Quigley, Eamonn M.M.

ABSTRACT Background Patients with gastric dysmotility exhibit abnormal transit and reduced contractility, for which quantification is limited with current methodologies. The Atmo Capsule is a wireless motility capsule that measures regional gastrointestinal transit. We tested its technical capabilities to evaluate gastric contractility by detecting changes in capsule acceleration during transit. Methods Data from 91 healthy controls and 182 patients with suspected dysmotility who ingested the Atmo Capsule following a standardized protocol were included. Gastric emptying times (GET) ≥ 5 h were considered delayed. Contraction frequencies (cycles per minute [cpm]) and amplitudes (as arbitrary units [au]) were identified following Fast Fourier Transformation of accelerometer data using 5‐min windows and were assessed in 30‐min windows post‐ingestion (early gastric phase) and before gastric emptying (late gastric phase). Data were compared via ANOVA, using Bonferroni corrections, between healthy controls, patients with normal gastric emptying, and patients with delayed gastric emptying. Key Results Gastric emptying was delayed in 53/182 (29%) patients. Three cpm contraction frequencies were identified across both gastric phases in controls and patients. Contraction amplitudes did not differ between groups in the early gastric phase. In the late phase, mean amplitudes were lower in patients with delayed gastric emptying (6.4 au) compared with subjects with normal gastric emptying (controls, 9.7 au, p < 0.0001; patients, 8.6 au, p < 0.0001). Conclusions & Inference The Atmo Capsule enables precise quantification of gastric contraction profiles, permitting differentiation of normal from pathological motor patterns. Findings of this technical assessment support its potential for evaluating gastric physiology and detecting pathophysiological patterns of gastric dysmotility.

AbstractBackgroundThere is compelling evidence that microbe‐host interactions in the intestinal tract underlie many human disorders, including disorders of gut‐brain interactions (previously termed functional bowel disorders), such as irritable bowel syndrome (IBS). Small intestinal bacterial overgrowth (SIBO) has been recognized for over a century in patients with predisposing conditions causing intestinal stasis, such as surgical alteration of the small bowel or chronic diseases, including scleroderma and is associated with diarrhea and signs of malabsorption. Over 20 years ago, it was hypothesized that increased numbers of small intestine bacteria might also account for symptoms in the absence of malabsorption in IBS and related disorders. This SIBO‐IBS hypothesis stimulated significant research and helped focus the profession's attention on the importance of microbe‐host interactions as a potential pathophysiological mechanism in IBS.PurposeHowever, after two decades, this hypothesis remains unproven. Moreover, it has led to serious unintended consequences, namely the widespread use of unreliable and unvalidated breath tests as a diagnostic test for SIBO and a resultant injudicious use of antibiotics. In this review, we examine why the SIBO hypothesis remains unproven and, given the unintended consequences, discuss why it is time to reject this hypothesis and its reliance on breath testing. We also examine recent IBS studies of bacterial communities in the GI tract, their composition and functions, and their interactions with the host. While these studies provide important insights to guide future research, they highlight the need for further mechanistic studies of microbe‐host interactions in IBS patients before we can understand their possible role in diagnosis and treatment of patient with IBS and related disorders.

Summary Background MRx1234 is a live biotherapeutic product that contains a strain of Blautia hydrogenotrophica. It is in development for the treatment of irritable bowel syndrome (IBS). Aims To assess the efficacy and safety of MRx1234 in patients with IBS with predominant constipation (IBS‐C) or diarrhoea (IBS‐D) Methods We conducted a multicentre, randomised, double‐blind, placebo‐controlled, phase 2 trial. Patients aged 18–70 years in two parallel cohorts (IBS‐C; IBS‐D) were randomised (1:1) to MRx1234 or placebo for 8 weeks. The primary efficacy endpoint was overall responder rate—a composite of improved bowel habit (IBS‐C: stool frequency; IBS‐D: stool consistency) and abdominal pain intensity—for ≥50% of the treatment period in each cohort. Statistical testing was at a one‐sided 0.10 significance level. Results Of 366 randomised patients (164 IBS‐C; 202 IBS‐D), 365 received any study medication (177 MRx1234, 188 placebo). Numerically, although not statistically significantly different, more patients who received MRx1234 than placebo were overall responders in the IBS‐C (25.0% vs. 17.1%) and IBS‐D (23.4% vs. 17.8%) cohorts. Similar results were observed in the additional combined cohort analysis (24.1% vs. 17.5%; p = 0.063). For the components of the primary endpoint, significantly more patients on MRx1234 than placebo reported improvement in bowel habit in the IBS‐C, IBS‐D and combined cohorts, while improvements in abdominal pain were observed in each cohort. The safety profile of MRx1234 was similar to placebo. Conclusions MRx1234 has the potential to become a novel, safe treatment option for patients with IBS‐C or IBS‐D, and for those who have mixed symptoms or transition between subtypes. ClinicalTrials.gov #NCT03721107.

Constipation is a common problem, affects 15% of the population, and is often self-diagnosed and self-managed. Over the past 3 decades, there have been significant advances in our understanding and management of chronic constipation, with the emerging recognition that occasional constipation (OC) is another subtype that falls outside current classifications. The purpose of this review was to describe the process of developing and proposing a new definition for OC based on expert consensus and taking into consideration the multifactorial nature of the problem such as alterations in bowel habit that include stool frequency and difficulty with stool passage, perception of the sufferer, duration of symptoms, and potential responsiveness to treatment. Leading gastroenterologists from 5 countries met virtually on multiple occasions through an online digital platform to discuss the problem of OC and recommended a practical, user-friendly definition: “OC can be defined as intermittent or occasional symptomatic alteration(s) in bowel habit. This includes a bothersome reduction in the frequency of bowel movements and/or difficulty with passage of stools but without alarming features. Bowel symptoms may last for a few days or a few weeks, and episodes may require modification of lifestyle, dietary habits and/or use of over-the-counter laxatives or bulking agents to restore a satisfactory bowel habit.” Prospective studies are required to validate this definition and determine OC prevalence in the community. This review highlights current knowledge gaps and could provide impetus for future research to facilitate an improved understanding of OC and development of evidence-based management guidelines.

AbstractIrritable bowel syndrome (IBS) is a gut‐brain disorder in which symptoms are shaped by serotonin acting centrally and peripherally. The serotonin transporter gene SLC6A4 has been implicated in IBS pathophysiology, but the underlying genetic mechanisms remain unclear. We sequenced the alternative P2 promoter driving intestinal SLC6A4 expression and identified single nucleotide polymorphisms (SNPs) that were associated with IBS in a discovery sample. Identified SNPs built different haplotypes, and the tagging SNP rs2020938 seems to associate with constipation‐predominant IBS (IBS‐C) in females. rs2020938 validation was performed in 1978 additional IBS patients and 6,038 controls from eight countries. Meta‐analysis on data from 2,175 IBS patients and 6,128 controls confirmed the association with female IBS‐C. Expression analyses revealed that the P2 promoter drives SLC6A4 expression primarily in the small intestine. Gene reporter assays showed a functional impact of SNPs in the P2 region. In silico analysis of the polymorphic promoter indicated differential expression regulation. Further follow‐up revealed that the major allele of the tagging SNP rs2020938 correlates with differential SLC6A4 expression in the jejunum and with stool consistency, indicating functional relevance. Our data consolidate rs2020938 as a functional SNP associated with IBS‐C risk in females, underlining the relevance of SLC6A4 in IBS pathogenesis.

AbstractThe available COVID‐19 literature has focused on specific disease manifestations, infection control, and delivery or prioritization of services for specific patient groups in the setting of the acute COVID‐19 pandemic. Local health systems aim to contain the COVID‐19 pandemic and hospitals and health‐care providers rush to provide the capacity for a surge of COVID‐19 patients. However, the short, medium‐term, and long‐term outcomes of patients with gastrointestinal (GI) diseases without COVID‐19 will be affected by the ability to develop locally adapted strategies to meet their service needs in the COVID‐19 setting. To mitigate risks for patients with GI diseases, it is useful to differentiate three phases: (i) the acute phase, (ii) the adaptation phase, and (iii) the consolidation phase. During the acute phase, service delivery for patients with GI disease will be curtailed to meet competing health‐care needs of COVID‐19 patients. During the adaptation phase, GI services are calibrated towards a “new normal,” and the consolidation phase is characterized by rapid introduction and ongoing refinement of services. Proactive planning with engagement of relevant stakeholders including consumer representatives is required to be prepared for a variety of scenarios that are dictated by thus far undefined long‐term economic and societal impacts of the pandemic. Because substantial changes to the delivery of services are likely to occur, it is important that these changes are embedded into quality and research frameworks to ensure that data are generated that support evidence‐based decision‐making during the adaptation and consolidation phases.

Objective Over half of patients with IBS have either diarrhoea (IBS-D) or a mixed stool pattern (IBS-M). The relative efficacy of licenced pharmacological therapies is unclear in the absence of head-to-head trials. We conducted a network meta-analysis to resolve this uncertainty. Design We searched MEDLINE, Embase, Embase Classic, the Cochrane central register of controlled trials, and Clinicaltrials.gov through January 2019 to identify randomised controlled trials (RCTs) assessing the efficacy of licenced pharmacological therapies (alosetron, eluxadoline, ramosetron and rifaximin) in adults with IBS-D or IBS-M. Trials included in the analysis reported a dichotomous assessment of overall response to therapy, and data were pooled using a random effects model. Efficacy and safety of all pharmacological therapies were reported as a pooled relative risk with 95% CIs to summarise the effect of each comparison tested. Treatments were ranked according to their p score. Results We identified 18 eligible RCTs (seven alosetron, five ramosetron, two rifaximin and four eluxadoline), containing 9844 patients. All were superior to placebo for the treatment of IBS-D or IBS-M at 12 weeks, according to the Food and Drug Administration (FDA)-recommended endpoint for trials in IBS. Alosetron 1 mg twice daily was ranked first for efficacy, based on the FDA-recommended composite endpoint of improvement in both abdominal pain and stool consistency, effect on global symptoms of IBS and effect on stool consistency. Ramosetron 2.5µg once daily was ranked first for effect on abdominal pain. Total numbers of adverse events were significantly greater with alosetron 1 mg twice daily and ramosetron 2.5µg once daily, compared with placebo. Rifaximin 550 mg three times daily ranked first for safety. Constipation was significantly more common with all drugs, except rifaximin 550 mg three times daily. Conclusion In a network meta-analysis of RCTs of pharmacological therapies for IBS-D and IBS-M, we found all drugs to be superior to placebo, but alosetron and ramosetron appeared to be the most effective.