The national prevalence of disorders of gut brain interaction in the United Kingdom in comparison to their worldwide prevalence: Results from the Rome foundation global epidemiology study.

BACKGROUND: There are minimal epidemiological data comparing the burden of disorders of gut brain interaction (DGBI) in the UK with other countries. We compared the prevalence of DGBI in the UK with other countries that participated in the Rome Foundation Global Epidemiology Study (RFGES) online. METHODS: Participants from 26 countries completed the RFGES survey online including the Rome IV diagnostic questionnaire and an in-depth supplemental questionnaire with questions about dietary habits. UK sociodemographic and prevalence data were compared with the other 25 countries pooled together. KEY RESULTS: The proportion of participants with at least one DGBI was lower in UK participants compared with in the other 25 countries (37.6% 95% CI 35.5%-39.7% vs. 41.2%; 95% CI 40.8%-41.6%, p = 0.001). The UK prevalence of 14 of 22 Rome IV DGBI, including irritable bowel syndrome (4.3%) and functional dyspepsia (6.8%), was similar to the other countries. Fecal incontinence, opioid-induced constipation, chronic nausea and vomiting, and cannabinoid hyperemesis (p < 0.05) were more prevalent in the UK. Cyclic vomiting, functional constipation, unspecified functional bowel disorder, and proctalgia fugax (p < 0.05) were more prevalent in the other 25 countries. Diet in the UK population consisted of higher consumption of meat and milk (p < 0.001), and lower consumption of rice, fruit, eggs, tofu, pasta, vegetables/legumes, and fish (p < 0.001). CONCLUSIONS AND INFERENCES: The prevalence and burden of DGBI is consistently high in the UK and in the rest of the world. Opioid prescribing, cultural, dietary, and lifestyle factors may contribute to differences in the prevalence of some DGBI between the UK and other countries.

Gastrointestinal symptoms and nutritional issues in patients with hypermobility disorders: assessment, diagnosis and management.

Patients diagnosed with hypermobile Ehlers-Danlos syndrome and hypermobile spectrum disorders are increasingly presenting to secondary and tertiary care centres with gastrointestinal (GI) symptoms and nutritional issues. Due to the absence of specific guidance, these patients are investigated, diagnosed and managed heterogeneously, resulting in a growing concern that they are at increased risk of iatrogenic harm. This review aims to collate the evidence for the causes of GI symptoms, nutritional issues and associated conditions as well as the burden of polypharmacy in this group of patients. We also describe evidence-based strategies for management, with an emphasis on reducing the risk of iatrogenic harm and improving multidisciplinary team care.

Factors associated with strong opioid use for noncancer pain in patients with chronic intestinal failure.

BACKGROUND: Chronic analgesic use is described in home parenteral nutrition (HPN)-dependent patients, but there are limited data on factors associated with opioid use for noncancerous pain. METHODS: Patients attending a national UK intestinal failure reference center were divided in two groups according to strong opioid (SO) usage; risk factors for SO usage were analyzed using logistic regression. RESULTS: A total of 168 HPN-dependent patients were included. During the study period, 73 patients (43.5%) had documented SO usage (SO group), whereas the remainder did not (No-SO group). The prevalence of Crohn's disease among the No-SO group was twofold higher than among the SO group (43.2% vs 24.7%; P = 0.013), whereas those with surgical complications were twice as prevalent among the SO group (19.2% vs 8.4%, respectively; P = 0.04). The rate of working-age unemployment was significantly higher in the SO group (90.6%) than the No-SO group (55.6%; P = 0.001). Multivariate regression showed unemployment as an independent risk factor for SO usage (OR, 6.005; 95% CI, 1.435-25.134), whereas Crohn's disease (OR, 0.284; 95% CI, 0.09-0.898) and <4 intravenous support (IVS) nights per week (OR, 0.113; 95% CI, 0.012-1.009) were protective factors. The life-long incidence of catheter-related bloodstream infection (CRBSI) was comparable between groups (34.2% SO vs 27.4% No-SO; P = 0.336). CONCLUSION: SO use is frequent among HPN-dependent patients and associated with high rates of unemployment and ≥4 IVS nights per week, but not with increased rate of CRBSI. The reduced usage among patients with Crohn's disease warrants further evaluation but might be due to the chronicity as compared with other IF etiologies.

British Society of Gastroenterology guidelines on the management of functional dyspepsia.

Functional dyspepsia (FD) is a common disorder of gut-brain interaction, affecting approximately 7% of individuals in the community, with most patients managed in primary care. The last British Society of Gastroenterology (BSG) guideline for the management of dyspepsia was published in 1996. In the interim, substantial advances have been made in understanding the complex pathophysiology of FD, and there has been a considerable amount of new evidence published concerning its diagnosis and classification, with the advent of the Rome IV criteria, and management. The primary aim of this guideline, commissioned by the BSG, is to review and summarise the current evidence to inform and guide clinical practice, by providing a practical framework for evidence-based diagnosis and treatment of patients. The approach to investigating the patient presenting with dyspepsia is discussed, and efficacy of drugs in FD summarised based on evidence derived from a comprehensive search of the medical literature, which was used to inform an update of a series of pairwise and network meta-analyses. Specific recommendations have been made according to the Grading of Recommendations Assessment, Development and Evaluation system. These provide both the strength of the recommendations and the overall quality of evidence. Finally, in this guideline, we consider novel treatments that are in development, as well as highlighting areas of unmet need and priorities for future research.

Review article: current and future treatment approaches for pain in IBS.

BACKGROUND: Abdominal pain is a core symptom of IBS and a primary driver of care seeking. Visceral hypersensitivity is a key pathophysiological mechanism and therapeutic target for pain in IBS, with components of peripheral and central sensitisation and psychological factors. AIM: To review current and future treatment approaches specifically for the pain component of IBS. METHODS: Pubmed search terms included combinations of irritable bowel, pain, visceral hypersensitivity, novel, new, emerging, future and advances. RESULTS: Established non-pharmacological treatments for IBS pain include the low FODMAP diet, probiotics and psychological interventions, especially hypnotherapy. Tricyclics remain the best evidenced pharmacological approach with GCC agonists, tenapanor, lubiprostone, eluxadoline and 5HT3 antagonists second line according to patient characteristics and availability. Less well-evidenced current options include anti-spasmodics, peppermint oil, SSRIs, SNRIs, alpha 2 delta ligands, melatonin and histamine antagonists. Patients are vulnerable to iatrogenesis and harmful approaches to be avoided include opioids and unwarranted surgical interventions. For severe pain, the concept of augmentation with combined gut-brain neuromodulators and psychotherapy in a multi-disciplinary setting is considered. A plethora of molecular targets and ligands are emerging from pre-clinical studies, together with early clinical evidence for a range of pharmacological, dietary, neurostimulation and novel psychological treatment delivery methods which are reviewed. The history of such emerging approaches, however, merits both caution and optimism in equal measure. CONCLUSIONS: Despite good in-roads and emerging options, the management of abdominal pain remains one of the biggest challenges and research priorities for patients with IBS.

British Society of Gastroenterology guidelines on the management of irritable bowel syndrome.

Irritable bowel syndrome (IBS) remains one of the most common gastrointestinal disorders seen by clinicians in both primary and secondary care. Since publication of the last British Society of Gastroenterology (BSG) guideline in 2007, substantial advances have been made in understanding its complex pathophysiology, resulting in its re-classification as a disorder of gut-brain interaction, rather than a functional gastrointestinal disorder. Moreover, there has been a considerable amount of new evidence published concerning the diagnosis, investigation and management of IBS. The primary aim of this guideline, commissioned by the BSG, is to review and summarise the current evidence to inform and guide clinical practice, by providing a practical framework for evidence-based management of patients. One of the strengths of this guideline is that the recommendations for treatment are based on evidence derived from a comprehensive search of the medical literature, which was used to inform an update of a series of trial-based and network meta-analyses assessing the efficacy of dietary, pharmacological and psychological therapies in treating IBS. Specific recommendations have been made according to the Grading of Recommendations Assessment, Development and Evaluation system, summarising both the strength of the recommendations and the overall quality of evidence. Finally, this guideline identifies novel treatments that are in development, as well as highlighting areas of unmet need for future research.

Hydrogen and methane breath test results are negatively associated with IBS and may reflect transit time in post-surgical patients.

BACKGROUND: Contention surrounds hydrogen and methane breath tests as putative measures of small intestinal bacterial overgrowth. We aimed to explore the clinical characteristics associated with positive and negative results to help clarify their role. METHODS: 525 glucose hydrogen/methane breath tests completed over 3 years were analyzed to look for positively and negatively associated predictive factors. Characteristics such as height and weight and underlying medical conditions, medications, and surgical history were collated. KEY RESULTS: There were 85 and 42 positive hydrogen and methane tests, respectively. Patients with irritable bowel syndrome (IBS) (HR = 0.17, p = 0.004) and those with a higher body mass index (HR = 0.93, p = 0.004) were significantly less likely to have a positive test. Patients who underwent the test post-surgically were significantly more likely to have a positive test (HR = 2.76, p = 0.001). A sub-analysis of post-surgical patients by type and region of surgical resection demonstrated that none were statistically more likely than the next to have a positive test. However, for the surgical group as a whole the number of motility-depressing drugs taken (such as opioids) was associated with a significantly decreased likelihood of a positive test (HR = 0.752, p = 0.045). CONCLUSION: Our data suggest that patients with a diagnosis of IBS are statistically less likely to have a positive test and it is of limited utility in this group. Post-surgical patients are more likely to have a positive test, possibly secondary to fast transit rather than bacterial overgrowth, as suggested by a significantly negative association with motility-suppressing drugs in this sub-group.

Jejunal feeding: when is it the right thing to do?

The decision to commence jejunal feeding in patients with structural abnormalities, which prevent oral or intragastric feeding, is usually straightforward. However, decisions surrounding the need for jejunal feeding can be more complex in individuals with no clear structural abnormality, but rather with foregut symptoms and pain-predominant presentations, suggesting a functional origin. This appears to be an increasing issue in polysymptomatic patients with multi-system involvement. We review the differential diagnosis together with the limitations of available functional clinical tests; symptomatic management options to avoid escalation where possible including for patients on opioids; tube feeding options where necessary; and an approach to weaning from established jejunal feeding in the context of a multidisciplinary approach to minimise iatrogenesis.

The management of adult patients with severe chronic small intestinal dysmotility.

Adult patients with severe chronic small intestinal dysmotility are not uncommon and can be difficult to manage. This guideline gives an outline of how to make the diagnosis. It discusses factors which contribute to or cause a picture of severe chronic intestinal dysmotility (eg, obstruction, functional gastrointestinal disorders, drugs, psychosocial issues and malnutrition). It gives management guidelines for patients with an enteric myopathy or neuropathy including the use of enteral and parenteral nutrition.

An international survey on clinicians' perspectives on the diagnosis and management of chronic intestinal pseudo-obstruction and enteric dysmotility.

BACKGROUND: Chronic intestinal pseudo-obstruction (CIPO) and enteric dysmotility (ED) are small intestinal motility disorders defined by radiological and manometric criteria. In the absence of consensus guidelines, we surveyed opinions on the diagnosis and management of CIPO and ED among experts from different countries. METHODS: A survey questionnaire was circulated electronically to members of the European society for Clinical Nutrition and Metabolism, European Society of Neurogastroenterology and Motility, and United European Gastroenterology. Only responses from participants completing all required components were included. KEY RESULTS: Of 154 participants, 93% agreed that CIPO and ED should be classified separately. Overall, 73% reported an increasing incidence of CIPO and ED, with hypermobile Ehlers-Danlos Syndrome the group with the largest increase in referrals (37%), particularly in the UK (P < .0001). The majority (95%) find diagnosing CIPO and ED difficult. Notably, antroduodenal manometry, a test mandated to diagnose ED, is infrequently used (only 21% respondents use in >50% cases) and full thickness biopsies were reported to seldom influence medical treatment, nutritional management, and prognosis. Respondents reported that very few treatments are useful for most patients, with bacterial overgrowth treatment, prucalopride, and psychological therapies felt to be the most useful. While only 23% of clinicians felt that parenteral nutrition (PN) improves gastrointestinal symptoms in >50% of cases, 68% reported PN dependency at 5 years in the majority of cases. CONCLUSIONS AND INFERENCES: These data highlight the difficulties with diagnosing and managing CIPO and ED and underscore the urgent need for international, multidisciplinary, clinical practice guidelines.

Chronic continuous abdominal pain: evaluation of diagnostic features, iatrogenesis and drug treatments in a cohort of 103 patients.

BACKGROUND: Chronic continuous abdominal pain (CCAP) is characteristic of centrally mediated gastrointestinal pain disorders. It consumes significant healthcare resources yet is poorly understood, with minimal cohort-specific data in the literature. AIMS: To examine in a large cohort of CCAP patients, (a) diagnostic features, (b) iatrogenic impact of opioids and surgery, (c) drug treatment effects and tolerance. METHODS: Consecutive tertiary CCAP referrals to a neurogastroenterology clinic (2009-2016) were reviewed for Rome IV and neuropathic pain criteria. Medical, surgical and drug histories, interventions and outcomes were correlated with clinical diagnosis and associated opioid use. RESULTS: Of 103 CCAP patients (mean age 40 ± 14, 85% female), 50% had physiological exacerbations precluding full Rome IV Centrally Mediated Abdominal Pain Syndrome criteria. However, there were no significant differences between patients who satisfied Rome IV criteria and those who did not. Overall, 81% had allodynia (a nonpainful stimulus evoking pain sensation). Opioid use was associated with allodynia (P = 0.003). Prior surgery was associated with further operations post CCAP onset (P < 0.001). Although 68% had undergone surgical interventions, surgery did not resolve pain in any patient and worsened pain in 35%. Whilst duloxetine was the most effective neuromodulator (P = 0.003), combination therapy was superior to monotherapy (P = 0.007). CONCLUSIONS: This is currently the largest cohort CCAP dataset that supports eliciting neuropathic features, including allodynia, for a positive clinical diagnosis, to guide treatment. Physiological exacerbation of CCAP may represent visceral allodynia, and need not preclude central origin. Use of centrally acting neuromodulators, and avoidance of detrimental opioids and surgical interventions appear to predict favourable outcomes.

The chronic intestinal pseudo-obstruction subtype has prognostic significance in patients with severe gastrointestinal dysmotility related intestinal failure.

BACKGROUND & AIMS: Severe gastrointestinal dysmotility (GID) is a significant cause of chronic intestinal failure (CIF) with unclear benefits of sub-classifying into Chronic Intestinal Pseudo-obstruction (CIPO) and non-CIPO sub-types. We compared outcomes between CIPO and non-CIPO sub-types in a tertiary cohort of patients with CIF resulting from severe GID. METHODS: Adults with primary GID, commenced on home parenteral nutrition (HPN) over a 16-year period at a national referral centre, were included. All patients satisfied GID clinical criteria which mandated evidence of small bowel involvement either objectively (abnormal antroduodenal manometry) or pragmatically (failure to progress on small bowel feeding). Clinical outcomes including HPN dependency and survival were compared between CIPO and non-CIPO sub-types. RESULTS: Patients with primary GID requiring HPN (n = 45, age 38 ± 2, 33 females, 23/45 (51%) CIPO, 22/45 (49%) non-CIPO) were included. Patients with CIPO had more surgical interventions (P = 0.03), higher incidence of bacterial overgrowth (P = 0.006), greater parenteral energy (P = 0.02) and volume requirements (P = 0.05). Overall, during a mean 6 years' follow-up, 36/45 (80%) patients remained HPN dependent. Multivariate analyses confirmed that the non-CIPO sub-type (P = 0.04) and catheter related blood stream infections/1000 days (P = 0.01) were predictive factors for time to discontinuing HPN. Overall 5-year survival on HPN was 85%, with no difference between sub-types (P = 0.83). CONCLUSIONS: The CIPO sub-type is associated with higher HPN dependency and should be recognized as a separate entity in severe GID. In multidisciplinary settings with continuous close monitoring of risks and benefits, our data confirm HPN is a safe, life-preserving therapy in severe GID related CIF.

Obeticholic acid for severe bile acid diarrhea with intestinal failure: A case report and review of the literature.

Bile acid diarrhea results from excessive amounts of bile acids entering the colon due to hepatic overexcretion of bile acids or bile acid malabsorption in the terminal ileum. The main therapies include bile acid sequestrants, such as colestyramine and colesevelam, which may be given in combination with the opioid receptor agonist loperamide. Some patients are refractory to conventional treatments. We report the use of the farnesoid X receptor agonist obeticholic acid in a patient with refractory bile acid diarrhea and subsequent intestinal failure. A 32-year-old woman with quiescent colonic Crohn's disease and a normal terminal ileum had been diagnosed with severe bile acid malabsorption and complained of watery diarrhea and fatigue. The diarrhea resulted in hypokalemia and sodium depletion that made her dependent on twice weekly intravenous fluid and electrolyte infusions. Conventional therapies with colestyramine, colesevelam, and loperamide had no effect. Second-line antisecretory therapies with pantoprazole, liraglutide, and octreotide also failed. Third-line treatment with obeticholic acid reduced the number of stools from an average of 13 to an average of 7 per 24 h and improved the patient's quality of life. The fluid and electrolyte balances normalized. The effect was sustained during follow-up for 6 mo with treatment at a daily dosage of 25 mg. The diarrhea worsened shortly after cessation of obeticholic acid. This case report supports the initial report that obeticholic acid may reduce bile acid production and improve symptoms in patients with bile acid diarrhea.

Endoscopic closure of a refractory gastrocutaneous fistula using a novel over-the-scope Padlock clip following de-epithelialisation of the fistula tract.

Persistent gastrocutaneous fistula (GCF) is a difficult to manage complication following gastrostomy tube removal, with leakage resulting in distressing sequelae including cutaneous injury, infection and dehydration. Many such patients are high-risk for invasive surgery and, to date, endoscopic closure techniques, including clipping systems, have limitations. We present the case of a 62-year-old woman with persistently leaking GCF 6 months postgastrostomy tube removal, despite maximal antisecretory therapy and postpyloric feeding, and describe failed attempted endoscopic closure with conventional clips. Treatment options were discussed and informed consent was given for an attempt at endoscopic closure using a novel radial closure device ('Padlock clip') combined with surgical de-epithelialisation, with the understanding that this device has never previously been used in this setting. At follow-up 2 weeks postprocedure, the patient was asymptomatic with complete healing of the GCF. This approach has advantages over other endoscopic closure techniques and can be considered as an alternative approach to GCF closure.

Quantifying bile acid malabsorption helps predict response and tailor sequestrant therapy.

Although recognised as a cause of chronic diarrhoea for over forty years, diagnostic tests and treatments for bile acid malabsorption (BAM) remain controversial. Recent National Institute for Health and Care Excellence (NICE) guidelines highlighted the lack of evidence in the field, and called for further research. This retrospective study explores the BAM subtype and severity, the use and response to bile acid sequestrants (BAS) and the prevalence of abnormal colonic histology. 264 selenium-75-labelled homocholic acid conjugated taurine (SeHCAT)-tested patient records were reviewed and the severity and subtype of BAM, presence of colonic histopathology and response to BAS were recorded. 53% of patients tested had BAM, with type-2 BAM in 45% of patients with presumed irritable bowel syndrome. Colonic histological abnormalities were similar overall between patients with (29%) or without (23%) BAM (p = 0.46) and between BAM subtypes, with no significant presence of inflammatory changes. 63% of patients with BAM had a successful BAS response which showed a trend to decreased response with reduced severity. Colestyramine was unsuccessful in 44% (38/87) and 45% of these (17/38) were related to medication intolerance, despite a positive SeHCAT. 47% (7/15) of colestyramine failures had a successful colesevelam response. No patient reported colesevelam intolerance. Quantifying severity of BAM appears to be useful in predicting BAS response. Colesevelam was better tolerated than colestyramine and showed some efficacy in colestyramine failures. Colestyramine failure should not be used to exclude BAM. Colonic histology is of no relevance.

Modulation of human visceral sensitivity by noninvasive magnetoelectrical neural stimulation in health and irritable bowel syndrome.

Visceral pain is a particularly difficult symptom to manage in patients with irritable bowel syndrome (IBS). Our aim was to examine whether noninvasive neurostimulation applied to the motor cortex or lumbosacral region can modulate human visceral sensation. Sixteen healthy adult volunteers and 10 patients with IBS were evaluated. Single-pulse lumbosacral magnetic stimulation (LSMS) or transcranial magnetic stimulation (TMS) was used to assess spinal root and cortical excitability as well as the effect of neurostimulation on anorectal sensation and pain, which were provoked by a local electrical stimulus. Initially, healthy volunteers received 6 stimulation paradigms in a randomised order (3 repetitive LSMS [1 Hz, 10 Hz, and sham]) and 3 repetitive TMS (1 Hz, 10 Hz, and sham) to investigate the effects on neural function and visceral sensation over 1 hour. The most effective cortical and spinal interventions were then applied in patients with IBS. Only 1-Hz rLSMS altered healthy anal motor excitability, increasing spinal (58 ± 12.3 vs 38.5 ± 5.7 µV, P = 0.04) but not cortical responses. Both 1-Hz rLSMS and 10-Hz repetitive transcranial magnetic stimulation increased healthy rectal pain thresholds for up to an hour after intervention (P < 0.05). When applied to patients with IBS, rectal pain thresholds were increased across all time points after both 1-Hz rLSMS and 10-Hz repetitive transcranial magnetic stimulation (P < 0.05) compared with sham. The application of magnetoelectric stimuli to the cortical and lumbosacral areas modulates visceral sensation in healthy subjects and patients with IBS. This proof-of-concept study provides supportive evidence for neurostimulation in managing functional gastrointestinal disorders.

Normal values and reproducibility of the real-time index of vagal tone in healthy humans: a multi-center study.

BACKGROUND: The parasympathetic nervous system has been implicated in the pathogenesis of a number of gastrointestinal disorders including irritable bowel syndrome. Within the field, cardiometric parameters of parasympathetic/vagal tone are most commonly derived from time, or frequency, domain analysis of heart rate variability (HRV), yet it has limited temporal resolution. Cardiac vagal tone (CVT) is a non-invasive beat-to-beat measure of brainstem efferent vagal activity that overcomes many of the temporal limitations of HRV parameters. However, its normal values and reproducibility in healthy subjects are not fully described. The aim of this study was to address these knowledge gaps. METHODS: 200 healthy subjects (106 males, median age 28 years, range 18-59 years) were evaluated across three study centers. After attachment of CVT recording equipment, 20 min of data (resting/no stimulation) was acquired. 30 subjects, selected at random, were restudied after 1 year. RESULTS: The mean CVT was 9.5±4.16 linear vagal scale (LVS). Thus, the normal range (mean±2 standard deviations) for CVT based on this data was 1.9-17.8 LVS. CVT correlated negatively with heart rate (r=-0.6, P=0.001). CVT reproducibility over 1 year, as indexed by an intra-class correlational coefficient of 0.81 (95% confidence interval 0.64-0.91), was good. CONCLUSIONS: In healthy subjects, the normal range for CVT should be considered to be 1.9-17.8 LVS and is reproducible over 1 year. Future research utilizing CVT should refer to these values although further study is warranted in patient groups.