Methanogenic archaea in the human gastrointestinal tract.

The human microbiome is strongly interwoven with human health and disease. Besides bacteria, viruses and eukaryotes, numerous archaea are located in the human gastrointestinal tract and are responsible for methane production, which can be measured in clinical methane breath analyses. Methane is an important readout for various diseases, including intestinal methanogen overgrowth. Notably, the archaea responsible for methane production are largely overlooked in human microbiome studies due to their non-bacterial biology and resulting detection issues. As such, their importance for health and disease remains largely unclear to date, in particular as not a single archaeal representative has been deemed to be pathogenic. In this Perspective, we discuss the current knowledge on the clinical relevance of methanogenic archaea. We explain the archaeal unique response to antibiotics and their negative and positive effects on human physiology, and present the current understanding of the use of methane as a diagnostic marker.

Practical application of breath tests in disorders of gut-brain interaction.

Frequently occurring diseases of disordered gut-brain interactions are the irritable bowel syndrome and functional dyspepsia. Breath tests are noninvasive and are used to monitor a variety of gastrointestinal functions or conditions. Their general principle is the oral application of a test substance, the metabolism of which results in a substrate that can be measured in expiratory air. Clinically used breath tests use carbohydrates or stable 13C-enriched substrates. This review will focus on two questions, which breath tests are relevant for initiating treatments and which breath tests are useful for assessing treatment response? Recently published guidelines have described breath tests in detail and the recommendations for their use will be based on recommendations of these guidelines.

European guideline on indications, performance, and clinical impact of hydrogen and methane breath tests in adult and pediatric patients: European Association for Gastroenterology, Endoscopy and Nutrition, European Society of Neurogastroenterology and Motility, and European Society for Paediatric Gastroenterology Hepatology and Nutrition consensus.

INTRODUCTION: Measurement of breath hydrogen (H2 ) and methane (CH4 ) excretion after ingestion of test-carbohydrates is used for different diagnostic purposes. There is a lack of standardization among centers performing these tests and this, together with recent technical developments and evidence from clinical studies, highlight the need for a European guideline. METHODS: This consensus-based clinical practice guideline defines the clinical indications, performance, and interpretation of H2 -CH4 -breath tests in adult and pediatric patients. A balance between scientific evidence and clinical experience was achieved by a Delphi consensus that involved 44 experts from 18 European countries. Eighty eight statements and recommendations were drafted based on a review of the literature. Consensus (≥80% agreement) was reached for 82. Quality of evidence was evaluated using validated criteria. RESULTS: The guideline incorporates new insights into the role of symptom assessment to diagnose carbohydrate (e.g., lactose) intolerances and recommends that breath tests for carbohydrate malabsorption require additional validated concurrent symptom evaluation to establish carbohydrate intolerance. Regarding the use of breath tests for the evaluation of oro-cecal transit time and suspected small bowel bacterial overgrowth, this guideline highlights confounding factors associated with the interpretation of H2 -CH4 -breath tests in these indications and recommends approaches to mitigate these issues. CONCLUSION: This clinical practice guideline should facilitate pan-European harmonization of diagnostic approaches to symptoms and disorders, which are very common in specialist and primary care gastroenterology practice, both in adult and pediatric patients. In addition, it identifies areas of future research needs to clarify diagnostic and therapeutic approaches.

European guideline on indications, performance and clinical impact of 13 C-breath tests in adult and pediatric patients: An EAGEN, ESNM, and ESPGHAN consensus, supported by EPC.

INTRODUCTION: 13 C-breath tests are valuable, noninvasive diagnostic tests that can be widely applied for the assessment of gastroenterological symptoms and diseases. Currently, the potential of these tests is compromised by a lack of standardization regarding performance and interpretation among expert centers. METHODS: This consensus-based clinical practice guideline defines the clinical indications, performance, and interpretation of 13 C-breath tests in adult and pediatric patients. A balance between scientific evidence and clinical experience was achieved by a Delphi consensus that involved 43 experts from 18 European countries. Consensus on individual statements and recommendations was established if ≥ 80% of reviewers agreed and <10% disagreed. RESULTS: The guideline gives an overview over general methodology of 13 C-breath testing and provides recommendations for the use of 13 C-breath tests to diagnose Helicobacter pylori infection, measure gastric emptying time, and monitor pancreatic exocrine and liver function in adult and pediatric patients. Other potential applications of 13 C-breath testing are summarized briefly. The recommendations specifically detail when and how individual 13 C-breath tests should be performed including examples for well-established test protocols, patient preparation, and reporting of test results. CONCLUSION: This clinical practice guideline should improve pan-European harmonization of diagnostic approaches to symptoms and disorders, which are very common in specialist and primary care gastroenterology practice, both in adult and pediatric patients. In addition, this guideline identifies areas of future clinical research involving the use of 13 C-breath tests.

13 C-gastric emptying breath tests: Clinical use in adults and children.

13 C-gastric emptying breath tests (13 C-GEBT) are validated, reliable, and non-invasive tools for measurement of gastric emptying (GE) velocity of solids and liquids without radiation exposure or risk of toxicity. They are recommended and routinely used for clinical purposes in adult as well as pediatric patients and can be readily performed onsite or even at the patient's home. However, the underlying methodology is rather complex and test results can be influenced by dietary factors, physical activity, concurrent diseases, and medication. Moreover, epidemiological factors can influence gastric emptying as well as production and exhalation of 13 CO2 , which is the ultimate metabolic product measured for all 13 C-breath tests. Accordingly, in this issue of Neurogastroenterology & Motility, Kovacic et al. report performance of the 13 C-Spirulina breath test in a large group of healthy children and show significant effects of gender, pubertal status, and body size on test results. The purpose of this mini-review is to evaluate the clinical use of 13 C-GEBT in adults and children, exploring available protocols, analytical methods, and essential prerequisites for test performance, as well as the role of GE measurements in the light of the current discussion on relevance of delayed GE for symptom generation.

Management of Chronic Diarrhea in Primary Care: The Gastroenterologists' Advice.

BACKGROUND: Chronic diarrhea is defined as more than 3 bowel movements per day, or loose stools, or stool weight >200 g/day for at least 4 weeks. Accompanying symptoms may include urgency, abdominal pain, or cramps. SUMMARY: A number of causes have to be considered, including inflammatory, neoplastic, malabsorptive, infective, vascular, and functional gastrointestinal diseases. Other causes include food intolerances, side effects of drugs, or postsurgical conditions. Diarrhea may also be symptom of a systemic disease, like diabetes or hyperthyroidism. Special patient groups, like the very elderly and immunocompromised patients, pose special challenges. This review follows a question-answer style and addresses questions raised on the intersection of primary and secondary care. What do you mean by diarrhea? Why is it important to distinguish between acute or chronic diarrhea? How shall the patient with chronic diarrhea be approached? How can history and physical exam help? How can routine laboratory tests help in categorizing diarrhea? Which additional laboratory tests may be helpful? How to proceed in undiagnosed or intractable diarrhea? What are the treatment options in patients with chronic diarrhea? Key Messages: Acute diarrhea is usually of infectious origin with the main treatment goal of preventing water and electrolyte disturbances. Chronic diarrhea is usually not of infectious origin and may be the symptom of a large number of gastrointestinal and general diseases or drug side effects. In undiagnosed or intractable diarrhea, the question shall be raised whether the appropriate tests have been performed and interpreted correctly.

Carbohydrate-induced gastrointestinal symptoms: development and validation of a test-specific symptom questionnaire for an adult population, the adult Carbohydrate Perception Questionnaire.

OBJECTIVES: Carbohydrate intolerances may affect a majority of the worlds-population but there is no validated, test-specific assessment of carbohydrate-induced symptoms during breath tests. We aimed to develop and validate a questionnaire for evaluation and quantification of carbohydrate intolerance. METHODS: A visual analog scale-questionnaire with five complaints (pain, nausea, bloating, flatulence, and diarrhea) was designed. The time frame of symptoms was 'current' (for baseline symptoms) and 'since filling out the last questionnaire'. Validity was determined in focus-group style interviews and during breath tests in an original (n = 342) and follow-up patient groups (n = 338). RESULTS: The questionnaire had good face validity, content validity ratio according to Lawshe was 1. Intraclass correlation coefficients (n = 195; 30-min' interval) demonstrated excellent reliability (P < 0.001), Cohen's d (measure of effect size) was small (≤0.19 for each symptom). Convergent and discriminant validity were supported against patient interviews. Questionnaire-derived results highly correlated with a medical interview (P < 0.001; n = 338). Responsiveness to change was verified during breath tests despite small effect sizes (≤0.32). Additional cross-validation and external validation studies (follow-up in-house: n = 182; external: n = 156) demonstrated generalizability and identified relevant numbers of patients in whom there was no co-occurrence of carbohydrate malabsorption and intolerance. CONCLUSIONS: The adult Carbohydrate Perception Questionnaire is a valid instrument for the assessment of gastrointestinal symptoms after carbohydrate ingestion with excellent psychometric properties. It allows standardized, test-specific diagnosis of carbohydrate intolerance and evaluation of the relation between malabsorption and intolerance. It shall be useful for future studies on treatment of carbohydrate intolerance.

Development of a Multinational Clinical Practice Guideline: A Practical Structured Procedure.

INTRODUCTION: The development of a clinical guideline is a challenging process. National and international organizations have established a variety of approaches, grading systems, evaluation scales, and voting modes; however, a practical description which illustrates all steps from starting the initiative to publication and dissemination of the guideline is usually not provided. We describe a structured guideline procedure that can be adjusted to the requirements of other multinational guidelines. METHODS: A group of European specialist gastroenterological societies and national societies initiated a guideline for the use of breath tests in gastroenterology. A balance between scientific evidence and clinical experience was achieved by involving European specialist societies and physicians from 18 European countries. For persons contributing to the guideline process, different levels of involvement were defined. The tasks were assigned to different groups of persons, which formed scientific institutions. RESULTS: We describe organizational structures and institutions, the stepwise approach, and illustrate the multistep guideline development procedure in a flowchart diagram that shows workflow and assigned responsibilities and provides details for the execution of each step, including timelines. The process is split into 4 phases: foundation, preparation, voting, and publication. DISCUSSION: This structured procedure of a gastroenterological clinical practice guideline can serve as a blueprint for future multinational guideline initiatives and may aid future attempts to standardize and harmonize guideline development processes in gastroenterology and in other medical fields. Although the described procedure is for a diagnostic guideline, it may also be appropriate for therapeutic guidelines by adjusting the acceptance criteria for recommendations.

EAGEN and UEG: A Long-Term Partnership with a Focus on Education.

EAGEN is one of the 7 founding sisters and an ordinary member society of UEG. EAGEN members have contributed significantly to the development of UEG in leading positions within UEG. The significant impact of UEG board members on science, education, and organization of European gastroenterology is demonstrated by the remarkable list of EAGEN board members who have received major UEG awards or prizes. The focus of EAGEN within UEG has been on postgraduate education. In this function, EAGEN has developed educational formats which after their establishment were handed over to UEG. EAGEN has established itself as an important provider of education in gastroenterology including pancreatic-biliary diseases, GI oncology, endoscopic procedures, nutrition, and intestinal microbiology. EAGEN has the goal to identify educational needs, fill existing gaps in medical education, and advance the quality of education. To fulfill these tasks, EAGEN is in close cooperation with the UEG education committee and UEG member societies. EAGEN puts a focus on reduction of pan-European health inequalities, provision of equal opportunity, promotion of young talent, and improvement of clinical standards and guidelines.

Multicentre, non-interventional study of the efficacy and tolerability of linaclotide in the treatment of irritable bowel syndrome with constipation in primary, secondary and tertiary centres: the Alpine study.

OBJECTIVES: We evaluated the effectiveness and tolerability of linaclotide, a minimally absorbed guanylate cyclase-C agonist, in patients with irritable bowel syndrome with constipation (IBS-C) in routine clinical practice. SETTING: A multicentre, non-interventional study conducted between December 2013 and November 2015 across 31 primary, secondary and tertiary centres in Austria and Switzerland. PARTICIPANTS: The study enrolled 138 patients aged ≥18 years with moderate-to-severe IBS-C. Treatment decision was at the physician's discretion. Patients with known hypersensitivity to the study drug or suspected mechanical obstruction were excluded. The mean age of participants was 50 years, and >75% of the patients were women. 128 patients completed the study. PRIMARY AND SECONDARY OUTCOME MEASURES: Data were collected at weeks 0 and 4 in Austria and weeks 0, 4 and 16 in Switzerland. The primary effectiveness endpoints included severity of abdominal pain and bloating (11-point numerical rating scale [0=no pain/bloating to 10=worst possible pain/bloating]), frequency of bowel movements and physicians' global effectiveness of linaclotide. Treatment-related adverse events (AEs) were recorded. RESULTS: Following a 4-week treatment period, the mean intensity score of abdominal pain was reduced from 5.8 at baseline to 2.7, while the bloating intensity score was reduced from 5.8 at baseline to 3.1e (both indices p<0.001). The frequency of mean weekly bowel movements increased from 2.1 at baseline to 4.5 at week 4 (p<0.001). Global effectiveness and tolerability of linaclotide were assessed by the treating physicians as 'good' or 'excellent' in >70% of patients. In total, 31 AEs were reported in 22 patients, the most common being diarrhoea, reported by 6 (7%) and 8 (15.4%) patients in Austria and Switzerland, respectively. CONCLUSIONS: Patients with IBS-C receiving linaclotide experienced effective treatment of moderate-to-severe symptoms in routine clinical practice. Linaclotide was safe and well tolerated and no new safety concerns were raised, supporting results from previous clinical trials.

Distribution, size and shape of colorectal adenomas as determined by a colonoscopist with a high lesion detection rate: Influence of age, sex and colonoscopy indication.

BACKGROUND: Increasing attention is focused on polyp-related features that may contribute to the operator-dependent nature of colonoscopy. Few data on polyps are available from high-yield colonoscopies, which may serve as a benchmark for quality control. OBJECTIVES: Describe regional distribution, histology, size and shape of polyps, and the influence of patient age and gender, in colonoscopies performed by a colonoscopist with high lesion detection rate. METHODS: Analysis of 698 consecutive patients with diagnostic, screening or surveillance colonoscopies. RESULTS: In 704 colonoscopies, 1908 polyps were removed (360 were protruded and 1548 flat; 1313 were hyperplastic, 562 adenomas, 5 serrated adenomas and 8 mixed). There were 232 adenomas in female patients and 343 in male patients; 39% of the adenomas were protruded and 61% were flat. The peak adenoma detection rate (ADR) was 51% in patients beyond age 79 years. Men older than 49 years had a higher ADR than women. In men and women, respectively: 40% and 32% of adenomas were in the right colon, 31% and 22% were in the transverse colon, and 30% and 47% were in the left colon. Beyond age 59 years, the majority of adenomas were in the proximal colon. CONCLUSIONS: An excess of adenomas in the proximal colon started at age 60 and this was more pronounced in men than in women. In all colonic regions, the majority of adenomas had a shape that was flat and smaller than 6 mm.

[Exocrine pancreatic insufficiency and diabetes mellitus]. / Exokrine Pankreasinsuffizienz und Diabetes mellitus.

Exocrine pancreatic insufficiency (EPI) in diabetic patients is frequent. Studies based on fecal elastase-1 measurement give prevalence rates of 10‒30 % of severe and 22‒56 % of moderate EPI in type 1 and rates of 5‒46 % in type 2 diabetic patients. Nevertheless, not all patients report typical symptoms like diarrhea, steatorrhea and weight loss. For noninvasive testing the determination of fecal elastase-1 has the highest sensitivity and specificity. This test should be performed at least in all symptomatic patients. As differential diagnosis celiac disease (with a prevalence of about 3-5 % of type 1 diabetic patients), autonomic neuropathy, but also diseases like irritable bowel syndrome and gastrointestinal tumors have to be taken into account. Patients with symptoms and a fecal elastase-1 < 100 µg/g should be treated with pancreatic enzymes in adequate daily doses administered at main meals. Treatment improves symptoms significantly, supply with fat soluble vitamins is normalised, risk for osteoporosis is reduced. However, improvement of glucose metabolism has not been demonstrated consistently. A pancreatogenic diabetes, also termed as type 3c diabetes, has not necessarily to be treated with insulin, often-at least initially-treatment with oral antidiabetic drugs is sufficient.

Diet therapy for inflammatory bowel diseases: The established and the new.

Although patients with inflammatory bowel diseases (IBD) have a strong interest in dietary modifications as part of their therapeutic management, dietary advice plays only a minor part in published guidelines. The scientific literature shows that dietary factors might influence the risk of developing IBD, that dysbiosis induced by nutrition contributes to the pathogenesis of IBD, and that diet may serve as a symptomatic treatment for irritable bowel syndrome-like symptoms in IBD. The role of nutrition in IBD is underscored by the effect of various dietary therapies. In paediatric patients with Crohn's disease (CD) enteral nutrition (EN) reaches remission rates similar to steroids. In adult patients, however, EN is inferior to corticosteroids. EN is not effective in ulcerative colitis (UC). Total parenteral nutrition in IBD is not superior to steroids or EN. The use of specific probiotics in patients with IBD can be recommended only in special clinical situations. There is no evidence for efficacy of probiotics in CD. By contrast, studies in UC have shown a beneficial effect in selected patients. For patients with pouchitis, antibiotic treatment followed by probiotics, like VSL#3 or Lactobacillus GG, is effective. When probiotics are used, the risk of bacterial translocation and subsequent bacteremia has to be considered. More understanding of the normal intestinal microflora, and better characterization of probiotic strains at the phenotypic and genomic levels is needed as well as clarification of the mechanisms of action in different clinical settings. A FODMAP reduced diet may improve symptoms in IBD.