Coffee, Alcohol, and Artificial Sweeteners Have Temporal Associations with Gastrointestinal Symptoms.

BACKGROUND: Various dietary strategies for managing irritable bowel syndrome (IBS) target mechanisms such as brain-gut interactions, osmotic actions, microbial gas production, and local immune activity. These pathophysiological mechanisms are diverse, making it unclear which foods trigger IBS symptoms for a substantial proportion of patients. AIM: To identify associations between foods and gastrointestinal symptoms. METHODS: From the mySymptoms smartphone app, we collected anonymized diaries of food intake and symptoms (abdominal pain, diarrhea, bloating, and gas). We selected diaries that were at least 3 weeks long. The diaries were analyzed for food-symptom associations using a proprietary algorithm. As the participants were anonymous, we conducted an app-wide user survey to identify IBS diagnoses according to Rome IV criteria. RESULTS: A total of 9,710 food symptom diaries that met the quality criteria were collected. Of the survey respondents, 70% had IBS according to Rome IV criteria. Generally, strong associations existed for caffeinated coffee (diarrhea, 1-2 h postprandial), alcoholic beverages (multiple symptoms, 4-72 h postprandial), and artificial sweeteners (multiple symptoms, 24-72 h postprandial). Histamine-rich food intake was associated with abdominal pain and diarrhea. Some associations are in line with existing literature, whilst the absence of an enriched FODMAP-symptom association contrasts with current knowledge. CONCLUSIONS: Coffee, alcohol, and artificial sweeteners were associated with GI symptoms in this large IBS-predominant sample. Symptom onset is often within 2 h postprandial, but some foods were associated with a delayed response, possibly an important consideration in implementing dietary recommendations. Clinical trials must test the causality of the demonstrated food-symptom associations.

New insights into the characterization of the mechanism of action of hyoscine butylbromide in the human colon ex vivo.

INTRODUCTION: Hyoscine butylbromide (HBB) is one of the most used antispasmodics in clinical practice. Recent translational consensus has demonstrated a similarity between human colonic motor patterns studied ex vivo and in vivo, suggesting ex vivo can predict in vivo results. It is unclear whether the mechanism of action of antispasmodics can predict different use in clinical practice. The aim of the present study is to bridge this gap dissecting HBB's role in excitatory and inhibitory neural pathways. METHODS: 309 colon samples from 48 patients were studied in muscle bath experiments. HBB was tested on: 1-spontaneous phasic contractions (SPCs); 2-carbachol-induced contractility; electrical field stimulation (EFS)-induced selective stimulation of 3-excitatory and 4-inhibitory pathways and 5- SPCs and EFS-induced contractions enhanced by neostigmine. Atropine, AF-DX116 (M2 blocker) and DAU-5884 (M3 blocker) were used as comparators. RESULTS: In the presence of tetrodotoxin (TTX), HBB and atropine 1 µM reduced SPCs. HBB and atropine concentration-dependently reduced carbachol- and EFS-induced contractions. Inhibitory effects of DAU-5884 on EFS-induced contractions were more potent than of AF-DX116. HBB did not affect the off-response associated to neural inhibitory responses. Neostigmine enhanced both SPCs and EFS-induced contractions. In the presence of TTX and ω-conotoxin (GVIA), neostigmine still enhanced SPCs. Addition of HBB and atropine reduced these responses. CONCLUSIONS: This study demonstrates that HBB inhibits neural cholinergic contractions associated to muscarinic (mainly M3) receptors. HBB has a potential role in reducing colonic spasm induced by the release of acetylcholine from enteric motor neurons and from an atypical source including a potential non-neuronal origin.

Perceptions, Definitions, and Therapeutic Interventions for Occasional Constipation: A Rome Working Group Consensus Document.

BACKGROUND & AIMS: Functional constipation is the most common of the disorders of gut-brain interaction, affecting approximately 12% of the world population. Although classically considered a chronic condition, many individuals experience shorter yet repetitive bouts of constipation representing a different clinical entity. There has been increased interest in this latter disorder, which has recently been classified as occasional constipation. This Rome Foundation working group document reflects the consensus of an international team of specialists who summarized currently available research to provide a working definition of and treatment algorithm for occasional constipation. The recommendations herein are based on current evidence, accounting for gaps in the literature as well as international variance in definitions and health seeking behaviors for constipation. METHODS: The committee members reviewed the scientific literature, focusing specifically on occasional constipation, with the understanding that as a new entity, a paucity of data would be available. We used Rome IV research and clinical definitions to establish the framework for our definition of occasional constipation. Where possible, treatment recommendations were determined on the basis of the earliest extractable data from functional constipation studies, focusing on positive results within the first 2 weeks of treatment. We used the Delphi method to create consensus with 100% agreement between the authors. RESULTS: An evidence-based review of the literature resulted in the definition of occasional constipation as follows: "individuals who experience the presence of at least 1 functional constipation symptom, in the absence of alarm signs or symptoms, occurring at irregular and infrequent intervals, which is bothersome enough to induce a patient to seek medical management." Medical management whether seeking medical care or self-treatment was left to the individual's discretion, and we did not include time anchors because these thresholds require further investigation. Polyethylene glycol and stimulant laxatives are recommended as first-line interventions, whereas magnesium-containing compounds are suggested in individuals failing to respond to these therapies. There are insufficient data to make recommendations for using fiber or stool softeners. Prescription laxatives should be reserved for individuals with chronic constipation. CONCLUSIONS: Occasional constipation is a unique clinical entity characterized by infrequent but recurrent symptoms. Data are limited because consensus definitions have been lacking. Establishing a standardized definition and therapeutic recommendations provides a framework for future studies focusing on epidemiologic and symptoms-based outcomes. Further studies are needed to confirm and refine these recommendations.

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.

Randomised, placebo-controlled trial and meta-analysis show benefit of ondansetron for irritable bowel syndrome with diarrhoea: The TRITON trial.

BACKGROUND: Ondansetron may be beneficial in irritable bowel syndrome with diarrhoea (IBS-D). AIM: To conduct a 12-week parallel group, randomised, double-blind, placebo-controlled trial of ondansetron 4 mg o.d. (titrated up to 8 mg t.d.s.) in 400 IBS-D patients. PRIMARY ENDPOINT: % responders using the Food and Drug Administration (FDA) composite endpoint. Secondary and mechanistic endpoints included stool consistency (Bristol Stool Form Scale) and whole gut transit time (WGTT). After literature review, results were pooled with other placebo-controlled trials in a meta-analysis to estimate relative risks (RR), 95% confidence intervals (CIs) and number needed to treat (NNT). RESULTS: Eighty patients were randomised. On intention-to-treat analysis, 15/37 (40.5%; 95% CI 24.7%-56.4%) met the primary endpoint on ondansetron versus 12/43 (27.9%; 95% CI 14.5%-41.3%) on placebo (p = 0.19). Ondansetron improved stool consistency compared with placebo (adjusted mean difference - 0.7; 95% CI -1.0 to-0.3, p < 0.001). Ondansetron increased WGTT between baseline and week 12 (mean (SD) difference 3.8 (9.1) hours, versus placebo -2.2 (10.3) hours, p = 0.01). Meta-analysis of 327 patients from this, and two similar trials, demonstrated ondansetron was superior to placebo for the FDA composite endpoint (RR of symptoms not responding = 0.86; 95% CI 0.75-0.98, NNT = 9) and stool response (RR = 0.65; 95% CI 0.52-0.82, NNT = 5), but not abdominal pain response (RR = 0.95; 95% CI 0.74-1.20). CONCLUSIONS: Although small numbers meant the primary endpoint was not met in this trial, when pooled with other similar trials meta-analysis suggests ondansetron improves stool consistency and reduces days with loose stool and urgency. Trial registration - http://www.isrctn.com/ISRCTN17508514.

A comparative, randomised MRI study of the physiological and appetitive responses to gelling (alginate) and non-gelling nasogastric tube feeds in healthy men.

Inclusion in nasogastric tube feeds (NGTF) of acid-sensitive, seaweed-derived alginate, expected to form a reversible gel in the stomach, may create a more normal intragastric state and modified gastrointestinal responses. This may ameliorate NGTF-associated risk of diarrhoea, upper gastrointestinal symptoms and appetite suppression. In a randomised, crossover, comparison study, undertaken in twelve healthy males, an alginate-containing feed (F + ALG) or one that was alginate-free (F-ALG) (300 ml) was given over 1 h with a 7-14-d washout period between treatments. Baseline and for 4-h post-feed initiation, MRI measurements were made to establish small bowel water content (SBWC), gastric contents volume (GCV) and appearance, and superior mesenteric artery blood flux. Blood glucose and gut peptides were measured. Subjective appetite and upper gastrointestinal symptoms scores were obtained. Ad libitum pasta consumption 3-h post-feeding was measured. F + ALG exhibited a gastric appearance consistent with gelling surrounded by a freely mobile water halo. Significant main effects of feed were seen for SBWC (P = 0·03) and peptide YY (PYY) (P = 0·004) which were attributed to generally higher values for SBWC with F + ALG (max difference between adjusted means 72 ml at 210 min) and generally lower values for PYY with F + ALG. GCV showed a faster reduction with F + ALG, less between-participant variation and a feed-by-time interaction (P = 0·04). Feed-by-time interactions were also seen with glucagon-like-peptide 1 (GLP-1) (P = 0·02) and glucose-dependent insulinotropic polypeptide (GIP) (P = 0·002), both showing a blunted response with F + ALG. Apparent intragastric gelling with F + ALG and subsequent differences in gastrointestinal and endocrine responses have been demonstrated between an alginate-containing and alginate-free feed.

Exploring Pharmacological Treatments for Chronic Idiopathic Constipation in Adults: A Look Back to the Future.

Despite great progress in pharmaceutical research, the medical treatment of chronic idiopathic constipation is far from ideal. The aim of the present article was to review literature data, focusing on poorly studied or commercially unavailable/unapproved drugs potentially useful for the treatment of chronic idiopathic constipation in adults. An extensive online literature search was conducted using the keywords "chronic constipation", "colon", "constipation", "drugs", "laxatives", and "treatment", in various combinations between January 1960 and December 2022. The literature search showed the presence of some drugs whose efficacy has only recently been demonstrated by modern investigations, and which are likely to be incorporated into future guidelines, of others that are proven effective and potentially effective on constipated patients but limited by small or relatively old studies, or by side effects which could be used in experienced hands, and of others that might be useful but lack a solid scientific background. Looking into the future for patients with chronic constipation might add some more tools to the therapeutic portfolio, especially for certain subgroups of these patients.

Italian guidelines for the management of irritable bowel syndrome: Joint Consensus from the Italian Societies of: Gastroenterology and Endoscopy (SIGE), Neurogastroenterology and Motility (SINGEM), Hospital Gastroenterologists and Endoscopists (AIGO), Digestive Endoscopy (SIED), General Medicine (SIMG), Gastroenterology, Hepatology and Pediatric Nutrition (SIGENP) and Pediatrics (SIP).

The irritable bowel syndrome (IBS) is a chronic disorder of gut-brain interaction. IBS is still associated with areas of uncertainties, especially regarding the optimal diagnostic work-up and the more appropriate management. Experts from 7 Italian Societies conducted a Delphi consensus with literature summary and voting process on 27 statements. Recommendations and quality of evidence were evaluated using the grading of recommendations, assessment, development, and evaluation (GRADE) criteria. Consensus was defined as >80% agreement and reached for all statements. In terms of diagnosis, the consensus supports a positive diagnostic strategy with a symptom-based approach, including the psychological comorbidities assessment and the exclusion of alarm symptoms, together with the digital rectal examination, full blood count, C-reactive protein, serology for coeliac disease, and fecal calprotectin assessment. Colonoscopy should be recommended in patients with alarm features. Regarding treatment, the consensus strongly supports a dietary approach for patients with IBS, the use of soluble fiber, secretagogues, tricyclic antidepressants, psychologically directed therapies and, only in specific IBS subtypes, rifaximin. A conditional recommendation was achieved for probiotics, polyethylene glycol, antispasmodics, selective serotonin reuptake inhibitors and, only in specific IBS subtypes, 5-HT3 antagonists, 5-HT4 agonists, bile acid sequestrants.

Hyoscine butylbromide mode of action on bowel motility: From pharmacology to clinical practice.

BACKGROUND: Hyoscine butylbromide (HBB) has been available for use as an antispasmodic since 1951 and is indicated for the treatment of abdominal pain associated with cramps. A previous review in 2007 summarized the evidence on the mode of action of HBB in vitro and in vivo in both animal and human studies. However, since then, novel publications have appeared within the literature and also our knowledge of what represents normal motility in humans has evolved. PURPOSE: This review is the result of the collaboration between a basic scientist and clinicians with the aim of providing an updated overview of the mechanisms of action of HBB and its clinical efficacy to guide not only use in clinical practice, but also future research.

Functional Abdominal Cramping Pain: Expert Practical Guidance.

Functional abdominal cramping pain (FACP) is a common complaint, which may present either on its own or in association with a functional gastrointestinal disorder. It is likely caused by a variety of, probably partly unknown, etiologies. Effective management of FACP can be challenging owing to the lack of usable diagnostic tools and the availability of a diverse range of treatment approaches. Practical guidance for their selection and use is limited. The objective of this article is to present a working definition of FACP based on expert consensus, and to propose practical strategies for the diagnosis and management of this condition for physicians, pharmacists, and patients. A panel of experts on functional gastrointestinal disorders was convened to participate in workshop activities aimed at defining FACP and agreeing upon a recommended sequence of diagnostic criteria and management recommendations. The key principles forming the foundation of the definition of FACP and suggested management algorithms include the primacy of cramping pain as the distinguishing symptom; the importance of recognizing and acting upon alarm signals of potential structural disease; the recognition of known causes that might be addressed through lifestyle adjustment; and the central role of antispasmodics in the treatment of FACP. The proposed algorithm is intended to assist physicians in reaching a meaningful diagnostic endpoint based on patient-reported symptoms of FACP. We also discuss how this algorithm may be adapted for use by pharmacists and patients.

Tolerability, gastric emptying patterns, and symptoms during the Nottingham Test Meal in 330 secondary care non-diabetic dyspeptic patients.

BACKGROUND: Scintigraphy is used for overall assessment of gastric emptying. Adherence to an international consensus protocol is recommended to ensure quality; however, this has not been widely adopted because preparation of the "egg-beater" meal is inconvenient in clinical practice. In this report, we audit the tolerability and the results of gastric emptying scintigraphy with the 400 ml Tc-99 m-labeled liquid nutrient Nottingham Test Meal (NTM). METHODS: Results from 330 consecutive adult, non-diabetic patients with dyspeptic symptoms referred for gastric scintigraphy were analyzed. Gastric half-emptying time (T50) and validated measurements of early- and late-phase gastric emptying were acquired. Postprandial sensations of fullness, bloating, heartburn, nausea, and epigastric pain were recorded using 100 mm visual analog scales (VAS) before and 0, 30, and 90 min after NTM ingestion. Results were compared with those previously obtained in healthy subjects. KEY RESULTS: Almost all (98%) of the patients were able to consume the 400 ml NTM. Considering early- and late-phase gastric emptying, frequently observed patterns included normal early- with slow late-phase (25%) and fast early- with slow late-phase emptying (27%). Abnormal score of fullness and/ or dyspeptic symptoms were observed in 88% of dyspeptic patients. Abnormal fullness at T0 (after completed drink ingestion) was associated with slow late phase of gastric emptying, especially in women. CONCLUSIONS: Gastric scintigraphy with the NTM is simple to perform and well tolerated. Whether the identified abnormal gastric emptying patterns could predict different treatment outcome in patients with functional dyspepsia is the subject of ongoing prospective studies.

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.

Functional bowel disorders with diarrhoea: Clinical guidelines of the United European Gastroenterology and European Society for Neurogastroenterology and Motility.

Irritable bowel syndrome with diarrhoea (IBS-D) and functional diarrhoea (FDr) are the two major functional bowel disorders characterized by diarrhoea. In spite of their high prevalence, IBS-D and FDr are associated with major uncertainties, especially regarding their optimal diagnostic work-up and management. A Delphi consensus was performed with experts from 10 European countries who conducted a literature summary and voting process on 31 statements. Quality of evidence was evaluated using the grading of recommendations, assessment, development, and evaluation criteria. Consensus (defined as >80% agreement) was reached for all the statements. The panel agreed with the potential overlapping of IBS-D and FDr. In terms of diagnosis, the consensus supports a symptom-based approach also with the exclusion of alarm symptoms, recommending the evaluation of full blood count, C-reactive protein, serology for coeliac disease, and faecal calprotectin, and consideration of diagnosing bile acid diarrhoea. Colonoscopy with random biopsies in both the right and left colon is recommended in patients older than 50 years and in presence of alarm features. Regarding treatment, a strong consensus was achieved for the use of a diet low fermentable oligo-, di-, monosaccharides and polyols, gut-directed psychological therapies, rifaximin, loperamide, and eluxadoline. A weak or conditional recommendation was achieved for antispasmodics, probiotics, tryciclic antidepressants, bile acid sequestrants, 5-hydroxytryptamine-3 antagonists (i.e. alosetron, ondansetron, or ramosetron). A multinational group of European experts summarized the current state of consensus on the definition, diagnosis, and management of IBS-D and FDr.

Review article: rethinking the "ladder" approach to reflux-like symptom management in the era of PPI "resistance" - a multidisciplinary perspective.

BACKGROUND: Despite widespread adoption of potent acid suppression treatment with proton pump inhibitors (PPI) for reflux-like symptoms, persistent symptoms are commonly reported in primary care and community studies. AIMS: This multidisciplinary review critically evaluates how the management of reflux-like symptoms could better reflect their multifactorial pathophysiology. METHODS: A panel of experts (from general practice, gastroenterology and gastropsychology) attended a series of workshops to review current management and propose a framework for the provision of more individualised care. RESULTS: It was agreed that the perceptual (as well as the physiological) causes of reflux-like symptoms should be considered at the start of management, not as a last resort when all else has failed. A short course of PPI is a pragmatic approach to address reflux-like symptoms, but equally important is counselling about the gut-brain axis and provision of symptom-specific behavioural interventions for those who show signs of somatisation, hypervigilance or co-existing disorders of gut-brain interaction. Other low-harm interventions such as lifestyle and dietary advice, should also be better integrated into care at an early stage. Multidisciplinary care management programmes (including dietary, weight loss, exercise and behavioural intervention) should be developed to promote greater self-management and take advantage of the general shift toward the use of remotely accessed health care resources. CONCLUSIONS: Management of reflux-like symptoms should be adapted to reflect the advances in knowledge about the multifactorial aetiology of these symptoms, addressing both acid-related and behavioural components early in management. The time has come to treat the patient, not the "disease".

Application of In Vivo Imaging Techniques and Diagnostic Tools in Oral Drug Delivery Research.

Drug absorption following oral administration is determined by complex and dynamic interactions between gastrointestinal (GI) physiology, the drug, and its formulation. Since many of these interactions are not fully understood, the COST action on "Understanding Gastrointestinal Absorption-related Processes (UNGAP)" was initiated in 2017, with the aim to improve the current comprehension of intestinal drug absorption and foster future developments in this field. In this regard, in vivo techniques used for the characterization of human GI physiology and the intraluminal behavior of orally administered dosage forms in the GI tract are fundamental to gaining deeper mechanistic understanding of the interplay between human GI physiology and drug product performance. In this review, the potential applications, advantages, and limitations of the most important in vivo techniques relevant to oral biopharmaceutics are presented from the perspectives of different research fields.