Review article: Current status and future directions of ingestible electronic devices in gastroenterology.

BACKGROUND: Advances in microelectronics have greatly expanded the capabilities and clinical potential of ingestible electronic devices. AIM: To provide an overview of the structure and potential impact of ingestible devices in development that are relevant to the gastrointestinal tract. METHODS: We performed a detailed literature search to inform this narrative review. RESULTS: Technical success of ingestible electronic devices relies on the ability to miniaturise the microelectronic circuits, sensors and components for interventional functions while being sufficiently powered to fulfil the intended function. These devices offer the advantages of being convenient and minimally invasive, with real-time assessment often possible and with minimal interference to normal physiology. Safety has not been a limitation, but defining and controlling device location in the gastrointestinal tract remains challenging. The success of capsule endoscopy has buoyed enthusiasm for the concepts, but few ingestible devices have reached clinical practice to date, partly due to the novelty of the information they provide and also due to the challenges of adding this novel technology to established clinical paradigms. Nonetheless, with ongoing technological advancement and as understanding of their potential impact emerges, acceptance of such technology will grow. These devices have the capacity to provide unique insight into gastrointestinal physiology and pathophysiology. Interventional functions, such as sampling of tissue or luminal contents and delivery of therapies, may further enhance their ability to sharpen gastroenterological diagnoses, monitoring and treatment. CONCLUSIONS: The development of miniaturised ingestible microelectronic-based devices offers exciting prospects for enhancing gastroenterological research and the delivery of personalised, point-of-care medicine.

Comparison of gastrointestinal landmarks using the gas-sensing capsule and wireless motility capsule.

BACKGROUND: Accurate definition of the gastroduodenal and ileocaecal junctions (GDJ, ICJ) is essential for the measurement of regional transit times. AIMS: To compare the assessment of these landmarks using the novel gas-sensing capsule and validated wireless motility capsule (WMC), and to evaluate intra-subject variance in transit times METHODS: Healthy subjects ingested the gas-sensing capsule and WMC tandemly in random order. Inter-observer agreement was evaluated by intra-class correlation coefficient (ICC). Agreement between the paired devices' transit times was assessed using Bland-Altman analysis; coefficient of variation was performed to express intra-individual variance in transit times. Similar analyses were completed with tandemly ingested gas-sensing capsules. RESULTS: The inter-observer agreement for landmarks for both capsules was excellent (mean ICC ≥0.97) in 50 studies. The GDJ was identifiable in 92% of the gas-sensing capsule studies versus 82% of the WMC studies (p = 0.27); the ICJ in 96% versus 84%, respectively (p = 0.11). In the primary cohort (n = 26), median regional transit times differed by less than 6 min between paired capsules. Bland-Altman revealed a bias of -0.12 (95% limits of agreement, -0.94 to 0.70) hours for GDJ and - 0.446 (-2.86 to 2.0) hours for ICJ. Similar results were found in a demographically distinct validation cohort (n = 24). For tandemly ingested gas-sensing capsules, coefficients of variation of transit times were 11%-35%, which were similar to variance between the paired gas-sensing capsule and WMC, as were the biases. The capsules were well tolerated. CONCLUSIONS: Key anatomical landmarks are accurately identified with the gas-sensing capsule in healthy individuals. Intra-individual differences in transit times between capsules are probably due to physiological factors. Studies in populations with gastrointestinal diseases are now required.

Hypermobile Ehlers-Danlos syndrome and disorders of the gastrointestinal tract: What the gastroenterologist needs to know.

BACKGROUND AND AIM: Hypermobile Ehlers-Danlos syndrome (hEDS) and the hypermobility spectrum disorders (HSD) can be challenging to diagnose and manage. Gastrointestinal symptoms and disorders of gut-brain interaction are common in this cohort and multifactorial in origin. The primary aim of this review is to arm the gastroenterologist with a clinically useful understanding of HSD/hEDS, by exploring the association of gastrointestinal disorders with HSD/hEDS, highlighting current pathophysiological understanding and providing a pragmatic approach to managing these patients. METHODS: Literature relevant to the gastrointestinal system and hypermobile Ehlers-Danlos syndrome was systematically searched, critically appraised, and summarized. RESULTS: Diagnosis is based upon clinical criteria and a genetic basis is yet to be defined. The prevalence of many gut symptoms, including abdominal pain (69% vs 27%, P < 0.0001), postprandial fullness (34% vs 16%, P = 0.01), constipation (73% vs 16%, P < 0.001), and diarrhea (47% vs 9%, P < 0.001) are significantly higher in HSD/hEDS compared with non-HSD/hEDS individuals. Disorders of gut-brain interaction are also common, particularly functional dyspepsia. The pathophysiology of gut symptoms is poorly understood but may involve effects of connective tissue laxity and its functional consequences, and the influence of autonomic dysfunction, medication and comorbid mental health disorders. Awareness is the key to early diagnosis. Management is limited in evidence-base but ideally should include an integrated multidisciplinary approach. CONCLUSIONS: HSD/hEDS is a multisystemic disorder in which gastrointestinal symptoms, particularly related to disorders of gut-brain interaction are common. Deficiencies in knowledge regarding the pathophysiological processes limit evidence-based interventions and remain important areas for future research.

Abnormal Perception of Urge to Defecate: An Important Pathophysiological Mechanism in Women With Chronic Constipation.

INTRODUCTION: Although the association of absent or attenuated "call to stool" with constipation is well-recognized, no studies have systematically evaluated the perception of urge to defecate in a well-defined cohort of patients with chronic constipation (CC). METHODS: A prospective study of 43 healthy adult women and 140 consecutive adult women attending a tertiary center for investigation of CC. All participants completed a 5-day viscerosensory questionnaire, and all women with CC also underwent anorectal physiologic investigations. Normal urge perception and abnormal urge perception were defined using a Naive Bayes model trained in healthy women (95% having normal urge). RESULTS: In total, 181 toilet visits in healthy women and 595 in women with CC were analyzed. Abnormal urge perception occurred in 70 (50.0%) women with CC. In this group, the urge to defecate was more often experienced as abdominal sensation (69.3% vs 41.4%; P < 0.0001), and the viscerosensory referral area was 81% larger (median pixels anterior: 1,849 vs 1,022; P < 0.0001) compared to women with CC and normal urge perception. Abnormal (vs normal) urge in women with CC was associated with more severe constipation (Cleveland Clinic constipation score: 19 vs 15 P < 0.0001), irritable bowel syndrome (45.7% vs 22.9% P < 0.0001), and a functional evacuation disorder on defecography (31.3% vs 14.3% P = 0.023). A distinct pattern of abnormal urge was found in women with CC and rectal hyposensitivity. DISCUSSION: Abnormal urge perception was observed in 50% of women with CC and was frequently described as abdominal sensation, supporting the concept that sensory dysfunction makes an important contribution to the pathophysiology of constipation.

Development and Validation of the Gastrointestinal Unhelpful Thinking Scale (GUTs): A Brief Self-Report Measure for Clinical and Research Settings.

This article describes the development and validation of the Gastrointestinal Unhelpful Thinking scale. The purpose of the research was to develop the Gastrointestinal Unhelpful Thinking scale to assess in tandem the primary cognitive-affective drivers of brain-gut dysregulation, gastrointestinal-specific visceral anxiety, and pain catastrophizing. The research involved 3 phases which included undergraduate and community samples. In the first phase, an exploratory factor analysis revealed a 15-item 2-factor (visceral sensitivity and pain catastrophizing) scale (N= 323), which then was confirmed in the second phase: N = 399, χ2(26) = 2.08, p = .001, Tucker-Lewis Index = 0.94, comparative fit index = 0.96, standardized root mean square residual = 0.05, and root mean square error of approximation = 0.07. Demonstrating convergent validity, Gastrointestinal Unhelpful Thinking scale total and subscales were strongly correlated with the modified Manitoba Index, Irritable Bowel Syndrome Symptom Severity Scale scores, Visceral Sensitivity Index, and the Pain Catastrophizing Scale. A third phase (N = 16) established test-retest reliability for the Gastrointestinal Unhelpful Thinking scale (total and subscales). The test-retest reliability correlation coefficient for the Gastrointestinal Unhelpful Thinking scale total score was .93 (p < .001) and for the subscales was .86 (p < .001) and .94 (p < .001), respectively. The Gastrointestinal Unhelpful Thinking scale is a brief psychometrically valid measure of visceral anxiety and pain catastrophizing that can be useful for both clinicians and researchers who wish to measure these thinking patterns and relate them to changes in gastrointestinal and psychological symptoms.

Clinical Impact of Rectal Hyposensitivity: A Cross-Sectional Study of 2,876 Patients With Refractory Functional Constipation.

INTRODUCTION: Normal bowel function requires intact sensory pathways. Diminished rectal sensation (rectal hyposensitivity [RH]) is associated with constipation, although its clinical importance remains unclear. METHODS: Consecutive patients (aged 18-80) attending a tertiary center (2004-2016) for investigation of refractory functional constipation (Rome IV core criteria defined, applied post hoc) were included. Patients completed a clinical symptom questionnaire and underwent anorectal physiologic investigations, including rectal sensory testing (balloon distension) to determine 3 well-established sensory thresholds. Multivariate regression analyses were performed to evaluate associations between RH, symptomology, and allied physiologic investigations. RESULTS: Of 2,876 patients meeting inclusion criteria, 722 (25%) had RH based on ≥1 elevated sensory thresholds (0: n = 2,154 [74.9%]; 1: n = 327 [11.4%]; 2: n = 209 [7.3%]; and 3: n = 186 [6.5%]). A linear relationship existed between increasing number of elevated sensory thresholds and constipation severity (Cleveland Clinic constipation score: mean difference per threshold [95% confidence interval] 0.69 [0.48-0.90]; P < 0.001). Several symptoms were significantly (P < 0.05) associated with RH including: infrequent defecation (odds ratio 1.29 [1.17-1.42]), painful evacuation (1.15 [1.05-1.27]), prolonged toileting (1.14 [1.05-1.24]), and digitation or enema use (1.18 [1.08-1.30]). On defecography, a "functional" evacuation disorder was also associated with RH (1.37 [1.25-1.50], P < 0.001), as was megarectum (2.52 [2.08-3.05], P < 0.001). DISCUSSION: RH occurs in 25% of patients with refractory functional constipation. Increased number of elevated sensory thresholds is associated with more severe constipation phenotype. These data, in the largest study to date, provide for the first time evidence to show that RH is a major pathophysiologic mechanism in constipation, with recognized clinical impact (http://links.lww.com/AJG/B765).(Equation is included in full-text article.).

Chronic constipation in adults: Contemporary perspectives and clinical challenges. 1: Epidemiology, diagnosis, clinical associations, pathophysiology and investigation.

BACKGROUND: Chronic constipation is a prevalent disorder that affects patients' quality of life and consumes resources in healthcare systems worldwide. In clinical practice, it is still considered a challenge as clinicians frequently are unsure as to which treatments to use and when. Over a decade ago, a Neurogastroenterology & Motility journal supplement devoted to the investigation and management of constipation was published (2009; 21 (Suppl.2)). This included seven articles, disseminating all themes covered during a preceding 2-day meeting held in London, entitled "Current perspectives in chronic constipation: a scientific and clinical symposium." In October 2018, the 3rd London Masterclass, entitled "Contemporary management of constipation" was held, again over 2 days. All faculty members were invited to author two new review articles, which represent a collective synthesis of talks presented and discussions held during this meeting. PURPOSE: This article represents the first of these reviews, addressing epidemiology, diagnosis, clinical associations, pathophysiology, and investigation. Clearly, not all aspects of the condition can be covered in adequate detail; hence, there is a focus on particular "hot topics" and themes that are of contemporary interest. The second review addresses management of chronic constipation, covering behavioral, conservative, medical, and surgical therapies.

Effects of fiber intake on intestinal pH, transit, and predicted oral mesalamine delivery in patients with ulcerative colitis.

BACKGROUND AND AIM: Limited data are available on the effects of fermentable fiber in altering intestinal pH and transit to predict efficacy-based delivery profiles of pH-dependent mesalamine coatings in ulcerative colitis (UC). This study aimed to examine regional pH and transit after acute changes in fermentable fiber intake in quiescent UC patients and their effects on drug release systems. METHODS: In a randomized, double-blind study, 18 patients with quiescent UC and 10 healthy controls were supplied meals high (13 g) or low (≤ 2 g) in fermentable fiber and subsequently ingested a wireless pH-motility capsule. After a ≥ 3-day washout, they crossed over to the other diet. Measurements of intestinal pH and transit were used to predict drug release for the various pH-dependent coatings. RESULTS: Increasing fermentable fiber intake lowered overall (median 6.2 [6.1-6.7] vs low: 6.9 [range or interquartile range: 6.4-7.4]; P = 0.01) and distal pH (7.8 [7.3-8.1] vs 8.2 [8.0-8.5]; P = 0.04) in controls. In UC patients, only cecal pH was decreased (high: 5.1 [4.8-5.5] vs low: 5.5 [5.3-5.7]; P < 0.01). Colonic transit in the UC cohort varied widely after a low-fiber intake but tended to normalize after the high fermentable fiber intake. Hypothetical coating dissolution profiles were heterogeneous in UC patients, with a multi-matrix delayed release system having the highest likelihood of patients (20-40%) with incomplete dissolution, and predominant small intestinal dissolution predicted for Eudragit L (94% patients) and S (44-69%). CONCLUSIONS: Patients with quiescent UC have abnormalities in intestinal pH and transit in response to acute changes in fermentable fiber intake. These have potentially detrimental effects on predicted luminal release patterns of pH-dependent 5-aminosalicylic acid release systems.

Randomised clinical trial: transabdominal interferential electrical stimulation vs sham stimulation in women with functional constipation.

BACKGROUND: Managing chronic constipation is challenging as patients frequently remain dissatisfied with laxative treatments. Novel studies using transabdominal electrical interferential therapy in children have shown benefit but there are inadequate adult studies. AIM: To examine the effects of transabdominal interferential stimulation on bowel symptoms and quality of life in women with refractory constipation. METHODS: In a single-blind, randomised, sham-controlled pilot study, women aged ≥18 years with refractory constipation were randomised to receive interferential stimulation (with crossing of electric currents) or a novel sham stimulation (with no crossing of currents) for 1 hour a day for 6 weeks. Primary outcome was the number of patients with ≥3 spontaneous bowel movements/week. Secondary endpoints included change in PAC-SYM (Patient Assessment of Constipation-SYMptoms), PAC-QOL (Patient Assessment of Constipation-Quality of Life) and an overall symptom severity score (measured at baseline, mid time point of stimulation, end of treatment and 3 months after cessation of treatment). RESULTS: Interferential therapy (n = 17) met the primary outcome in 9(53%) compared with 2(12%) with sham therapy (n = 16) (P = 0.02). Interferential therapy resulted in reductions in PAC-SYM (P = 0.03) and overall symptom scores (P = 0.05). Laxative use more than halved in 66% with interferential therapy compared with 14% with sham therapy (P = 0.01). Significant improvements in symptom outcomes were maintained at 3 months. There were no treatment-related adverse effects. CONCLUSION: Transabdominal interferential electrical stimulation is effective in reducing constipation in adult women. Three months after therapy, response is maintained and quality of life improved. Not allowing currents to cross intra-abdominally was an effective placebo. (Australianclinicaltrials.gov.au ACTRN12614000736640).

Chronic constipation and abdominal pain: Independent or closely interrelated symptoms?

Constipation is both a symptom and a disorder, seen in both functional constipation and irritable bowel syndrome with constipation predominance (IBS-C). Despite the Rome IV criteria distinguishing between these conditions, they share many therapeutic approaches. This review aims to explore the relationship between constipation and abdominal pain and assess the evidence surrounding whether laxation improves abdominal pain and whether such a response to laxation differs between IBS-C and functional constipation. In patients with functional constipation, increasing frequency of bowel motions by laxatives regardless of mechanism of action is associated with reductions in the severity of abdominal pain, supporting the role of constipation as a contributor to abdominal discomfort. In patients with IBS-C, evidence from systematic reviews indicates that abdominal pain is driven by factors additional to constipation alone and that visceral analgesic modulation is also needed to optimize pain. Changing definitions of IBS-C and heterogeneity in clinical trial design including endpoints have raised uncertainty about the comparative ability of older laxatives without known neuromodulatory effects to improve chronic abdominal pain compared with new secretagogues and prokinetics for the management of IBS-C. While it is known that abdominal pain is associated with constipation and laxation contributes to relief of that pain, it remains unproven whether proposed visceral analgesic properties of new laxatives provide greater pain relief than laxation alone. However, it is likely that the response to laxation in IBS-C is only part of the puzzle.

Intestinal gases: influence on gut disorders and the role of dietary manipulations.

The inner workings of the intestines, in which the body and microbiome intersect to influence gut function and systemic health, remain elusive. Carbon dioxide, hydrogen, methane and hydrogen sulfide, as well as a variety of trace gases, are generated by the chemical interactions and microbiota within the gut. Profiling of these intestinal gases and their responses to dietary changes can reveal the products and functions of the gut microbiota and their influence on human health. Indeed, different tools for measuring these intestinal gases have been developed, including newly developed gas-sensing capsule technology. Gases can, according to their type, concentration and volume, induce or relieve abdominal symptoms, and might also have physiological, pathogenic and therapeutic effects. Thus, profiling and modulating intestinal gases could be powerful tools for disease prevention and/or therapy. As the interactions between the microbiota, chemical constituents and fermentative substrates of the gut are principally influenced by dietary intake, altering the diet, which, in turn, changes gas profiles, is the main therapeutic approach for gastrointestinal disorders. An improved understanding of the complex interactions within the intestines that generate gases will enhance our ability to prevent, diagnose, treat and monitor many gastrointestinal disorders.

A Protocol-Driven Assessment Promotes a More Accurate Diagnosis of Irritable Bowel Syndrome.

A diverse range of conditions share symptoms commonly identified with irritable bowel syndrome. The objective of this study was to examine the diagnostic process in identifying additional diagnoses in women who are attending a clinic for evaluation of symptoms suggestive of irritable bowel syndrome. A retrospective audit was conducted of anonymous data gathered on consecutive female patients presenting to a specialist nurse-led service in Christchurch, New Zealand, with a provisional diagnosis of irritable bowel syndrome. A protocol containing routine pathology investigations and physical examination was used. Alarm features were identified and pertinent investigations were implemented. Rectocele was detected on rectal examination. Final diagnosis was noted and compared with baseline symptom data. Of 231 patients, 187 initially met Rome III criteria for irritable bowel syndrome. Red flags and abnormal investigations led to an alternate diagnosis in a further 27 patients. Of the 160 patients with irritable bowel syndrome, 31% were found to have a rectocele. They were seven times more likely to report a symptom associated with pelvic floor dysfunction (p < .0001) and four times more likely to report constipation (p = .0003). The use of a protocol including routine investigations and physical examination improves diagnostic yield. Pelvic floor dysfunction should be considered in those with unique symptom patterns and rectocele in the setting of irritable bowel syndrome.

The safety and sensitivity of a telemetric capsule to monitor gastrointestinal hydrogen production in vivo in healthy subjects: a pilot trial comparison to concurrent breath analysis.

BACKGROUND: Intestinal gases are currently used for the diagnosis of disorders including small intestinal bacterial overgrowth and carbohydrate malabsorption. AIM: To compare the performance of measuring hydrogen production within the gut directly with the telemetric gas-sensing capsule with that of indirect measurement through breath testing. METHODS: Using standard breath testing protocols, the capsules and breath tests were simultaneously evaluated in a single-blinded trial in 12 healthy subjects. Eight received a single dose of 1.25-40 g inulin and four 20 or 40 g glucose. Safety and reliability of the capsules were also assessed. RESULTS: There were no reported adverse events. All capsules were retrieved and operated without failure. Capsule measurements were in agreement with breath test measurements in magnitude but not in timing; minimal hydrogen production was observed after glucose ingestion and capsule measurements correlated with breath hydrogen after ingestion of 40 g inulin. A dose-dependent increase in concentration of hydrogen was observed from the capsule following ingestion of inulin as low as 1.25 g compared with >10 g for breath measurements. Specifically, the capsule measured >3000 times higher concentrations of hydrogen compared to breath tests, resulting in a signal-to-noise ratio of 23.4 for the capsule compared to 4.2 for the breath test. CONCLUSIONS: The capsule showed high sensitivity and signal-to-noise ratio in measuring luminal hydrogen concentrations, provided information on the site of intestinal gas production, and demonstrated safety and reliability. The capsule has potential for improving diagnostic precision for disorders such as small intestinal bacterial overgrowth.

Neuromodulation via Interferential Electrical Stimulation as a Novel Therapy in Gastrointestinal Motility Disorders.

The concept of therapeutic percutaneous neuromodulation has, until recently, been limited by the ability to penetrate deeply enough to stimulate internal organs. By utilizing 2 medium frequency, slightly out of phase electrical currents passing diagonally through the abdomen, a third, low frequency current is created at the point of bisection. This interferential current appears to stimulate nerve fibers in the target organs and may have a therapeutic action. The aim of the study is to review the use of transcutaneous interferential electrical stimulation with a focus on its application in gastroenterology, particularly in motility disorders. Studies involving use of interferential current therapy were searched from Medline, PubMed, and Scopus databases, and articles pertaining to history, its application and all those treating abdominal and gastrointestinal disorders were retrieved. Seventeen studies were identified, 13 involved children only. Eleven of these were randomised controlled trials (3 in adults). Four trials were from the one center, where each paper reported on different outcomes such as soiling, defecation frequency, quality of life, and colon transit studies from the one pool of children. All studies found statistically significant improvement in symptom reduction. However, weaknesses in study design were apparent in some. In particular, finding an adequate placebo to interferential current therapy has been difficult. Interferential current therapy shows potential as a novel, non-pharmacological and economical means of treating gastrointestinal dysfunction such as constipation. More studies are needed particularly in the adult population. However, the design of a suitable placebo is challenging.

Endometriosis in patients with irritable bowel syndrome: Specific symptomatic and demographic profile, and response to the low FODMAP diet.

BACKGROUND: Women with endometriosis are frequently misdiagnosed with irritable bowel syndrome (IBS) for some time before a correct diagnosis is made. Visceral hypersensitivity is a key feature in both conditions. AIMS: To determine if there are distinct symptom patterns in women with IBS and endometriosis, and to determine the response of these women to a low FODMAP diet in comparison to those with IBS alone. MATERIALS AND METHODS: A retrospective analysis of prospectively collected data from women attending a specialist IBS service in Christchurch New Zealand. Data from those who met Rome III criteria for IBS were sorted into two groups: concurrent endometriosis and those with IBS alone. Demographics and symptom patterns were identified from a prospective questionnaire. A low FODMAP (fermentable oligosaccharides, disaccharides, monosaccharides and polyols) diet was taught to all women as the primary therapeutic intervention. Responses to the diet were noted against their ultimate disposition. RESULTS: Of the 160 women who met Rome III criteria for IBS, 36% had concurrent endometriosis. The presence of dyspareunia (P > 0.0001), referred pain (P = 0.005), bowel symptoms exacerbated by menstruation (P = 0.0004) and a family history of endometriosis (P = 0.0003) were associated with concurrent endometriosis. Seventy two percent of these women reported a >50% improvement in bowel symptoms after four weeks of a low FODMAP diet compared with 49% in those with no known endometriosis (P = 0.001, odds ratio 3.11, 95% CI, 1.5-6.2). CONCLUSIONS: Women with concurrent endometriosis and IBS report a unique symptom phenotype. The low FODMAP diet appears effective in women with gut symptoms and endometriosis.