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Safety and efficacy of hydrothermal duodenal mucosal resurfacing in patients with type 2 diabetes: the randomised, double-blind, sham-controlled, multicentre REVITA-2 feasibility trial.
Mingrone, G, van Baar, AC, Devière, J, Hopkins, D, Moura, E, Cercato, C, Rajagopalan, H, Lopez-Talavera, JC, White, K, Bhambhani, V, et al
Gut. 2022;(2):254-264
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Abstract
OBJECTIVE Hydrothermal duodenal mucosal resurfacing (DMR) is a safe, outpatient endoscopic procedure. REVITA-2, a double-blind, superiority randomised controlled trial, investigates safety and efficacy of DMR using the single catheter Revita system (Revita DMR (catheter and system)), on glycaemic control and liver fat content in type 2 diabetes (T2D). DESIGN Eligible patients (haemoglobin A1c (HbA1c) 59-86 mmol/mol, body mass index≥24 and ≤40 kg/m2, fasting insulin >48.6 pmol/L, ≥1 oral antidiabetic medication) enrolled in Europe and Brazil. Primary endpoints were safety, change from baseline in HbA1c at 24 weeks, and liver MRI proton-density fat fraction (MRI-PDFF) at 12 weeks. RESULTS Overall mITT (DMR n=56; sham n=52), 24 weeks post DMR, median (IQR) HbA1c change was -10.4 (18.6) mmol/mol in DMR group versus -7.1 (16.4) mmol/mol in sham group (p=0.147). In patients with baseline liver MRI-PDFF >5% (DMR n=48; sham n=43), 12-week post-DMR liver-fat change was -5.4 (5.6)% in DMR group versus -2.9 (6.2)% in sham group (p=0.096). Results from prespecified interaction testing and clinical parameter assessment showed heterogeneity between European (DMR n=39; sham n=37) and Brazilian (DMR n=17; sham n=16) populations (p=0.063); therefore, results were stratified by region. In European mITT, 24 weeks post DMR, median (IQR) HbA1c change was -6.6 mmol/mol (17.5 mmol/mol) versus -3.3 mmol/mol (10.9 mmol/mol) post-sham (p=0.033); 12-week post-DMR liver-fat change was -5.4% (6.1%) versus -2.2% (4.3%) post-sham (p=0.035). Brazilian mITT results trended towards DMR benefit in HbA1c, but not liver fat, in context of a large sham effect. In overall PP, patients with high baseline fasting plasma glucose ((FPG)≥10 mmol/L) had significantly greater reductions in HbA1c post-DMR versus sham (p=0.002). Most adverse events were mild and transient. CONCLUSIONS DMR is safe and exerts beneficial disease-modifying metabolic effects in T2D with or without non-alcoholic liver disease, particularly in patients with high FPG. TRIAL REGISTRATION NUMBER NCT02879383.
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Anti-Microbial Antibody Response is Associated With Future Onset of Crohn's Disease Independent of Biomarkers of Altered Gut Barrier Function, Subclinical Inflammation, and Genetic Risk.
Lee, SH, Turpin, W, Espin-Garcia, O, Raygoza Garay, JA, Smith, MI, Leibovitzh, H, Goethel, A, Turner, D, Mack, D, Deslandres, C, et al
Gastroenterology. 2021;(5):1540-1551
Abstract
BACKGROUND AND AIMS Altered host immune reactivity to microbial antigens is hypothesized to trigger the onset of Crohn's disease (CD). We aimed to assess whether increased serum anti-microbial antibody response in asymptomatic first-degree relatives (FDRs) of CD patients is an independent risk factor for future CD development. METHODS We measured host serum antibody response to 6 microbial antigens at enrollment (Prometheus enzyme-linked immunosorbent assay test: anti-Saccharomyces cerevisiae antibodies immunoglobulin A/immunoglobulin G, anti-OmpC, anti-A4-Fla2, anti-FlaX, anti-CBir1) and derived the sum of positive antibodies (AS). We used samples at enrollment of prospectively followed healthy FDRs from a nested case-control cohort of the Crohn's and Colitis Canada Genetics Environment Microbial Project. Those who later developed CD (n = 77) were matched 1:4 by age, sex, follow-up duration, and geographic location with control FDRs remaining healthy (n = 307). To address our research aims, we fitted a multivariable conditional logistic regression model and performed causal mediation analysis. RESULTS High baseline AS (≥2) (43% of cases, 11% of controls) was associated with higher risk of developing CD (adjusted odds ratio, 6.5; 95% confidence interval, 3.4-12.7; P < .001). Importantly, this association remained significant when adjusted for markers of gut barrier function, fecal calprotectin, C-reactive protein, and CD-polygenic risk score, and in subjects recruited more than 3 years before diagnosis. Causal mediation analysis showed that the effect of high AS on future CD development is partially mediated (42%) via preclinical gut inflammation. CONCLUSIONS Our results suggest that increased anti-microbial antibody responses are associated with risk of future development of CD, independent of biomarkers of abnormal gut barrier function, subclinical inflammation, and CD-related genetic risks. This suggests that anti-microbial antibody responses are an early predisease event in the development of CD.
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Endoscopic duodenal mucosal resurfacing for the treatment of type 2 diabetes mellitus: one year results from the first international, open-label, prospective, multicentre study.
van Baar, ACG, Holleman, F, Crenier, L, Haidry, R, Magee, C, Hopkins, D, Rodriguez Grunert, L, Galvao Neto, M, Vignolo, P, Hayee, B, et al
Gut. 2020;(2):295-303
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Abstract
BACKGROUND The duodenum has become a metabolic treatment target through bariatric surgery learnings and the specific observation that bypassing, excluding or altering duodenal nutrient exposure elicits favourable metabolic changes. Duodenal mucosal resurfacing (DMR) is a novel endoscopic procedure that has been shown to improve glycaemic control in people with type 2 diabetes mellitus (T2D) irrespective of body mass index (BMI) changes. DMR involves catheter-based circumferential mucosal lifting followed by hydrothermal ablation of duodenal mucosa. This multicentre study evaluates safety and feasibility of DMR and its effect on glycaemia at 24 weeks and 12 months. METHODS International multicentre, open-label study. Patients (BMI 24-40) with T2D (HbA1c 59-86 mmol/mol (7.5%-10.0%)) on stable oral glucose-lowering medication underwent DMR. Glucose-lowering medication was kept stable for at least 24 weeks post DMR. During follow-up, HbA1c, fasting plasma glucose (FPG), weight, hepatic transaminases, Homeostatic Model Assessment for Insulin Resistance (HOMA-IR), adverse events (AEs) and treatment satisfaction were determined and analysed using repeated measures analysis of variance with Bonferroni correction. RESULTS Forty-six patients were included of whom 37 (80%) underwent complete DMR and 36 were finally analysed; in remaining patients, mainly technical issues were observed. Twenty-four patients had at least one AE (52%) related to DMR. Of these, 81% were mild. One SAE and no unanticipated AEs were reported. Twenty-four weeks post DMR (n=36), HbA1c (-10±2 mmol/mol (-0.9%±0.2%), p<0.001), FPG (-1.7±0.5 mmol/L, p<0.001) and HOMA-IR improved (-2.9±1.1, p<0.001), weight was modestly reduced (-2.5±0.6 kg, p<0.001) and hepatic transaminase levels decreased. Effects were sustained at 12 months. Change in HbA1c did not correlate with modest weight loss. Diabetes treatment satisfaction scores improved significantly. CONCLUSIONS In this multicentre study, DMR was found to be a feasible and safe endoscopic procedure that elicited durable glycaemic improvement in suboptimally controlled T2D patients using oral glucose-lowering medication irrespective of weight loss. Effects on the liver are examined further. TRIAL REGISTRATION NUMBER NCT02413567.
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Role of capsule endoscopy in alarm features and non-responsive celiac disease: A European multicenter study.
Perez-Cuadrado-Robles, E, Lujan-Sanchis, M, Elli, L, Juanmartinena-Fernandez, JF, Garcıa-Lledo, J, Ruano-Dıaz, L, Egea-Valenzuela, J, Jimenez-Garcıa, VA, Arguelles-Arias, F, Juan-Acosta, MS, et al
Digestive endoscopy : official journal of the Japan Gastroenterological Endoscopy Society. 2018;(4):461-466
Abstract
BACKGROUND AND AIM The role of capsule endoscopy (CE) in established celiac disease (CD) remains unclear. Our objective was to analyze the usefulness of CE in the suspicion of complicated CD. METHODS This was a retrospective multicenter study. One hundred and eighty-nine celiac patients (mean age: 46.6 ± 16.6, 30.2% males) who underwent CE for alarm symptoms (n = 86, 45.5%) or non-responsive CD (n = 103, 54.5%) were included. Diagnostic yield (DY), therapeutic impact and safety were analyzed. RESULTS Capsule endoscopy was completed in 95.2% of patients (small bowel transit time: 270.5 ± 100.2 min). Global DY was 67.2%, detecting atrophic mucosa (n = 92, 48.7%), ulcerative jejunoileitis (n = 21, 11.1%), intestinal lymphoma (n = 7, 3.7%) and other enteropathies (n = 7, 3.7%, six Crohn's disease cases and one neuroendocrine tumor). The DY of CE was significantly higher in patients presenting with non-responsive disease compared to patients with alarm symptoms (73.8% vs 59.3%, P = 0.035). The new findings of the CE modified management in 59.3% of the cases. There were no major complications. CONCLUSION Capsule endoscopy may be a moderately helpful and safe diagnostic tool in the suspicion of complicated CD, modifying the clinical course of these patients.
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Factors associated with villus atrophy in symptomatic coeliac disease patients on a gluten-free diet.
Mahadev, S, Murray, JA, Wu, TT, Chandan, VS, Torbenson, MS, Kelly, CP, Maki, M, Green, PH, Adelman, D, Lebwohl, B
Alimentary pharmacology & therapeutics. 2017;(8):1084-1093
Abstract
BACKGROUND Duodenal injury persists in some coeliac disease patients despite gluten-free diet, and is associated with adverse outcomes. AIM: To determine the prevalence and clinical risk factors for persistent villus atrophy among symptomatic coeliac disease patients. METHODS A nested cross-sectional analysis was performed on coeliac disease patients with self-reported moderate or severe symptoms while following a gluten-free diet, who underwent protocol-mandated duodenal biopsy upon enrolment in the CeliAction clinical trial. Demographic factors, symptom type, medication use, and serology were examined to determine predictors of persistent villus atrophy. RESULTS Of 1345 symptomatic patients, 511 (38%, 95% CI, 35-41%) were found to have active coeliac disease with persistent villus atrophy, defined as average villus height to crypt depth ratio ≤2.0. On multivariable analysis, older age (OR, 5.1 for ≥70 vs. 18-29 years, 95% CI, 2.5-10.4) was a risk factor while longer duration on gluten-free diet was protective (OR, 0.37, 95% CI, 0.24-0.55 for 4-5.9 vs. 1-1.9 years). Villus atrophy was associated with use of proton-pump inhibitors (PPIs; OR, 1.6, 95% CI, 1.1-2.3), non-steroidal anti-inflammatory drugs (NSAIDs; OR, 1.64, 95% CI, 1.2-2.2), and selective serotonin reuptake inhibitors (SSRIs; OR, 1.74, 95% CI, 1.2-2.5). Symptoms were not associated with villus atrophy after adjusting for covariates. Conclusions A majority of symptomatic coeliac disease patients did not have active disease on follow-up histology. Symptoms were poorly predictive of persistent mucosal injury. The impact of NSAIDs, PPIs, and SSRIs on mucosal healing in coeliac disease warrants further study.
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No Difference Between Latiglutenase and Placebo in Reducing Villous Atrophy or Improving Symptoms in Patients With Symptomatic Celiac Disease.
Murray, JA, Kelly, CP, Green, PHR, Marcantonio, A, Wu, TT, Mäki, M, Adelman, DC, ,
Gastroenterology. 2017;(4):787-798.e2
Abstract
BACKGROUND & AIMS Gluten ingestion leads to symptoms and small intestinal mucosal injury in patients with celiac disease. The only option is the strict lifelong exclusion of dietary gluten, which is difficult to accomplish. Many patients following a gluten-free diet continue to have symptoms and have small intestinal mucosal injury. Nondietary therapies are needed. We performed a phase 2 study of the ability of latiglutenase, an orally administered mixture of 2 recombinant gluten-targeting proteases, to reduce mucosal morphometric measures in biopsy specimens from patients with celiac disease. METHODS We performed a double-blind, placebo-controlled, dose-ranging study to assess the efficacy and safety of latiglutenase in 494 patients with celiac disease (with moderate or severe symptoms) in North America and Europe, from August 2013 until December 2014. Participants reported following a gluten-free diet for at least 1 year before the study began. Patients with documented moderate or severe symptoms and villous atrophy (villous height:crypt depth ratio of ≤2.0) were assigned randomly to groups given placebo or 100, 300, 450, 600, or 900 mg latiglutenase daily for 12 or 24 weeks. Subjects completed the Celiac Disease Symptom Diary each day for 28 days and underwent an upper gastrointestinal endoscopy with duodenal biopsy of the distal duodenum at baseline and at weeks 12 and 24. The primary end point was a change in the villous height:crypt depth ratio. Secondary end points included numbers of intraepithelial lymphocytes, serology test results (for levels of antibodies against tissue transglutaminase-2 and deamidated gliadin peptide), symptom frequencies, and safety. RESULTS In a modified intent-to-treat population, there were no differences between latiglutenase and placebo groups in change from baseline in villous height:crypt depth ratio, numbers of intraepithelial lymphocytes, or serologic markers of celiac disease. All groups had significant improvements in histologic and symptom scores. CONCLUSIONS In a phase 2 study of patients with symptomatic celiac disease and histologic evidence of significant duodenal mucosal injury, latiglutenase did not improve histologic and symptom scores when compared with placebo. There were no significant differences in change from baseline between groups. ClinicalTrials.gov no: NCT01917630.
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Positive regulatory effects of perioperative probiotic treatment on postoperative liver complications after colorectal liver metastases surgery: a double-center and double-blind randomized clinical trial.
Liu, Z, Li, C, Huang, M, Tong, C, Zhang, X, Wang, L, Peng, H, Lan, P, Zhang, P, Huang, N, et al
BMC gastroenterology. 2015;:34
Abstract
BACKGROUND Colorectal liver metastases (CLM) occur frequently and postoperative intestinal infection is a common complication. Our previous study showed that probiotics could decrease the rate of infectious complications after colectomy for colorectal cancer. To determine the effects of the perioperative administration of probiotics on serum zonulin levels which is a marker of intestinal permeability and the subsequent impact on postoperative infectious complications in patients with CLM. METHODS 150 patients with CLM were randomly divided into control group (n = 68) and probiotics group (n = 66). Probiotics and placebo were given orally for 6 days preoperatively and 10 days postoperatively to control group and probiotics group respectively. We used the local resection for metastatic tumor ,while for large tumor, the segmental hepatectomy. Postoperative outcome were recorded. Furthermore, complications in patients with normal intestinal barrier function and the relation with serum zonulin were analyzed to evaluate the impact on the liver barrier dysfunction. RESULTS The incidence of infectious complications in the probiotics group was lower than control group. Analysis of CLM patients with normal postoperative intestinal barrier function paralleled with the serum zonulin level. And probiotics could also reduce the concentration of serum zonulin (P = 0.004) and plasma endotoxin (P < 0.001). CONCLUSION Perioperative probiotics treatment could reduce the serum zonulin level, the rate of postoperative septicemia and maintain the liver barrier in patients undergoing CLM surgery. we propose a new model about the regulation of probiotics to liver barrier via clinical regulatory pathway. We recommend the preoperative oral intake of probiotics combined with postoperative continued probiotics treatment in patients who undergo CLM surgery. TRIAL REGISTRATION ChiCTR-TRC- 12002841 . 2012/12/21.
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Teduglutide enhances structural adaptation of the small intestinal mucosa in patients with short bowel syndrome.
Tappenden, KA, Edelman, J, Joelsson, B
Journal of clinical gastroenterology. 2013;(7):602-7
Abstract
BACKGROUND Intestinotrophic therapies, such as glucagon-like peptide-2 (GLP-2) analogs, may enhance intestinal adaptation and reduce dependence on parenteral nutrition (PN) in patients with intestinal failure associated with short bowel syndrome (SBS-IF). However, because GLP-2 enhances cellular growth, there is concern that GLP-2 analogs may also encourage growth of malignant cells. AIMS To histologically examine the effects of teduglutide, a recombinant human GLP-2 analog, on the mucosa of the small and large intestine for indications of dysplastic transformation. METHODS In a multicenter, prospective, randomized, placebo-controlled study, 83 PN-dependent patients with SBS-IF were monitored for several weeks to ensure optimal and stable PN. Patients were then randomized to receive 24 weeks of placebo (n=16), teduglutide (0.5 mg/kg/d; n=35), or teduglutide (0.10 mg/kg/d; n=32). RESULTS Biopsies were obtained from 77 patients to yield 390 individual histologic interpretations. After 6 months of treatment, no features of dysplasia were found in any biopsy from the large or small intestine of patients receiving placebo or either dose of teduglutide. New secondary diagnoses, such as eosinophilic colitis or Crohn's disease, were found at a low frequency overall: teduglutide (0.05 mg/kg/d; range, 3.1% to 6.3%); teduglutide (0.10 mg/kg/d, 3.3%); placebo (range, 6.7% to 13.3%). CONCLUSIONS Although this histologic substudy of biopsy samples was not powered to detect differences in occurrence of dysplasia between teduglutide-treated patients and those randomized to placebo, it demonstrated that no dysplasia or other pathologic processes were evident within the intestinal mucosa in the placebo group or the 2 teduglutide groups after 6 months of treatment.
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Ensure preparation and capsule endoscopy: a two-center prospective study.
Niv, E, Ovadia, B, Ron, Y, Santo, E, Mahajna, E, Halpern, Z, Fireman, Z
World journal of gastroenterology. 2013;(8):1264-70
Abstract
AIM: To compare small bowel (SB) cleanliness and capsule endoscopy (CE) image quality following Ensure(®), polyethylene glycol (PEG) and standard preparations. METHODS A preparation protocol for CE that is both efficacious and acceptable to patients remains elusive. Considering the physiological function of the SB as a site for the digestion and absorption of food and not as a stool reservoir, preparation consisting of a liquid, fiber-free formula ingested one day before a CE study might have an advantage over other kinds of preparations. We conducted a prospective, blind-to-preparation, two-center study that compared four types of preparations. The participants' demographic and clinical data were collected. Gastric and SB transit times were calculated. The presence of bile in the duodenum was scored by a single, blinded-to-preparation gastroenterologist expert in CE, as was cleanliness within the proximal, middle and distal part of the SB. A four-point scale was used (grade 1 = no bile or residue, grade 4 ≥ 90% of lumen full of bile or residual material). RESULTS The 198 consecutive patients who were referred to CE studies due to routine medical reasons were divided into four groups. They all observed a 12-h overnight fast before undergoing CE. Throughout the 24 h preceding the fast, control group 1 (n = 45 patients) ate light unrestricted meals, control group 2 (n = 81) also ate light meals but free of fruits and vegetables, the PEG group (n = 50) ate unrestricted light meals and ingested the PEG preparation, and the Ensure group (n = 22) ingested only the Ensure formula. Preparation with Ensure improved the visualization of duodenal mucosa (a score of 1.76) by decreasing the bile content compared to preparation with PEG (a score of 2.9) (P = 0.053). Overall, as expected, there was less residue and stool in the proximal part of the SB than in the middle and distal parts in all groups. The total score of cleanliness throughout the length of the SB showed some benefit for Ensure (a score of 1.8) over control group 2 (a score of 2) (P = 0.06). The cleanliness grading of the proximal and distal parts of the SB was similar in all four groups (P = 0.6 for both). The cleanliness in the middle part of the SB in the PEG (a score of 1.8) and Ensure groups (a score of 1.7) was equally better than that of control group 2 (a score of 2.1) (P = 0.057 and P = 0.07, respectively). All 50 PEG patients had diarrhea as an anticipated side effect, compared with only one patient in the Ensure group. CONCLUSION Preparation with Ensure, a liquid, fiber-free formula has advantages over standard and PEG preparations, with significantly fewer side effects than PEG.
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An endoscopic comparison of the effects of alendronate and risedronate on upper gastrointestinal mucosae.
Lanza, F, Schwartz, H, Sahba, B, Malaty, HM, Musliner, T, Reyes, R, Quan, H, Graham, DY
The American journal of gastroenterology. 2000;(11):3112-7
Abstract
OBJECTIVES The nitrogen-containing bisphosphonates alendronate and risedronate have been reported to have upper gastrointestinal (GI) safety and tolerability profiles comparable to those of placebo. Nevertheless, both agents have demonstrated similar potential for irritation of gastric mucosa at high doses in preclinical studies. The present study compared the potential for alendronate and risedronate to produce endoscopic upper GI mucosal irritation using the highest approved dosage regimens for the two agents. METHODS This was a multicenter, randomized, parallel-group, double-blind, placebo-controlled trial in which a total of 235 patients (men or postmenopausal women, aged 45-80 yr) with normal upper GI endoscopy at baseline received 28-day treatments with the following: alendronate 40 mg/day (N = 90), risedronate 30 mg/day (N = 89), placebo (N = 36), or placebo with aspirin 650 mg q.i.d. for the last 7 days (N = 20). Endoscopy was repeated on day 29 using standardized scoring scales. RESULTS After 28 days of treatment, the alendronate and risedronate groups had comparable mean gastric and duodenal erosion scores that were significantly lower than those of the aspirin group. Esophageal scores were comparable in all groups. Gastric ulcers and/or large numbers of gastric erosions occurred in approximately 3% of alendronate and risedronate patients versus 60% with aspirin. Both bisphosphonates were clinically well tolerated. CONCLUSIONS The potential for gastroduodenal irritation is similar for alendronate and risedronate and is markedly less than for aspirin. The findings of this study, together with the large placebo-controlled clinical trial experience with both agents and extensive epidemiological data for alendronate, suggest that the risk for clinically important gastric irritation with these bisphosphonates is very low, even at the highest available doses.