radius, and whole body aBMD (P < 0.001); and increased bone turnover markers, including collagen type I C-telopeptide (CTX), procollagen type I N-propeptide (P1NP), sclerostin, and osteopontin (P < 0.05). Compared with RYGB only, exercise mitigated the percent loss of aBMD at femoral neck [estimated mean difference (EMD), -2.91%; P = 0.007;], total hip (EMD, -2.26%; P = 0.009), distal radius (EMD, -1.87%; P = 0.038), and cortical volumetric bone mineral density at distal radius (EMD, -2.09%; P = 0.024). Exercise also attenuated CTX (EMD, -0.20 ng/mL; P = 0.002), P1NP (EMD, -17.59 ng/mL; P = 0.024), and sclerostin levels (EMD, -610 pg/mL; P = 0.046) in comparison with RYGB. Exercise did not affect biochemical markers (e.g., 25(OH)D, calcium, intact PTH, phosphorus, and magnesium). CONCLUSION: Exercise mitigated bariatric surgery-induced bone loss, possibly through mechanisms involving suppression in bone turnover and sclerostin. Exercise should be incorporated in postsurgery care to preserve bone mass.

Cholecystectomy in Patients Submitted to Bariatric Procedure: A Systematic Review and Meta-analysis.

Weight loss following bariatric surgery increases risk for biliary stones. This study performed a meta-analysis evaluating cholecystectomy risks in bariatric patients. A systematic review and meta-analysis were performed. We evaluated the incidence rate for biliary complications in patients followed after bariatric surgery. We compared the risks for mortality, complications, and in hospital stay among patient submitted to cholecystectomy before, concomitantly with or after bariatric surgery, as well as patients submitted to bariatric surgery and cholecystectomy, and patients submitted only to bariatric surgery in order to evaluate when to perform cholecystectomy in morbidly obese patients. The incidence rate of biliary complications was 5.54 cases/1000 patient year. The addition of cholecystectomy to bariatric surgery resulted in an increased risk for complications (RD = 0.02). The risk for complications (RD = - 0.09) and reoperation (RD = - 0.02) was lower when performed concomitantly with bariatric surgery compared to post-bariatric procedure. Prophylactic cholecystectomy may be avoided. Patients submitted to bariatric surgery have low incidence rate of biliary complications, and concomitant cholecystectomy increases the risk for postoperative complications and operative time. If cholecystectomy is not indicated, patients should be carefully followed with attention for biliary complications, once cholecystectomy performed post-bariatric surgery is at higher risk for complications and reoperations.

Assessment of Weight Loss With the Intragastric Balloon in Patients With Different Degrees of Obesity.

INTRODUCTION: The intragastric balloon (IGB) is an endoscopic device for the treatment of obesity. Best results are observed in patients who follow a dietary program but few studies have assessed the results of this treatment in patients with different degrees of obesity. AIM: The aim of this study is to compare the efficacy of IGB in patients with different degrees of obesity. METHOD: A total of 2002 patients with IGB were retrospectively evaluated and were divided into groups according to initial body mass index (BMI) range, as follows: group 1, 27 to 29.9 kg/m; group 2, 30 to 34.9 kg/m; group 3, 35 to 39.9 kg/m; group 4, 40 to 44.9 kg/m; group 5, ≥45 kg/m. Weight was assessed in 3 different times: before (T0), 1 month (T1), 6 months (T2), and 6 months after removal of the IGB (T3). RESULTS: A total of 946 patients lost follow-up. Overall, 40 (3.78%) removed the device before programmed by intolerance, and 1016 patients completed the 6-month treatment. The mean weight loss was 18.9%, excess weight loss 60.1% and an BMI reduction of 6.76 points. 6 months after removal of the balloon 842 patients had continued follow-up (82.8%). At this time, weight loss was 19.84%, excess weight loss was 59.49%, and BMI reduction of 7.06 points. In all groups there was statistical difference between the times T0 and T1 and between T1 and T2 (P<0.001). There was no statistical difference between T2 and T3, in any group. CONCLUSION: IGB provided sustained weight loss in patients who remained in dietary follow-up for 1 year.

Gastrointestinal Transcriptomic Response of Metabolic Vitamin B12 Pathways in Roux-en-Y Gastric Bypass.

OBJECTIVES: Vitamin B12 (B12) deficiency after Roux-en-Y gastric bypass (RYGB) is highly prevalent and may contribute to postoperative complications. Decreased production of intrinsic factor owing to gastric fundus removal is thought to have a major role, but other components of B12 metabolism may also be affected. We evaluated changes in the expression levels of multiple B12 pathway-encoding genes in gastrointestinal (GI) tissues to evaluate the potential roles in contributing to post-RYGB B12 deficiency. METHODS: During double-balloon enteroscopy, serial GI biopsies were collected from 20 obese women (age, 46.9±6.2 years; body mass index, 46.5±5.3 kg/m2) with adult-onset type 2 diabetes (fasting plasma glucose ≥126 mg/dl; hemoglobin A1c≥6.5%) before and, at the same site, 3 months after RYGB. Gene expression levels were assessed by the Affymetrix Human GeneChip 1.0 ST microarray. Findings were validated by real-time quantitative PCR (RT-qPCR). RESULTS: Gene expression levels with significant changes (P≤0.05) included: transcobalamin I (TCN1) in remnant (-1.914-fold) and excluded (-1.985-fold) gastric regions; gastric intrinsic factor (GIF) in duodenum (-0.725-fold); and cubilin (CUBN) in duodenum (+0.982-fold), jejunum (+1.311-fold), and ileum (+0.685-fold). Validation by RT-qPCR confirmed (P≤0.05) observed changes for TCN1 in the remnant gastric region (-0.132-fold) and CUBN in jejunum (+2.833-fold). CONCLUSIONS: RYGB affects multiple pathway-encoding genes that may be associated with postoperative B12 deficiency. Decreased TCN1 levels seem to be the main contributing factor. Increased CUBN levels suggest an adaptive genetic reprogramming of intestinal tissue aiming to compensate for impaired intestinal B12 delivery.

Factors associated with complications or failure of endoscopic balloon dilation of anastomotic stricture secondary to Roux-en-Y gastric bypass surgery.

INTRODUCTION: Roux-en-Y gastric bypass is a commonly used technique of bariatric surgery. One of the most important complications is gastrojejunal anastomotic stricture. Endoscopic balloon dilation appears to be well tolerated and effective, but well-designed randomized, controlled trials have not yet been conducted. OBJECTIVE: Identify factors associated with complications or failure of endoscopic balloon dilation of anastomotic stricture secondary to Roux-en-Y gastric bypass surgery. SETTING: Gastrointestinal endoscopy service, university hospital, Brazil. METHODS: The records of 64 patients with anastomotic stricture submitted to endoscopic dilation with hydrostatic balloon dilation were reviewed. Information was collected on gastric pouch length, anastomosis diameter before dilation, number of dilation sessions, balloon diameter at each session, anastomosis diameter after the last dilation session, presence of postsurgical complications, endoscopic complications, and outcome of dilation. Comparisons were made among postsurgical and endoscopic complications; number of dilations, balloon diameter; anastomosis diameter before dilation; and dilation outcome. RESULTS: Success of dilation treatment was 95%. Perforation was positively and significantly associated with the number of dilation sessions (P = .03). Highly significant associations were found between ischemic segment and perforation (P<.001) and between ischemic segment and bleeding (P = .047). Ischemic segment (P = .02) and fistula (P = .032) were also associated with dilation failure. CONCLUSION: Ischemic segment and fistula were found to be important risk factors for balloon dilation failure. The greater the number of dilation sessions, the greater the number of endoscopic complications.

Metabolic improvements in obese type 2 diabetes subjects implanted for 1 year with an endoscopically deployed duodenal-jejunal bypass liner.

BACKGROUND: The purpose of this study was to evaluate the effect of the duodenal-jejunal bypass liner (DJBL), a 60-cm, impermeable fluoropolymer liner anchored in the duodenum to create a duodenal-jejunal bypass, on metabolic parameters in obese subjects with type 2 diabetes. METHODS: Twenty-two subjects (mean age, 46.2±10.5 years) with type 2 diabetes and a body mass index between 40 and 60 kg/m(2) (mean body mass index, 44.8±7.4 kg/m(2)) were enrolled in this 52-week, prospective, open-label clinical trial. Endoscopic device implantation was performed with the patient under general anesthesia, and the subjects were examined periodically during the next 52 weeks. Primary end points included changes in fasting blood glucose and insulin levels and changes in hemoglobin A1c (HbA1c). The DJBL was removed endoscopically at the end of the study. RESULTS: Thirteen subjects completed the 52-week study, and the mean duration of the implant period for all subjects was 41.9±3.2 weeks. Reasons for early removal of the device included device migration (n=3), gastrointestinal bleeding (n=1), abdominal pain (n=2), principal investigator request (n=2), and discovery of an unrelated malignancy (n=1). Using last observation carried forward, statistically significant reductions in fasting blood glucose (-30.3±10.2 mg/dL), fasting insulin (-7.3±2.6 µU/mL), and HbA1c (-2.1±0.3%) were observed. At the end of the study, 16 of the 22 subjects had an HbA1c<7% compared with only one of 22 at baseline. Upper abdominal pain (n=11), back pain (n=5), nausea (n=7), and vomiting (n=7) were the most common device-related adverse events. CONCLUSIONS: The DJBL improves glycemic status in obese subjects with diabetes and therefore represents a nonsurgical, reversible alternative to bariatric surgery.

Biochemical correlates of bariatric-responsive diabetes.

OBJECTIVE: In a prospective observational cohort study, the biochemical profile of bariatrically managed diabetes was documented, aiming to assess its association with clinical outcome. METHODS: The population (n = 82; age, 50.7 +/- 10.3 years; 92.7% women; followed up for 93 +/- 34 months) was stratified as responsive diabetes (Group I) (36.6%, 30 of 82) and controls without diabetes (Group II) (57.3%, 47 of 82). A few refractory subjects were identified in this cohort (Group III [refractory diabetes], 6.3%, five of 82). Nonbariatric overweight and obese diabetes subjects with similar follow-up (n = 21) were documented as well. Main outcome measures were diabetes regression, body mass índex (BMI), glucose, glycosylated hemoglobin A1c (HbA1c), serum lipids, and white blood cell count (WBC) count. RESULTS: Preoperative BMI was somewhat discrepant among operated groups but leveled off from 2 years on. Baseline WBC count, total cholesterol, low-density lipoprotein-cholesterol, blood glucose, and HbA1c were higher in responsive subjects, but a downward shift occurred, without differences regarding controls, in the subsequent period. Conservatively managed diabetes displayed favorable changes of some lipid fractions, but not glucose, HbA1c, total cholesterol, or WBC count. CONCLUSIONS: Diabetes regression rate was 94.3% at 5 years and 84.7% at around 8 years. In responsive patients, both BMI and biochemical indices normalized in the first 2 years and followed a stable path thereafter. Nonoperative treatment was unable to reduce HbA1c, glucose, or WBC count, and HbA1c was a clear prognostic marker of persistent disease in surgical cases. Further studies emphasizing the metabolic and inflammatory signature of obesity-related diabetes are worthwhile.

Digestive Adaptation with Intestinal Reserve: a neuroendocrine-based operation for morbid obesity.

BACKGROUND: Mechanical obstacles to food ingestion, nutrient-excluded segments and malabsorption are common strategies of bariatric surgery which are a potential cause of symptoms or complications. We describe an operation "Digestive Adaptation with Intestinal Reserve" (DAIR) that does not utilize these tools, aiming fundamentally at neuroendocrine changes. METHODS: The operation includes sleeve gastrectomy, omentectomy and enterectomy, maintaining the initial 40 cm of jejunum and final 260 cm of ileum (keeping the bowel length at the lower limit for adaptation to normal). Jejunum is laterally anastomosed to ileum 80 cm proximal to the cecum. A gastroileostomy creates a transit bipartition (ileum and proximal bowel in transit). 55 patients are presented whose follow-up is >12 months (12-34 months). Fasting ghrelin and resistin, and postprandial GLP-1 and PYY were measured. RESULTS: Mean BMI reduction was 4.8, 9.5, 15.4 and 20.1 kg/m(2) respectively at 1, 3, 6 and 12 months. Patients have early satiety and major improvement in pre-surgical co-morbidities, especially diabetes and hypertension. GLP-1 and PYY response to food ingestion were enhanced; fasting ghrelin and resistin were significantly reduced (P<0.05). Radiographic studies show nutrient transit through the pylorus and through the gastroileostomy. Early surgical complications (2 in 55 patients) resolved without sequelae. There were no signals of malabsorption, no deaths, and most patients present no symptoms at all. CONCLUSIONS: DAIR amplifies postprandial neuroendocrine response and provokes intense weight loss. DAIR reduces production of ghrelin and resistin and enables more nutrients to be absorbed distally enhancing GLP-1 and PYY secretion. Diabetes improved significantly without duodenal exclusion.