Duodenal-jejunal lining increases postprandial unconjugated bile acid responses and disrupts the bile acid-FXR-FGF19 axis in humans.

BACKGROUND AND AIMS: Placement of the duodenal-jejunal bypass liner (DJBL) leads to rapid weight loss and restoration of insulin sensitivity in a similar fashion to bariatric surgery. Increased systemic bile acid levels are candidate effectors for these effects through postprandial activation of their receptors TGR5 and FXR. We aimed to quantify postprandial bile acid, GLP-1 and FGF19 responses and assess their temporal relation to the weight loss and metabolic and hormonal changes seen after DJBL placement. METHODS: We performed mixed meal testing in 17 obese patients with type 2 diabetes mellitus (DM2) directly before, one week after and 6 months after DJBL placement. RESULTS: Both fasting and postprandial bile acid levels were unchanged at 1 week after implantation, and greatly increased 6 months after implantation. The increase consisted of unconjugated bile acid species. 3 hour-postprandial GLP-1 levels increased after 1 week and were sustained, whereas FGF19 levels and postprandial plasma courses were unaffected. CONCLUSIONS: DJBL placement leads to profound increases in unconjugated bile acid levels after 6 months, similar to the effects of bariatric surgery. The temporal dissociation between the changes in bile acids, GLP-1 and FGF19 and other gut hormone responses warrant caution about the beneficial role of bile acids after DJBL placement. This observational uncontrolled study emphasizes the need for future controlled studies.

Effect of the EndoBarrier Device: a 4-Year Follow-up of a Multicenter Randomized Clinical Trial.

OBJECTIVE: To evaluate the long-term effect of the duodenal-jejunal bypass liner (DJBL) on weight loss and glycemic control. BACKGROUND: Data on the long-term effect of DJBL treatment is still missing. METHODS: From 2010 to 2012, 29 patients were treated with the DJBL at center A and center B, as part of a multicenter randomized controlled trial. Prior to implantation and after removal of the DJBL, all patients underwent standardized physical examination and blood sampling. Four years after removal of the DJBL, included patients underwent standardized physical examination and blood sampling as previously performed during the initial study. RESULTS: Out of the 29 patients, 15 patients were eligible for follow-up with a median duration of 42 months. Five patients had successfully received additional bariatric surgery. Four years after explantation of the DJBL, median weight in these 15 patients was 102.0 kg (IQR 94.0-124.6), which was not statistically significantly different from the 106.1 kg at baseline (IQR 99.0-128.4). Median BMI changed from 33.1 kg/m2 (IQR 32.3-38.5) at baseline to 33.7 kg/m2 (IQR 31.2-36.9) after follow-up. Patients had a TWL of 2.2% (IQR - 1.3-5.6) compared to baseline weight. None of the parameters were significantly different after follow-up compared to baseline. CONCLUSIONS: The effect of weight reduction of initial DJBL treatment seems to be diminished after 4 years of follow-up. However, larger prospective studies with long-term follow-up need to be conducted in the future.

The Effect of 6 and 12 months Duodenal-Jejunal Bypass Liner Treatment on Obesity and Type 2 Diabetes: a Crossover Cohort Study.

OBJECTIVE: The aim of this research was to study the duodenal-jejunal bypass liner (DJBL) treatment for obesity and type 2 diabetes mellitus (T2DM) in patients after dietary treatment in a cross-over design. BACKGROUND: DJBL treatment has been proven effective for treatment of obesity and T2DM. However, data on safety and efficacy of a 12-month DJBL treatment is limited. METHODS: In 2014, our research group reported on a multicenter randomized clinical trial. Patients were randomized to DJBL or dietary treatment (control group). Twenty-eight patients crossed over after their dietary treatment and received up to 12 months of DJBL treatment. Patient visits were conducted at baseline, during DJBL treatment (1 week, 1-6, 9, 12 months) and 6 months after removal of the liner. Patients underwent a standard physical examination, blood sampling, assessment of adverse events, nutritional and diabetes counseling, and a standardized meal tolerance test. RESULTS: Of the 28 patients included in this study, 24 patients completed 6 months of treatment. Eighteen patients were extended to 12 months of DJBL treatment; 13 patients completed this treatment period. After 6 months of DJBL treatment, a significant increase in excess weight loss (EWL) and decrease in weight, BMI, HbA1c, fasting glucose, cholesterol, HDL and LDL improved significantly. After 12 months of DJBL treatment, these parameters stabilized. CONCLUSIONS: The DJBL is an effective, minimally invasive treatment option. Even after successful treatment with dietary restrictions, the DJBL is still capable of significantly reducing weight and improving cardiovascular and type 2 diabetes mellitus parameters in obese patients.

Impact of Duodenal-Jejunal Exclusion on Satiety Hormones.

OBJECTIVE: Bariatric procedures that exclude the proximal small intestine lead to significant weight loss which is probably mediated by changes in hormones that alter appetite, such as peptide YY (PYY), ghrelin, cholecystokinin (CCK), and leptin. Here, the effect of the non-surgical duodenal-jejunal bypass liner (DJBL) on concentrations of hormones implicated in appetite control was investigated. SUBJECTS: A two-center prospective study was conducted between January and December 2010. Seventeen obese subjects with type 2 diabetes were treated with the DJBL for 24 weeks. Fasting concentrations of leptin and meal responses of plasma PYY, CCK, and ghrelin were determined prior to and after implantation of the DJBL. RESULTS: At baseline, subjects had an average body weight of 116.0 ± 5.8 kg. One week after implantation, subjects had lost 4.3 ± 0.6 kg (p < 0.01), which progressed to 12.7 ± 1.3 kg at week 24 (p < 0.01). Postprandial concentrations of PYY and ghrelin increased (baseline vs. week 1 vs. week 24 PYY: 2.6 ± 0.2 vs. 4.1 ± 0.4 vs. 4.1 ± 0.7 nmol/L/min and ghrelin: 7.8 ± 1.8 vs. 11.0 ± 1.8 vs. 10.6 ± 1.8 ng/mL/min, all p < 0.05). In parallel, the CCK response decreased (baseline vs. week 1 vs. week 24: 434 ± 51 vs. 229 ± 52 vs. 256 ± 51 pmol/L/min, p < 0.01). Fasting leptin concentrations also decreased (baseline vs. week 24: 98 ± 17 vs. 53 ± 10 ng/mL, p < 0.01). CONCLUSIONS: DJBL treatment induces weight loss paralleled by changes in concentrations of hormones involved in appetite control.

Complement alternative pathway activation in human nonalcoholic steatohepatitis.

The innate immune system plays a major role in the pathogenesis of nonalcoholic steatohepatitis (NASH). Recently we reported complement activation in human NASH. However, it remained unclear whether the alternative pathway of complement, which amplifies C3 activation and which is frequently associated with pathological complement activation leading to disease, was involved. Here, alternative pathway components were investigated in liver biopsies of obese subjects with healthy livers (n = 10) or with NASH (n = 12) using quantitative PCR, Western blotting, and immunofluorescence staining. Properdin accumulated in areas where neutrophils surrounded steatotic hepatocytes, and colocalized with the C3 activation product C3c. C3 activation status as expressed by the C3c/native C3 ratio was 2.6-fold higher (p<0.01) in subjects with NASH despite reduced native C3 concentrations (0.94±0.12 vs. 0.57±0.09; p<0.01). Hepatic properdin levels positively correlated with levels of C3c (rs = 0.69; p<0.05) and C3c/C3 activation ratio (rs = 0.59; p<0.05). C3c, C3 activation status (C3c/C3 ratio) and properdin levels increased with higher lobular inflammation scores as determined according to the Kleiner classification (C3c: p<0.01, C3c/C3 ratio: p<0.05, properdin: p<0.05). Hepatic mRNA expression of factor B and factor D did not differ between subjects with healthy livers and subjects with NASH (factor B: 1.00±0.19 vs. 0.71±0.07, p = 0.26; factor D: 1.00±0.21 vs. 0.66±0.14, p = 0.29;). Hepatic mRNA and protein levels of Decay Accelerating Factor tended to be increased in subjects with NASH (mRNA: 1.00±0.14 vs. 2.37±0.72; p = 0.22; protein: 0.51±0.11 vs. 1.97±0.67; p = 0.28). In contrast, factor H mRNA was downregulated in patients with NASH (1.00±0.09 vs. 0.71±0.06; p<0.05) and a similar trend was observed with hepatic protein levels (1.12±0.16 vs. 0.78±0.07; p = 0.08). Collectively, these data suggest a role for alternative pathway activation in driving hepatic inflammation in NASH. Therefore, alternative pathway factors may be considered attractive targets for treating NASH by inhibiting complement activation.

The effect of the endoscopic duodenal-jejunal bypass liner on obesity and type 2 diabetes mellitus, a multicenter randomized controlled trial.

OBJECTIVE: Investigate the safety and efficacy of 6 months' duodenal-jejunal bypass liner (DJBL) treatment in comparison with dietary intervention for obesity and type 2 diabetes mellitus (T2DM). BACKGROUND: The DJBL is a bariatric procedure involving an impermeable sleeve that is delivered endoscopically in the proximal intestine. This procedure not only is less invasive than conventional surgical techniques but also has beneficial effects on obesity and T2DM. METHODS: A multicenter randomized controlled trial was conducted. Seventy-seven patients with obesity and T2DM were included. Thirty-eight patients were randomized to 6 months' DJBL treatment in combination with dietary intervention (34 successfully implanted, 31 completed the study), 39 patients received only dietary intervention (controls, 35 completed the study). Total study duration for both groups was 12 months, including 6 months of post-DJBL removal follow-up. RESULTS: After 6 months, just before DJBL removal, the DJBL group had lost 32.0% [22.0%-46.7%] of their excess weight versus 16.4% [4.1%-34.6%] in the control group (P < 0.05). Glycated hemoglobin A1c levels improved to 7.0% [6.4%-7.5%] in the DJBL group and to 7.9% [6.6%-8.3%] in the control group (P < 0.05). In addition, 85.3% of DJBL patients showed decreased postprandial glucose excursions versus 48.7% of control patients (P < 0.05). At 12 months, excess weight loss of the DJBL group was 19.8% [10.6%-45.0%] versus 11.7% [1.4%-25.4%] in the control group (P < 0.05). HbA1c was 7.3% [6.6%-8.0%] versus 8.0% [6.8%-8.8%], DJBL versus control respectively (P = ns). CONCLUSIONS: The DJBL is a safe and effective alternative to invasive bariatric procedures. Six months of DJBL treatment combined with diet leads to superior weight loss and improvement of T2DM when compared with diet alone.

Six months of treatment with the endoscopic duodenal-jejunal bypass liner does not lead to decreased systemic inflammation in obese patients with type 2 diabetes.

Obesity is associated with chronic low-grade systemic inflammation. Bariatric surgery has been shown to reduce this inflammation. Here, the effect of a nonsurgical bariatric technique, the duodenal-jejunal bypass liner (DJBL), on systemic inflammation was investigated. Seventeen obese patients with type 2 diabetes were treated with the DJBL for 6 months. Plasma C-reactive protein (CRP), myeloperoxidase (MPO), interleukin-6 (IL-6), and tumor necrosis factor alpha (TNF-α) were determined prior to and during DJBL treatment. Three months after initiation of DJBL treatment, TNF-α levels had increased from 1.8 ± 0.1 to 2.1 ± 0.1 pg/mL, whereas IL-6 increased from 2.7 ± 0.3 to 4.0 ± 0.5 pg/mL (both p < 0.05). CRP and MPO also increased, though the differences were not significant. After 6 months, the levels of all parameters were similar to baseline levels (CRP, 4.2 ± 0.6 mg/L; TNF-α, 2.0 ± 0.1 pg/mL; IL-6, 3.5 ± 0.5 pg/mL; MPO, 53.6 ± ng/mL; all p = ns compared to baseline). In the current study, 6 months of endoscopic DJBL treatment did not lead to decreased systemic inflammation.

Endoscopic duodenal-jejunal bypass liner rapidly improves plasma parameters of nonalcoholic fatty liver disease.

Bariatric surgery reduces nonalcoholic fatty liver disease (NAFLD). We investigated the effects of duodenal-jejunal bypass liner (DJBL), nonsurgical bariatric device, on plasma parameters of NAFLD. Seventeen obese subjects with type 2 diabetes received the DJBL for 24 weeks. Before, during, and after DJBL implantation, we determined plasma levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), γ-glutamyltransferase (γ-GT), albumin, caspase-cleaved cytokeratin-18 (CK-18), and liver fatty acid-binding protein (L-FABP). At baseline, subjects had increased levels of AST (35 ± 4 IU/L), ALT (54 ± 5 IU/L), and γ-GT (66 ± 14 IU/L), compared with healthy individuals; subjects' mean concentrations of caspase-cleaved CK-18 and L-FABP were 214.4 ± 35.6 U/L and 29.3 ± 2.6 ng/mL, respectively. Three months after implantation of DJBL, all NAFLD-related parameters had decreased from baseline (AST, 28 ± 3 IU/L; ALT, 32 ± 2 IU/L; γ-GT, 44 ±7 IU/L; caspase-cleaved CK-18, 140.6 ± 16.3U/L; and L-FABP, 18.2 ± 1.5 ng/mL; all P < .05). After 6 months, levels of ALT and γ-GT had further decreased (ALT, 28 ± 2 IU/L and γ-GT, 35 ± 5 IU/L), whereas levels of AST, caspase-cleaved CK-18, and L-FABP had stabilized (P = not significant). Six months after DJBLs were removed, levels of ALT (37 ± 3 IU/L), γ-GT (42 ± 5 IU/L), and caspase-cleaved CK-18 (124.5 ± 12.5U/L) were still reduced (P < .05), whereas AST and L-FABP had returned to near baseline levels (P = not significant). Therefore, in obese subjects, DJBL reduces plasma parameters of NAFLD. ClinicalTrials.gov, Number: NCT00985114.

PET/CT-based metabolic tumour volume for response prediction of neoadjuvant chemoradiotherapy in oesophageal carcinoma.

PURPOSE: Neoadjuvant chemoradiotherapy is increasingly used in oesophageal cancer patients. In general, small tumours are associated with a survival benefit compared to large tumours. Little is known, however, about the relationship between initial tumour volume and response to chemoradiotherapy. Therefore, the aim of this study was to determine whether the pretherapy metabolic tumour volume (MTV) on diagnostic PET/CT in oesophageal cancer patients is correlated with response to chemoradiotherapy in the resection specimen. METHODS: A consecutive series of patients underwent diagnostic PET/CT scanning prior to chemoradiotherapy and oesophagectomy. MTVs were determined on PET/CT and an automated tumour contour was generated using specified standard uptake value thresholds. Response to chemoradiotherapy was determined in the resection specimen according to the scoring system developed by Mandard et al. Patients were divided into different groups according to response to chemoradiotherapy. RESULTS: Between January 2008 and May 2011 a total of 115 patients underwent an oesophagectomy. The MTV determined on diagnostic PET/CT scans was available in 79 patients. Of these 79 patients, 30 (38 %) showed no residual tumour cells at the location of the primary tumour. Three of these patients presented with residual tumour cells in the lymph nodes; 27 patients (34 %) had a complete pathological response. There was a trend towards a better response in patients with a smaller MTV (p = 0.084). CONCLUSION: This study demonstrated a trend towards a correlation between response to chemoradiotherapy in oesophageal cancer patients and smaller MTVs as determined on diagnostic PET/CT prior to neoadjuvant chemoradiotherapy. However, tumour volumes overlapped between groups, indicating the need for multifactorial parameters as predictors. In addition, a complete local tumour response may be accompanied by residual disease in the regional lymph nodes.

Endoscopic duodenal-jejunal bypass liner rapidly improves type 2 diabetes.

BACKGROUND: Bariatric procedures excluding the proximal small intestine improve glycemic control in type 2 diabetes within days. To gain insight into the mediators involved, we investigated factors regulating glucose homeostasis in patients with type 2 diabetes treated with the novel endoscopic duodenal-jejunal bypass liner (DJBL). METHODS: Seventeen obese patients (BMI 30-50 kg/m(2)) with type 2 diabetes received the DJBL for 24 weeks. Body weight and type 2 diabetes parameters, including HbA1c and plasma levels of glucose, insulin, glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP), and glucagon, were analyzed after a standard meal before, during, and 1 week after DJBL treatment. RESULTS: At 24 weeks after implantation, patients had lost 12.7 ± 1.3 kg (p < 0.01), while HbA1c had improved from 8.4 ± 0.2 to 7.0 ± 0.2 % (p < 0.01). Both fasting glucose levels and the postprandial glucose response were decreased at 1 week after implantation and remained decreased at 24 weeks (baseline vs. week 1 vs. week 24: 11.6 ± 0.5 vs. 9.0 ± 0.5 vs. 8.6 ± 0.5 mmol/L and 1,999 ± 85 vs. 1,536 ± 51 vs. 1,538 ± 72 mmol/L/min, both p < 0.01). In parallel, the glucagon response decreased (23,762 ± 4,732 vs. 15,989 ± 3,193 vs. 13,1207 ± 1,946 pg/mL/min, p < 0.05) and the GLP-1 response increased (4,440 ± 249 vs. 6,407 ± 480 vs. 6,008 ± 429 pmol/L/min, p < 0.01). The GIP response was decreased at week 24 (baseline-115,272 ± 10,971 vs. week 24-88,499 ± 10,971 pg/mL/min, p < 0.05). Insulin levels did not change significantly. Glycemic control was still improved 1 week after explantation. CONCLUSIONS: The data indicate DJBL to be a promising treatment for obesity and type 2 diabetes, causing rapid improvement of glycemic control paralleled by changes in gut hormones.

Human intestinal microbiota composition is associated with local and systemic inflammation in obesity.

OBJECTIVE: Intestinal microbiota have been suggested to contribute to the development of obesity, but the mechanism remains elusive. The relationship between microbiota composition, intestinal permeability, and inflammation in nonobese and obese subjects was investigated. DESIGN AND METHODS: Fecal microbiota composition of 28 subjects (BMI 18.6-60.3 kg m(-2) ) was analyzed by a phylogenetic profiling microarray. Fecal calprotectin and plasma C-reactive protein levels were determined to evaluate intestinal and systemic inflammation. Furthermore, HbA1c , and plasma levels of transaminases and lipids were analyzed. Gastroduodenal, small intestinal, and colonic permeability were assessed by a multisaccharide test. RESULTS: Based on microbiota composition, the study population segregated into two clusters with predominantly obese (15/19) or exclusively nonobese (9/9) subjects. Whereas intestinal permeability did not differ between clusters, the obese cluster showed reduced bacterial diversity, a decreased Bacteroidetes/Firmicutes ratio, and an increased abundance of potential proinflammatory Proteobacteria. Interestingly, fecal calprotectin was only detectable in subjects within the obese microbiota cluster (n = 8/19, P = 0.02). Plasma C-reactive protein was also increased in these subjects (P = 0.0005), and correlated with the Bacteroidetes/Firmicutes ratio (rs = -0.41, P = 0.03). CONCLUSIONS: Intestinal microbiota alterations in obese subjects are associated with local and systemic inflammation, suggesting that the obesity-related microbiota composition has a proinflammatory effect.

Non-alcoholic steatohepatitis: a non-invasive diagnosis by analysis of exhaled breath.

BACKGROUND & AIMS: Histological evaluation of a liver biopsy is the current gold standard to diagnose non-alcoholic steatohepatitis (NASH), but the procedure to obtain biopsies is associated with morbidity and high costs. Hence, only subjects at high risk are biopsied, leading to underestimation of NASH prevalence, and undertreatment. Since analysis of volatile organic compounds in breath has been shown to accurately identify subjects with other chronic inflammatory diseases, we investigated its potential as a non-invasive tool to diagnose NASH. METHODS: Wedge-shaped liver biopsies from 65 subjects (BMI 24.8-64.3 kg/m(2)) were obtained during surgery and histologically evaluated. The profile of volatile organic compounds in pre-operative breath samples was analyzed by gas chromatography-mass spectrometry and related to liver histology scores and plasma parameters of alanine aminotransferase (ALT) and aspartate aminotransferase (AST). RESULTS: Three exhaled compounds were sufficient to distinguish subjects with (n=39) and without NASH (n=26), with an area under the ROC curve of 0.77. The negative and positive predictive values were 82% and 81%. In contrast, elevated ALT levels or increased AST/ALT ratios both showed negative predictive values of 43%, and positive predictive values of 88% and 70%, respectively. The breath test reduced the hypothetical percentage of undiagnosed NASH patients from 67-79% to 10%, and of misdiagnosed subjects from 49-51% to 18%. CONCLUSIONS: Analysis of volatile organic compounds in exhaled air is a promising method to indicate NASH presence and absence. In comparison to plasma transaminase levels, the breath test significantly reduced the percentage of missed NASH patients and the number of unnecessarily biopsied subjects.

[Practice guideline for the treatment of morbid obesity]. / Richtlijn voor de behandeling van morbide obesitas.

The increasing prevalence of obesity and its related comorbidities represents an increasing burden for the Dutch health care and requires effective therapy. The primary treatment of obesity consists of lifestyle interventions directed at lifestyle change; in morbidly obese subjects only bariatric surgery is cost-effective in the long term, with respect to both weight loss and reduction in comorbidity. There is a new Dutch multidisciplinary practice guideline on the treatment of morbid obesity, in which the following aspects are covered: indications for surgery, pre-operative policy advice, considerations for the type of operation, and the short and long term follow-up after bariatric surgery. Patients between 18 and 65 years old are eligible for bariatric surgery if they have a BMI ≥ 40 kg/m2 or a BMI ≥ 35 kg/m2 in the presence of comorbidity. In adolescents under 18 bariatric surgery should only be performed in a research setting; in patients older than 65 years bariatric surgery can be performed exceptionally, preferably in a centre with large experience.