Andres Acosta

Endoscopic Sleeve Gastroplasty Alters Gastric Physiology and Induces Loss of Body Weight in Obese Individuals

BACKGROUND & AIMS: Although bariatric surgery is the most effective therapy for obesity, only a small proportion of candidates undergo this surgery. Endoscopic sleeve gastroplasty (ESG) is a minimally invasive procedure that reduces the size of the gastric reservoir. We investigated its durability and effects on body weight and gastrointestinal function in a prospective study of obese individuals. METHODS: Twenty‐five obese individuals (21 female; mean body mass index, 35.5 ± 2.6 kg/m2; mean age, 47.6 ± 10 years) underwent ESG with endoluminal creation of a sleeve along the gastric lesser curve from September 2012 through March 2015 at the Mayo Clinic in Rochester, Minnesota. Subjects were followed for a median period of 9 months. We measured changes in body weight and recorded adverse events; patients were assessed by endoscopy after 3 months. Four participants underwent pre‐ESG and post‐ESG analyses to measure solid and liquid gastric emptying, satiation (meal tolerance), and fasting and postprandial levels of insulin, glucose, and gut hormones. RESULTS: Subjects had lost 53% ± 17%, 56% ± 23%, 54% ± 40%, and 45% ± 41% of excess body weight at 6, 9, 12, and 20 months, respectively, after the procedure (P < .01). Endoscopy at 3 months showed intact gastroplasty in all subjects. After ESG, physiological analyses of 4 participants showed a decrease by 59% in caloric consumption to reach maximum fullness (P = .003), slowing of gastric emptying of solids (P = .03), and a trend toward increased insulin sensitivity (P = .06). Three patients had serious adverse events (a perigastric inflammatory collection, a pulmonary embolism, and a small pneumothorax) but made full recoveries with no need for surgical interventions. No further serious adverse events occurred after the technique was adjusted. CONCLUSIONS: ESG delays gastric emptying, induces early satiation, and significantly reduces body weight. ESG could be an alternative to bariatric surgery for selected patients with obesity. ClincialTrials.gov number: NCT 01682733.

Recent advances in clinical practice challenges and opportunities in the management of obesity

Despite advances in understanding the roles of adiposity, food intake, GI and adipocyte-related hormones, inflammatory mediators, the gut–brain axis and the hypothalamic nervous system in the pathophysiology of obesity, the effects of different therapeutic interventions on those pathophysiological mechanisms are controversial. There are still no low-cost, safe, effective treatments for obesity and its complications. Currently, bariatric surgical approaches targeting the GI tract are more effective than non-surgical approaches in inducing weight reduction and resolving obesity-related comorbidities. However, current guidelines emphasise non-surgical approaches through lifestyle modification and medications to achieve slow weight loss, which is not usually sustained and may be associated with medication-related side effects. This review analyses current central, peripheral or hormonal targets to treat obesity and addresses challenges and opportunities to develop novel approaches for obesity.

Effect of colesevelam on faecal bile acids and bowel functions in diarrhoea‐predominant irritable bowel syndrome

About one‐third of patients with IBS‐diarrhoea (irritable bowel syndrome‐D) have evidence of increased bile acid synthesis or excretion.

Salivary PYY: A Putative Bypass to Satiety

Peptide YY3-36 is a satiation hormone released postprandially into the bloodstream from L-endocrine cells in the gut epithelia. In the current report, we demonstrate PYY3-36 is also present in murine as well as in human saliva. In mice, salivary PYY3-36 derives from plasma and is also synthesized in the taste cells in taste buds of the tongue. Moreover, the cognate receptor Y2R is abundantly expressed in the basal layer of the progenitor cells of the tongue epithelia and von Ebners gland. The acute augmentation of salivary PYY3-36 induced stronger satiation as demonstrated in feeding behavioral studies. The effect is mediated through the activation of the specific Y2 receptor expressed in the lingual epithelial cells. In a long-term study involving diet-induced obese (DIO) mice, a sustained increase in PYY3-36 was achieved using viral vector-mediated gene delivery targeting salivary glands. The chronic increase in salivary PYY3-36 resulted in a significant long-term reduction in food intake (FI) and body weight (BW). Thus this study provides evidence for new functions of the previously characterized gut peptide PYY3-36 suggesting a potential simple and efficient alternative therapeutic approach for the treatment of obesity.

Effect of increased bile acid synthesis or fecal excretion in irritable bowel syndrome-diarrhea

OBJECTIVES:Approximately 25% of patients with irritable bowel syndrome-diarrhea (IBS-D) have increased total fecal bile acids (BA) and serum C4 (surrogate for BA synthesis). BA synthesis-related genes (KLB and FGFR4) are associated with colonic transit (CT) in IBS-D. Our aims were: (i) to compare phenotype and pathophysiology in IBS-D patients with increased or normal fecal excretion or synthesis of BA; and (ii) to explore association of variations in two candidate bile-acid synthesis genes (KLB and FGFR4) in these two subgroups of IBS-D.METHODS:A total of 64 IBS-D patients underwent on one occasion: fasting serum C4 and FGF19, total fecal fat and BA excretion, CT, intestinal and colonic permeability, and candidate genotyping (rs17618244 (KLB), rs351855 (FGFR4)). Colonic sensation and tone were measured in 47 of the IBS-D patients. IBS-D subgroups were identified by fecal BA >2,337 mM per 48 h or by serum C4 >47.1 ng/ml.RESULTS:IBS-D patients with fecal BA >2,337 mM per 48 h (19/54) had significantly greater body mass index, fecal fat, percent chenodeoxycholic acid (CDCA) in feces, and intestinal permeability, and borderline increased CT (P=0.13). Those IBS-D patients with serum C4 >47.1 ng/ml (13/54) had increased total fecal BA excretion and borderline increased colonic permeability. Variants in genes involved in feedback regulation of BA synthesis (KLB, P=0.06 and FGFR4, P=0.09) were potentially associated with the subgroup with elevated serum C4.CONCLUSIONS:IBS-D with increased BA excretion or synthesis is associated with significant pathophysiological changes relative to patients with normal BA profile. BA diarrhea is identified more effectively with total fecal BA than with serum C4.

Prokinetics in Gastroparesis

Prokinetic agents are medications that enhance coordinated gastrointestinal motility and transit of content in the gastrointestinal tract, mainly by amplifying and coordinating the gastrointestinal muscular contractions. In addition to dietary therapy, prokinetic therapy should be considered as a means to improve gastric emptying and symptoms of gastroparesis, balancing benefits and risks of treatment. In the United States, metoclopramide remains the first-line prokinetic therapy, because it is the only approved medication for gastroparesis. Newer agents are being developed for the management of gastroparesis. This article provides detailed information about prokinetic agents for the treatment of gastroparesis.

Elobixibat and its potential role in chronic idiopathic constipation

Chronic idiopathic constipation is highly prevalent among adults. Bile acids (BAs) and the enterohepatic BA circulation modulate colonic secretion and motility that affect transit. BAs in the colon have a dual action as osmotic and stimulant agents. Newer agents, such as elobixibat (A3309), an inhibitor of the ileal BA transporter, have the potential to improve significantly the management of chronic constipation, with minimal adverse effects. Elobixibat modulates the enterohepatic BA circulation, enhancing the delivery of BAs to the colon where they induce secretory and motor effects. Secondary effects of the inhibition of BA absorption are reduced activation of the farnesoid X receptor, decreased secretion of fibroblast growth factor-19 into the portal circulation, and increased BA synthesis. This review focuses on the role of BAs, the enterohepatic BA circulation, and an ileal BA transporter inhibitor (elobixibat) in chronic constipation.

Validating biomarkers of treatable mechanisms in irritable bowel syndrome.

A valid biomarker is ‘an indicator of normal biologic or pathogenic processes, or pharmacological responses to a therapeutic intervention’. There is no validated biomarker for irritable bowel syndrome (IBS). The aim of the study was to assess ability of three quantitative traits to identify treatable processes to discriminate between IBS‐diarrhea (IBS‐D) patients, IBS‐constipation (IBS‐C) patients and healthy volunteers (HV).

RNA Sequencing Shows Transcriptomic Changes in Rectosigmoid Mucosa in Patients with Irritable Bowel Syndrome-Diarrhea: A Pilot Case-Control Study

Our aim was to conduct a pilot case-control study of RNA expression profile using RNA sequencing of rectosigmoid mucosa of nine females with -diarrhea-predominant irritable bowel syndrome (IBS-D) with accelerated colonic transit and nine female healthy controls. Mucosal total RNA was isolated and purified, and next-generation pair-end sequencing was performed using Illumina TruSeq. Analysis was carried out using a targeted approach toward 12 genes previously associated with IBS and a hypothesis-generating approach. Of the 12 targeted genes tested, patients with IBS-D had decreased mRNA expression of TNFSF15 (fold change controls to IBS-D: 1.53, P = 0.01). Overall, up- and downregulated mRNA expressions of 21 genes (P = 10(-5) to 10(-8); P values with false detection rates are shown) were potentially relevant to IBS-D including the following: neurotransmitters [P2RY4 (P = 0.001), vasoactive intestinal peptide (VIP, P = 0.02)]; cytokines [CCL20 (P = 0.019)]; immune function [C4BPA complement cascade (P = 0.0187)]; interferon-related [IFIT3 (P = 0.016)]; mucosal repair and cell adhesion [trefoil protein (TFF1, P = 0.012)], retinol binding protein [RBP2 (P = 0.017)]; fibronectin (FN1, P = 0.009); and ion channel functions [guanylate cyclase (GUCA2B, P = 0.017), PDZ domain-containing protein 3 (PDZD3, P = 0.029)]. Ten genes associated with functions related to pathobiology of IBS-D were validated by RT-PCR. There was significant correlation in fold changes of the selected genes (Rs = 0.73, P = 0.013). Up- or downregulation of P2RY4, GUC2AB, RBP2, FNI, and C4BPA genes were confirmed on RT-PCR, which also revealed upregulation of farnesoid X receptor (FXR) and apical sodium-coupled bile acid transporter (IBAT/ASBT). RNA-Seq and RT-PCR analysis of rectosigmoid mucosa in IBS-D show transcriptome changes that provide the rationale for validation studies to explore the role of mucosal factors in the pathobiology of IBS-D.

Biomarkers for bile acid diarrhoea in functional bowel disorder with diarrhoea: a systematic review and meta-analysis

There is no universally available laboratory test to diagnose bile acid diarrhoea (BAD). Objective To conduct a systematic review and meta-analysis to identify a biomarker for idiopathic BAD in patients with functional bowel disorder (FBD) with diarrhoea. Design We searched multiple databases through 15 May 2015. Data were only available to estimate the diagnostic yield of each test (the prevalence of a positive test). Estimates were pooled across studies using the random effects model. Results We included 36 studies, enrolling 5028 patients (24 using 75selenium homotaurocholic acid test (75SeHCAT) retention of <10%, 6 using fasting serum C4, 3 using fasting serum fibroblast growth factor 19 (FGF19) and 2 based on total faecal bile acid (BA) excretion over 48 h). The diagnostic yields (and 95% CI) of abnormal tests were: 0.308 (0.247 to 0.377) for 75SeHCAT retention (<10%), 0.171 (0.134 to 0.217) for serum C4, 0.248 (0.147 to 0.385) for serum FGF19 and 0.255 (0.071 to 0.606) for total faecal BA excretion over 48 h. The majority of the analyses were associated with substantial heterogeneity. Performance characteristics relative to a gold standard test could not be estimated. Conclusions Overall, the test with the highest diagnostic yield conducted in the largest number of studies was 75SeHCAT retention, which is not widely available in many countries outside Europe and Canada. Using different diagnostic tests, 25% (average) of patients with lower FBD with diarrhoea has evidence of idiopathic BAD. These tests serve to identify idiopathic BAD among patients with FBD with diarrhoea. Further studies are required to appraise the performance characteristics of tests for idiopathic BAD.