No distinct microbiome signature of irritable bowel syndrome found in a Swedish random population.

OBJECTIVE: The ethiopathogenesis of irritable bowel syndrome (IBS) is unknown. While a link to the gut microbiome is postulated, the heterogeneity of the healthy gut makes it difficult to draw definitive conclusions. We aimed to describe the faecal and mucosa-associated microbiome (MAM) and health correlates on a community cohort of healthy and IBS individuals with no colonoscopic findings. DESIGN: The PopCol study recruited a random sample of 3556 adults; 745 underwent colonoscopy. IBS was defined by Rome IV criteria and organic disease excluded. 16S rRNA gene sequencing was conducted on sigmoid biopsy samples from 376 representative individuals (63 IBS cases) and faecal samples from 185 individuals (32 IBS cases). RESULTS: While sigmoid MAM was dominated by Lachnospiraceae, faeces presented a higher relative abundance of Ruminococcaceae. Microbial richness in MAM was linearly correlated to that in faeces from the same individual (R²=0.255, p<3E-11) as was diversity (R²=0.06, p=0.0022). MAM diversity decreased with increasing body mass index (BMI; Pearson's r=-0.1, p=0.08) and poorer self-rated health (r=-0.15, p=0.007), but no other health correlates. Faecal microbiome diversity was correlated to stool consistency (r=-0.16, p=0.043). Several taxonomic groups were correlated to age, BMI, depression and self-reported health, including Coprococcus catus associated with lower levels of depression (r=-0.003, p=0.00017). The degree of heterogeneity observed between IBS patients is higher than that observed between healthy individuals. CONCLUSIONS: No distinct microbial signature was observed in IBS. Individuals presenting with low self-rated health or high BMI have lower gut microbiome richness.

Peptide YY3-36 and glucagon-like peptide-1 in functional dyspepsia. Secretion and role in symptom generation.

OBJECTIVE: The role of peptide YY3-36 (PYY3-36), glucagon-like peptide-1 (GLP-1), and glucose homoeostasis in symptom development in functional dyspepsia (FD) is unclear. The aim was to investigate postprandial changes in plasma PYY3-36, GLP-1, glucose and insulin, and the relationship between PYY3-36, GLP-1, dyspeptic symptoms, and satiety measurements. MATERIALS AND METHODS: Thirty-six patients with functional dyspepsia and 18 healthy controls consumed a liquid meal at two occasions. Firstly, a fixed amount of 250 mL (300 kcal) was consumed and gastric emptying was assessed using the paracetamol method. Secondly, participants drank 75 mL (90 kcal) per five min until maximal satiety. PYY3-36, GLP-1, glucose, and insulin concentrations were assessed. Satiety measures and dyspeptic symptoms were registered using visual analogue scales. RESULTS: Gastric emptying, glucose, PYY3-36, and GLP-1 concentrations were similar in patients and controls. Patients with epigastric pain syndrome had higher postprandial insulin levels. Patients reported more satiety, nausea, and pain. Area under the curve (AUC) for GLP-1 correlated positively to nausea in patients and negatively to nausea in controls during a single meal. AUC for PYY3-36 correlated similarly to sensation of fullness in the two groups; however, the correlation was negative for the single meal and positive for the satiety test. CONCLUSIONS: In epigastric pain syndrome, postprandial insulin secretion seems to be increased. Neither GLP-1 nor PYY3-36 secretion is altered in functional dyspepsia, but postprandial GLP-1 secretion seems to correlate with nausea and PYY3-36 to the sensation of fullness, and therefore, these hormones might be involved in symptom generation.

Genetic variants in CDC42 and NXPH1 as susceptibility factors for constipation and diarrhoea predominant irritable bowel syndrome.

OBJECTIVE: The complex genetic aetiology underlying irritable bowel syndrome (IBS) needs to be assessed in large-scale genetic studies. Two independent IBS cohorts were genotyped to assess whether genetic variability in immune, neuronal and barrier integrity genes is associated with IBS. DESIGN: 384 single nucleotide polymorphisms (SNPs) covering 270 genes were genotyped in an exploratory cohort (935 IBS patients, 639 controls). 33 SNPs with Puncorrected<0.05 were validated in an independent set of 497 patients and 887 controls. Genotype distributions of single SNPs were assessed using an additive genetic model in IBS and clinical subtypes, IBS-C and IBS-D, both in individual and combined cohorts. Trait anxiety (N=614 patients, 533 controls), lifetime depression (N=654 patients, 533 controls) and mRNA expression in rectal biopsies (N=22 patients, 29 controls) were correlated with SNP genotypes. RESULTS: Two SNPs associated independently in the exploratory and validation cohort: rs17837965-CDC42 with IBS-C (ORexploratory=1.59 (1.05 to 1.76); ORvalidation=1.76 (1.03 to 3.01)) and rs2349775-NXPH1 with IBS-D (ORexploratory=1.28 (1.06 to 1.56); ORvalidation=1.42 (1.08 to 1.88)). When combining both cohorts, the association of rs2349775 withstood post hoc correction for multiple testing in the IBS-D subgroup. Additionally, three SNPs in immune-related genes (rs1464510-LPP, rs1881457-IL13, rs2104286-IL2RA), one SNP in a neuronal gene (rs2349775-NXPH1) and two SNPs in epithelial genes (rs245051-SLC26A2, rs17837965-CDC42) were weakly associated with total-IBS (Puncorrected<0.05). At the functional level, rs1881457 increased IL13 mRNA levels, whereas anxiety and depression scores did not correlate with rs2349775-NXPH1. CONCLUSIONS: Rs2349775 (NXPH1) and rs17837965 (CDC42) were associated with IBS-D and IBS-C, respectively, in two independent cohorts. Further studies are warranted to validate our findings and to determine the mechanisms underlying IBS pathophysiology.

Training nonanesthetist administration of propofol for gastrointestinal endoscopy in scenario-based full-scale hybrid simulation--a pilot study.

OBJECTIVE: The use of nonanesthetist-administered propofol (NAAP) in GI endoscopy has long been controversial. In the setting of NAAP, acute situations can develop during endoscopy and thus training before starting with NAAPs is considered crucial. The aim was to evaluate a pilot study on crew resource management (CRM)-based training of teams of endoscopists and endoscopy nurses in NAAP in a full-scale hybrid simulation consisting of a full-scale human patient simulator and an endoscopy simulator. Our hypothesis was that the training would increase the self-efficacy of the participants. MATERIAL AND METHODS: Four scenarios were created, each with typical side effects of propofol administration. All scenarios included the need for prompt decision-making and treatment. Colonoscopy, gastroscopy or endoscopic retrograde cholangiopancreatography (ERCP) cases were assigned to the course participants in coherence with their main clinical expertise in order to facilitate situated and contextualized training. Twenty-one participants (ten doctors and eleven nurses) completed a questionnaire on self-efficacy before and after the course. A questionnaire regarding the quality and yield of the course was also completed. RESULTS: For all participants, the self-efficacy score was 26.0 (24.0-28.0; interquartile range) before training and 30.0 (27.0-30.5) after training (p = 0.0003). The ten doctors had a self-efficacy score before training of 26.5 (25.0-29.5) and 30.0 (29.0-33.0) after (p = 0.0078). The eleven nurses scored 24.0 (22.0-26.0) before and 28.0 (27.0-30.0) after training (p = 0.0098). CONCLUSIONS: Systematic target focused scenario-based training with hybrid simulation of NAAP in endoscopy resulted in increased self-efficacy in both nurses and physicians.

The Effectiveness and Tolerability of a Very Low-Volume Bowel Preparation for Colonoscopy Compared to Low and High-Volume Polyethylene Glycol-Solutions in the Real-Life Setting.

Adequate bowel cleansing is essential for high-quality colonoscopy. Recently, a new very low-volume 1 litre (1L) polyethylene glycol (PEG) plus ascorbate solution (ASC) has been introduced. Our aims were to assess the effectiveness and tolerability of this product compared to low-volume 2L PEG-ASC and high-volume 4L PEG solutions, in a real-life setting. In six endoscopy units in Sweden, outpatients undergoing colonoscopy were either prescribed solutions according to local routines, or the very low-volume solution in split dose regimen. Bowel cleansing effectiveness and patient experience was assessed using the Boston Bowel preparation scale (BBPS) and a patient questionnaire. A total of 1098 patients (mean age 58 years, 52% women) were included. All subsegment and the total BBPS scores were significantly greater for 1L PEG-ASC in comparison to other solutions (p < 0.05 for 1L PEG-ASC and 4L PEG for transverse and left colon, otherwise p < 0.001). Nausea was more frequent with 1L PEG-ASC compared to 2L PEG-ASC (p < 0.001) and vomiting were more often reported compared to both other solutions (p < 0.01 and p < 0.05 for 2L PEG-ASC and 4L PEG, respectively). Smell, taste, and total experience was better for 1L PEG-ASC compared to 4L PEG (p < 0.001), and similar compared to the 2L PEG-ASC. In conclusion, 1L PEG-ASC leads to better bowel cleansing compared to 2L PEG-ASC or 4L PEG products, with similar or greater patient satisfaction.

Involvement of endogenous glucagon-like peptide-1 in regulation of gastric motility and pancreatic endocrine secretion.

OBJECTIVE: To study the role of endogenous glucagon-like peptide-1 (GLP-1) on gastric emptying rates of a solid meal as well as postprandial hormone secretion and glucose disposal. MATERIAL AND METHODS: In nine healthy subjects, gastric emptying of a 310-kcal radio-labelled solid meal and plasma concentrations of insulin, glucagon and glucose were measured during infusion of saline or the GLP-1 receptor antagonist exendin(9-39)amide (Ex(9-39)) at 300 pmol·kg(-1)·min(-1). RESULTS: Ex(9-39) infusion had no effect on the total gastric emptying curve, but changed the intra-gastric distribution of the meal. During infusion of Ex(9-39), more content stayed in the upper stomach (79.1 ± 2.5% of total during Ex(9-39) compared to 66.6 ± 5.7% during saline at 5 min). During Ex(9-39) infusion, higher concentrations of plasma glucagon were measured both before (after 40 min of Ex(9-39) infusion the glucagon level was 15.1 ± 0.7 pmol·L(-1) compared to 5.4 ± 1.4 during saline) and after the meal, and postprandial GLP-1 levels increased. Basal insulin and glucose levels were not affected by Ex(9-39), but the postprandial rise of insulin and glucose enhanced during Ex(9-39). CONCLUSIONS: Endogenous GLP-1 is involved in the regulation of gastric motility in relation to meal intake and also in the regulation of postprandial insulin and glucose levels. Furthermore, endogenous GLP-1 seems to tonically restrain glucagon secretion.

miR-16 and miR-103 impact 5-HT4 receptor signalling and correlate with symptom profile in irritable bowel syndrome.

Irritable bowel syndrome (IBS) is a gut-brain disorder involving alterations in intestinal sensitivity and motility. Serotonin 5-HT4 receptors are promising candidates in IBS pathophysiology since they regulate gut motor function and stool consistency, and targeted 5-HT4R selective drug intervention has been proven beneficial in subgroups of patients. We identified a single nucleotide polymorphism (SNP) (rs201253747) c.*61 T > C within the 5-HT4 receptor gene HTR4 to be predominantly present in diarrhoea-IBS patients (IBS-D). It affects a binding site for the miR-16 family and miR-103/miR-107 within the isoforms HTR4b/i and putatively impairs HTR4 expression. Subsequent miRNA-profiling revealed downregulation of miR-16 and miR-103 in the jejunum of IBS-D patients correlating with symptoms. In vitro assays confirmed expression regulation via three 3'UTR binding sites. The novel isoform HTR4b_2 lacking two of the three miRNA binding sites escapes miR-16/103/107 regulation in SNP carriers. We provide the first evidence that HTR4 expression is fine-tuned by miRNAs, and that this regulation is impaired either by the SNP c.*61 T > C or by diminished levels of miR-16 and miR-103 suggesting that HTR4 might be involved in the development of IBS-D.

Tachykinin-stimulated small bowel myoelectric pattern: sensitization by NO inhibition, reversal by neurokinin receptor blockade.

UNLABELLED: Tachykinins stimulate motility whereas NO inhibits motility in the gastrointestinal tract. AIM: To investigate if inhibition of NO production sensitizes myoelectric activity to subthreshold doses of tachykinins in the small intestine of awake rats. METHODS: Rats were supplied with a venous catheter and bipolar electrodes at 5, 15 and 25 cm distal to pylorus for electromyography of small intestine. The motor responses were evaluated using pattern recognition. Substance P and neurokinin A dose-dependently stimulated gut motility, with neurokinin A being more potent than substance P. Therefore, neurokinin A was chosen and administered under baseline conditions and 45-60 min after N(omega)-nitro-L-arginine (L-NNA) 1 mg kg(-1), with or without pretreatment with L-arginine 300 mg kg(-1). In addition, myoelectric activity effects of neurokinin A in conjunction with L-NNA were studied before and after administration of the tachykinin receptor antagonists, SR140333 (NK1), SR48968 (NK2) and SR142801 (NK3), each at 2.5 mg kg(-1). RESULTS: Dose-finding studies verified 10 pmol kg(-1) min(-1) to be the threshold dose at which NKA caused phase II-like activity in a low percentage of experiments (12%, n=41). This dose was therefore used in combination with L-NNA for sensitization experiments of gut myoelectric activity. In experiments where NKA-induced no response, pretreatment with L-NNA led to phase II-like activity in 9 of 18 (50%, p<0.05) experiments. Co-administration of SR140333 and SR48968 abolished this effect. CONCLUSION: NO counteracts the stimulatory effect of tachykinins on small bowel myoelectric activity in the rat. Inhibition of the L-arginine/NO pathway sensitizes the gut to tachykinin-stimulated motor activity.

Depletion of mucosal substance P in acute otitis media.

OBJECTIVE: The neuropeptide substance P (SP) is an inducer of neurogenic inflammation and bone resorption in the middle ear. Resorption of the bone tissue structures surrounding the middle ear cavity is a distinct feature of the initial stage of acute otitis media (AOM), which may be due to nerve fiber release of SP. MATERIAL AND METHODS: To investigate possible release of SP in the middle ear mucosa during AOM, we used a well-established rat model of AOM caused by Streptococcus pneumoniae. Following tissue extraction on Days 1, 3 and 6 post-inoculation, the mucosal concentration of SP was measured using a radioimmunoassay. RESULTS: Compared to sham-inoculated control ears, the concentration of SP was significantly reduced on Day 1 and even further reduced on Day 3, whereas partial replenishment was found on Day 6. CONCLUSION: SP seems to be depleted in the rat middle ear mucosa in the hyperacute phase of AOM. This depletion is followed by replenishment and the concentration of SP approaches its normal level 6 days post-inoculation. The release of SP may be the trigger of the concurrent bone resorption and may further augment the inflammatory response to the bacterial colonization.

An additional case of gastric serrated adenoma.

Gastric serrated adenoma is an apparently rare adenoma phenotype characterized by branched villi exhibiting lateral saw-tooth indentations lined with dysplastic cells. Out of the 21 gastric serrated adenomas now in record, including the case reported here, 76% (n=16) exhibited invasive carcinoma. In contrast, only 15% of the gastric tubular/villous (that is, non-serrated) adenomas reported in the literature revealed invasive growth. Although the cause for the virulent behaviour of gastric serrated adenomas remains elusive, it would appear that not only the degree of severity of the cellular dysplasia but also the serrated ornamental configurations might play a particular role in the unusual virulence of these adenomas.

Benign and precursor lesions in the esophagus.

The following, from the 12th OESO World Conference: Cancers of the Esophagus, includes commentaries on the role of salivary stimulation and esophageal secretion of protective factors in prevention of adenocarcinoma sequelae in gastroesophageal reflux disease; the pediatric conditions associated with esophageal cancer; the relationship of achalasia and pseudoachalasia with esophageal cancer; the potential for malignant transformation in eosinophilic esophagitis and overlap syndromes; the role of lymphocytic esophagitis as an overlapping phenotype; the role of Barrett's esophagus as a premalignant condition; the indications and type of treatment of premalignant conditions of the esophagus; and the decision for use of endoscopical procedures in premalignant conditions of the esophagus.

Duodenal epithelial transport in functional dyspepsia: Role of serotonin.

AIM: To investigate functional duodenal abnormalities in functional dyspepsia (FD) and the role of serotonin (5-hydroxytryptamine, 5-HT) in mucosal ion transport and signalling. METHODS: Duodenal mucosal biopsies were obtained from 15 patients with FD and 18 healthy controls. Immunohistochemistry was used to study the number of 5-HT-containing cells and real-time polymerase chain reaction for expression of 5-HT receptors 1A, 1B, 2A, 2B, 3A, 3B, 3C, 3D, 3E, 4 and 7, as well as expression of the serotonin re-uptake transporter (SERT) gene SLC6A4 and tryptophan hydroxylase 1 (TPH1). Biopsies were mounted in Ussing chambers for evaluation of basal and 5-HT-stimulated short-circuit current (SCC). RESULTS: Conductance was lower in FD [42.4 ± 4.7 mS/cm(2) (n = 15) vs 62.5 ± 4.5 mS/cm(2) (n = 18), P = 0.005]. 5-HT induced a dose dependent rise in SCC in both FD (n = 8) and controls (n = 9), the rise was lower in FD (P < 0.001). Mean number of 5-HT stained cells per high power field was the same [34.4 ± 8.4 in FD (n = 15) and 30.4 ± 3.7 in controls (n = 18), P = 0.647]. The following genes were highly expressed: 5-HT receptor HTR3E, HTR4, HTR7, SERT gene (SLC6A4) and TPH1. Differences in expression levels were observed for HTR3E (higher expression in FD, P = 0.008), HTR7 (lower expression in FD, P = 0.027), SLC6A4 (higher expression in FD, P = 0.033) and TPH1 (lower expression in FD, P = 0.031). CONCLUSION: Duodenal ion transport in response to exogenous 5-HT is abnormal in FD patients and associated with high expression of the HTR3E receptor and the serotonin transporter.