Therapeutic applications of ghrelin agonists in the treatment of gastroparesis

There remains an unmet need for effective pharmacologic treatments for gastroparesis. Ghrelin is the endogenous ligand for the growth hormone secretagogue receptor and has been shown to regulate energy homeostasis and exert prokinetic effects on gastrointestinal motility. In recent years, several ghrelin receptor agonists have been studied in clinical trials of patients with diabetic gastroparesis. The intravenous macrocyclic peptidomimetic, TZP-101, initially suggested improvement in gastroparesis symptoms with intravenous administration when compared to placebo. However, in subsequent studies of oral preparations, TZP-102 failed to confirm these results. Another ghrelin receptor agonist, RM-131, was recently shown to significantly accelerate gastric emptying (GE) in patients with type 1 and type 2 diabetes and delayed GE. RM-131 reduced total Gastroparesis Cardinal Symptom Index-Daily Diary (GCSI-DD) and composite scores among type 1 diabetics. Continued development of ghrelin agonists should be explored in attempts to expand therapeutic options for the treatment of gastroparesis

Genetic analysis of safflower domestication.

BackgroundSafflower (Carthamus tinctorius L.) is an oilseed crop in the Compositae (a.k.a. Asteraceae) that is valued for its oils rich in unsaturated fatty acids. Here, we present an analysis of the genetic architecture of safflower domestication and compare our findings to those from sunflower (Helianthus annuus L.), an independently domesticated oilseed crop within the same family.We mapped quantitative trait loci (QTL) underlying 24 domestication-related traits in progeny from a cross between safflower and its wild progenitor, Carthamus palaestinus Eig. Also, we compared QTL positions in safflower against those that have been previously identified in cultivated x wild sunflower crosses to identify instances of colocalization.ResultsWe mapped 61 QTL, the vast majority of which (59) exhibited minor or moderate phenotypic effects. The two large-effect QTL corresponded to one each for flower color and leaf spininess. A total of 14 safflower QTL colocalized with previously reported sunflower QTL for the same traits. Of these, QTL for three traits (days to flower, achene length, and number of selfed seed) had cultivar alleles that conferred effects in the same direction in both species.ConclusionsAs has been observed in sunflower, and unlike many other crops, our results suggest that the genetics of safflower domestication is quite complex. Moreover, our comparative mapping results indicate that safflower and sunflower exhibit numerous instances of QTL colocalization, suggesting that parallel trait transitions during domestication may have been driven, at least in part, by parallel genotypic evolution at some of the same underlying genes

Transcriptome profiling reveals significant changes in the gastric muscularis externa with obesity that partially overlap those that occur with idiopathic gastroparesis

BACKGROUND: Gastric emptying is impaired in patients with gastroparesis whereas it is either unchanged or accelerated in obese individuals. The goal of the current study was to identify changes in gene expression in the stomach muscularis that may be contributing to altered gastric motility in idiopathic gastroparesis and obesity. METHODS: Quantitative real time RT-PCR and whole transcriptome sequencing were used to compare the transcriptomes of lean individuals, obese individuals and either lean or obese individuals with idiopathic gastroparesis. RESULTS: Obesity leads to an increase in mRNAs associated with muscle contractility whereas idiopathic gastroparesis leads to a decrease in mRNAs associated with PDGF BB signaling. Both obesity and idiopathic gastroparesis were also associated with similar alterations in pathways associated with inflammation. CONCLUSIONS: Our findings show that obesity and idiopathic gastroparesis result in overlapping but distinct changes in the gastric muscularis transcriptome. Increased expression of mRNAs encoding smooth muscle contractile proteins may be contributing to the increased gastric motility observed in obese subjects, whereas decreased PDGF BB signaling may be contributing to the impaired motility seen in subjects with idiopathic gastroparesis

Gastroparesis is associated with decreased FOXF1 and FOXF2 in humans, and loss of FOXF1 and FOXF2 results in gastroparesis in mice

Background and Aims The transcription factors FOXF1 and FOXF2 have been implicated in the development of the gastrointestinal tract but their role in adults or in gastrointestinal diseases is poorly understood. We have recently shown that expression of serum response factor (SRF), a transcription factor whose activity is modulated by FOXF proteins, is decreased in the stomach muscularis of patients with gastroparesis. The aim of the current study was to determine whether FOXF expression is decreased in gastroparesis patients and whether loss of FOXF1 and/or FOXF2 from adult smooth muscle is sufficient to impair gastric emptying in mice. Methods Full‐thickness stomach biopsy samples were collected from control subjects and from patients with gastroparesis. mRNA was isolated from the muscularis externa, and FOXF mRNA expression levels were determined by quantitative reverse transcriptase (RT)‐PCR. Foxf1 and Foxf2 were knocked out together and separately from smooth muscle cells in adult mice, and the subsequent effect on liquid gastric emptying and contractile protein expression was determined. Key Results Expression of FOXF1 and FOXF2 is decreased in smooth muscle tissue from gastroparesis patients. Knockout of Foxf1 and Foxf2 together, but not alone, from mouse smooth muscle resulted in delayed liquid gastric emptying. Foxf1/2 double knockout mice had decreased expression of smooth muscle contractile proteins, SRF, and myocardin in stomach muscularis. Conclusions and Inferences Our findings suggest that decreased expression of FOXF1 and FOXF2 may be contributing to the impaired gastric emptying seen in gastroparesis patients

Idiopathic gastroparesis is associated with specific transcriptional changes in the gastric muscularis externa

BACKGROUND: The molecular changes that occur in the stomach that are associated with idiopathic gastroparesis are poorly described. The aim of this study was to use quantitative analysis of mRNA expression to identify changes in mRNAs encoding proteins required for the normal motility functions of the stomach. METHODS: Full-thickness stomach biopsy samples were collected from non-diabetic control subjects who exhibited no symptoms of gastroparesis and from patients with idiopathic gastroparesis. mRNA was isolated from the muscularis externa and mRNA expression levels were determined by quantitative reverse transcriptase (RT)-PCR. KEY RESULTS: Smooth muscle tissue from idiopathic gastroparesis patients had decreased expression of mRNAs encoding several contractile proteins, such as MYH11 and MYLK1. Conversely, there was no significant change in mRNAs characteristic of interstitial cells of Cajal (ICCs) such as KIT or ANO1. There was also a significant decrease in mRNA-encoding platelet-derived growth factor receptor α (PDGFRα) and its ligand PDGFB and in Heme oxygenase 1 in idiopathic gastroparesis subjects. In contrast, there was a small increase in mRNA characteristic of neurons. Although there was not an overall change in KIT expression in gastroparesis patients, KIT expression showed a significant correlation with gastric emptying whereas changes in MYLK1, ANO1 and PDGFRα showed weak correlations to the fullness/satiety subscore of patient assessment of upper gastrointestinal disorder-symptom severity index scores. CONCLUSIONS AND INFERENCES: Our findings suggest that idiopathic gastroparesis is associated with altered smooth muscle cell contractile protein expression and loss of PDGFRα+ cells without a significant change in ICCs

Characterization of Proximal Small Intestinal Microbiota in Patients With Suspected Small Intestinal Bacterial Overgrowth: A Cross-Sectional Study

OBJECTIVES: The composition of the small intestinal microbiota has not yet been characterized thoroughly using culture-independent techniques. We compared small intestinal microbial communities in patients with and without small intestinal bacterial overgrowth (SIBO) using culture-dependent and culture-independent bacterial identification approaches. METHODS: Small bowel aspirate and mucosal samples were collected from patients with suspected SIBO. The aspirates were cultured to diagnose SIBO, defined as ≥10 colony-forming units/mL coliform or ≥10 colony-forming units/mL upper aerodigestive tract bacteria. Bacteria in the aspirates and mucosa were identified using 16S rRNA gene sequencing. We compared small intestinal microbiome composition between groups with and without a culture-based SIBO diagnosis. RESULTS: Analysis of the aspirate and mucosal microbial communities from 36 patients revealed decreased α-diversity but no differences in β-diversity in patients with SIBO compared with those without SIBO. There were no significant differences in the relative abundance of individual taxa from the aspirates or mucosa after adjustment for false discovery rate between patients with and without SIBO. Subgroup analysis revealed significant differences in mucosal β-diversity between the coliform and upper aerodigestive tract subgroups. Relative abundances of a mucosal Clostridium spp. (P = 0.05) and an aspirate Granulicatella spp. (P = 0.02) were higher in coliform SIBO vs non-SIBO subgroups. The microbial composition and relative abundance of multiple taxa significantly differed in the mucosal and aspirate specimens. DISCUSSION: Culture-based results of small bowel aspirates do not correspond to aspirate microbiota composition but may be associated with species richness of the mucosal microbiota

An emerging method to noninvasively measure and identify vagal response markers to enable bioelectronic control of gastroparesis symptoms with gastric electrical stimulation

Background: Gastric electrical stimulation (GES) can be a life-changing, device-based treatment option for drug-resistant nausea and vomiting associated with diabetic or idiopathic gastroparesis (GP). Despite over two decades of clinical use, the mechanism of action remains unclear. We hypothesize a vagal mechanism. New method: Here, we describe a noninvasive method to investigate vagal nerve involvement in GES therapy in 66 human subjects through the compound nerve action potential (CNAP). Results: Of the 66 subjects, 28 had diabetic GP, 35 had idiopathic GP, and 3 had postsurgical GP. Stimulus charge per pulse did not predict treatment efficacy, but did predict a significant increase in total symptom score in type 1 diabetics as GES stimulus charge per pulse increased (p < 0.01), representing a notable side effect and providing a method to identify it. In contrast, the number of significant left and right vagal fiber responses that were recorded directly related to patient symptom improvement. Increased vagal responses correlated with significant decreases in total symptom score (p < 0.05). Comparison with existing method(s): We have developed transcutaneous recording of cervical vagal activity that is synchronized with GES in conscious human subjects, along with methods of discriminating the activity of different nerve fiber groups with respect to conduction speed and treatment response. Conclusions: Cutaneous vagal CNAP analysis is a useful technique to unmask relationships among GES parameters, vagal recruitment, efficacy and side-effect management. Our results suggest that CNAP-guided GES optimization will provide the most benefit to patients with idiopathic and type 1 diabetic gastroparesis

Impact of a ring fitted cap on insertion time and adenoma detection: a randomized controlled trial

Background and Aims: Devices for flattening colon folds can improve polyp detection at colonoscopy. However, there are few data on the endoscopic ring fitted cap (EndoRings, EndoAid, Caesarea, Israel). We sought to compare adenoma detection with EndoRings with that of standard high-definition colonoscopy. Methods: A single-center randomized controlled trial of 562 patients (284 randomized to EndoRings and 278 to standard colonoscopy) at 2 outpatient endoscopy units in the Indiana University Hospital system. Adenoma detection was the primary outcome measured as adenoma detection rate (ADR) and adenomas per colonoscopy (APC). We also compared sessile serrated polyp detection rate (SSPDR), insertion times, withdrawal times, and ease of passage through the sigmoid colon. Results: EndoRings was superior to standard colonoscopy in terms of APC (1.46 vs 1.06, p=0.025) but there were no statistically significant differences in ADR or SSPDR. Mean withdrawal time (in patients with no polyps) was shorter and insertion time (all patients) was longer in the EndoRings arm by 1.8 minutes and 0.75 minutes, respectively. One provider had significantly higher detection with EndoRings and contributed substantially to the overall results. Conclusions: EndoRings can increase adenoma detection without significant increase in procedure time, but the effect varies between operators. EndoRings slows colonoscope insertion

Glucagon-like peptide 1 improved glycemic control in type 1 diabetes

BACKGROUND: Glucagon-like peptide-1 (GLP-1) and its agonists are under assessment in treatment of type 2 diabetes, by virtue of their antidiabetic actions, which include stimulation of insulin secretion, inhibition of glucagon release, and delay of gastric emptying. We examined the potential of GLP-1 to improve glycemic control in type 1 diabetes with no endogenous insulin secretion. METHODS: Dose-finding studies were carried out to establish mid range doses for delay of gastric emptying indicated by postponement of pancreatic polypeptide responses after meals. The selected dose of 0.63 micrograms/kg GLP-1 was administered before breakfast and lunch in 8-hour studies in hospital to establish the efficacy and safety of GLP-1. In outside-hospital studies, GLP-1 or vehicle was self-administered double-blind before meals with usual insulin for five consecutive days by five males and three females with well-controlled C-peptide-negative type 1 diabetes. Capillary blood glucose values were self-monitored before meals, at 30 and 60 min after breakfast and supper, and at bedtime. Breakfast tests with GLP-1 were conducted on the day before and on the day after 5-day studies. Paired t-tests and ANOVA were used for statistical analysis. RESULTS: In 8-hour studies time-averaged incremental (delta) areas under the curves(AUC) for plasma glucose through 8 hours were decreased by GLP-1 compared to vehicle (3.2 ± 0.9, mean ± se, vs 5.4 ± 0.8 mmol/l, p < .05), and for pancreatic polypeptide, an indicator of gastric emptying, through 30 min after meals (4.0 ± 3.1 vs 37 ± 9.6 pmol/l, p < .05) with no adverse effects. Incremental glucagon levels through 60 min after meals were depressed by GLP-1 compared to vehicle (-3.7 ± 2.5 vs 3.1 ± 1.9 ng/l, p < .04). In 5-day studies, AUC for capillary blood glucose levels were lower with GLP-1 than with vehicle (-0.64 ± 0.33 vs 0.34 ± 0.26 mmol/l, p < .05). No assisted episode of hypoglycaemia or change in insulin dosage occurred. Breakfast tests on the days immediately before and after 5-day trials showed no change in the effects of GLP-1. CONCLUSION: We have demonstrated that subcutaneous GLP-1 can improve glucose control in type 1 diabetes without adverse effects when self-administered before meals with usual insulin during established intensive insulin treatment programs