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Lactose is the main source of calories in milk, an essential nutriedigestion, patients with visceral hypersensitivity nt in infancy and a key part of the diet in populations that maintain the ability to digest this disaccharide in adulthood. Lactase deficiency (LD) is the failure to express the enzyme that hydrolyses lactose into galactose and glucose in the small intestine. The genetic mechanism of lactase persistence in adult Caucasians is mediated by a single C→T nucleotide polymorphism at the LCTbo −13’910 locus on chromosome-2. Lactose malabsorption (LM) refers to any cause of failure to digest and/or absorb lactose in the small intestine. This includes primary genetic and also secondary LD due to infection or other conditions that affect the mucosal integrity of the small bowel. Lactose intolerance (LI) is defined as the onset of abdominal symptoms such as abdominal pain, bloating and diarrhoea after lactose ingestion by an individual with LM. The likelihood of LI depends on the lactose dose, lactase expression and the intestinal microbiome. Independent of lactose digestion, patients with visceral hypersensitivity associated with anxiety or the Irritable Bowel Syndrome (IBS) are at increased risk of the condition. Diagnostic investigations available to diagnose LM and LI include genetic, endoscopic and physiological tests. The association between self-reported LI, objective findings and clinical outcome of dietary intervention is variable. Treatment of LI can include low-lactose diet, lactase supplementation and, potentially, colonic adaptation by prebiotics. The clinical outcome of these treatments is modest, because lactose is just one of a number of poorly absorbed carbohydrates which can cause symptoms by similar mechanisms.

Low-quality bowel preparation reduces efficacy of colonoscopy. We aimed to summarize effects of bowel preparation on detection of adenomas, advanced adenomas and colorectal cancer. A systematic literature search was performed regarding detection of colonic lesions after normal and low-quality bowel preparation. Reported bowel preparation quality was transformed to the Aronchick scale with its qualities \"excellent\", \"good\", \"fair\", \"poor\", and \"insufficient\" or \"optimal\" (good/excellent), \"suboptimal\" (fair/poor/insufficient), \"adequate\" (good/excellent/fair) and \"inadequate\" (poor/insufficient). We identified two types of studies: i) Comparative studies, directly comparing lesion detection according to bowel preparation quality, and ii) repeat colonoscopy studies, reporting results of a second colonoscopy after previous low-quality preparation. The detection of early adenomas was reduced with inadequate vs. adequate bowel preparation (Odds Ratio (OR) 0.53, CI: 0.46-0.62, p<0.001). The advanced adenomas were affected less in comparison (0.74, CI: 0.62-0.87, p<0.001). The large number of subjects considered in the present meta-analysis resulted in smaller confidence intervals compared to earlier studies. Classifying the bowel-preparation quality as suboptimal vs. optimal led to the same qualitative conclusion (OR: 0.81, CI: 0.74-0.89, p<0.001 for early adenomas, OR: 0.94, CI: 0.87-1.01, n.s. for advanced adenomas). Bowel preparation was equally important for right-sided/ flat/ serrated vs. other lesions in most observational studies but more relevant in some repeat colonoscopy studies; data regarding carcinoma detection were insufficient. Inadequate bowel preparation affects detection of early colonic lesions stronger than advanced lesions.

Background: Treatment of inflammatory bowel diseases (IBD) has tremendously improved during the last 20 years; however, a substantial fraction of patients does not respond to available therapies or lose response, and new strategies are needed. Summary: Two pharmacological principles have been successfully used for IBD treatment: inhibition of cellular signaling and interference with leukocyte trafficking. Besides tumor necrosis factor, interleukin (IL)-23 is a promising drug target, and antibodies for the combined inhibition of IL-23 and IL-12 (ustekinumab and briakinumab) or selective IL-23 inhibition (brazikumab, risankizumab, and mirikizumab) seem to be effective in Crohn’s disease (CD) with emerging evidence also for ulcerative colitis (UC). Janus kinase (JAK) mediates intracellular signaling of a large number of cytokines. Tofacitinib is the first JAK inhibitor approved for UC, and the JAK inhibitors filgotinib and upadacitinib showed potential in CD. Leukocyte trafficking can be inhibited by interference with lymphocyte integrin-α4β7 or endothelial MadCAM-1. The α4β7 integrin inhibitor vedolizumab is an established treatment in IBD, and long-term data of pivotal studies are now available. Additional molecules with therapeutic potential are α4β7-specific abrilumab, β7-specific etrolizumab, and the α4-specific small molecule AJM300. PF-00547659, an antibody against endothelial MadCAM-1, also showed therapeutic potential in UC. Modulation of sphingosine-1-phosphate receptor (S1PR) activity is necessary for the egress of lymphocytes into the circulation, and S1PR modulation results in lymphocyte trapping in lymphatic organs. Ozanimod, an S1PR1 and S1PR5 inhibitor, has been successfully tested in initial studies in UC. Mesenchymal stem cell therapy has been approved for the treatment of complex, active CD fistula, and mesenchymal stem cell therapy might be a paradigm shift for this condition. Autologous stem cell transplantation (ASCT) has been successfully used in CD case series; however, in a randomized trial, a highly stringent endpoint was not met. However, considering positive effects in secondary endpoints, ASCT might be a future treatment of last resort in severe, refractory CD cases, provided that safer protocols can be provided. Key messages: New IBD treatments are successful for a significant fraction of patients. However, new strategies for patient selection, treatment combinations, and/or additional therapies must be developed to serve the need of all IBD patients.

Gallstones and kidney stones are known complications of inflammatory bowel diseases (IBD). Risk factors have been insufficiently studied and explanatory studies date back up to 30 years. It remains unclear, whether improved treatment options also influenced risk factors for these complications. Identifying risk factors for gallstones and kidney stones in IBD patients. Using data from the Swiss Inflammatory Bowel Disease Cohort Study we assessed associations of diseases characteristics with gallstones and kidney stones in univariate and multivariate logistic regression analyses. Out of 2323 IBD patients, 104 (7.8%) Crohn's disease (CD) and 38 (3.8%) ulcerative colitis (UC) patients were diagnosed with gallstones. Significant risk factors for gallstones were diagnosis of CD, age at diagnosis, disease activity and duration, NSAID intake, extra-intestinal manifestations and intestinal surgery. Kidney stones were described in 61 (4.6%) CD and 30 (3.0%) UC patients. Male gender, disease activity, intestinal surgery, NSAID usage and reduced physical activity were significant risk factors. Hospitalization was associated with gallstones and kidney stones. The presence of gallstones increased the risk for kidney stones (OR 4.87, p<0.001). The diagnosis of CD, intestinal surgery, prolonged NSAID use, disease activity and duration and bowel stenosis were significantly associated with cholecystonephrolithiasis in IBD.

Introduction: The use of proton-pump inhibitors (PPI) may be associated with an increased risk of gastric cancer (GC). Objective: To review and meta-analyse available literature investigating the association between PPI use and GC risk. Methods: Two independent reviewers systematically searched Ovid MEDLINE, EMBASE, and Cochrane Library (inception to July 2020) for case-control and cohort studies assessing the association between PPI use and GC according to a predefined protocol in PROSPERO (CRD42018102536). Reviewers independently assessed study quality, extracted data, and meta-analysed available and newly calculated odds ratios (ORs) using a random-effects model, and stratified for GC site (cardia versus non-cardia) and PPI duration (<1 year, 1–3 years, >3 years). Results: We screened 2,396 records and included five retrospective cohort and eight case-control studies comprising 1,662,881 individuals in our meta-analysis. In random-effect models, we found an increased GC risk in PPI users [OR: 1.94, 95% confidence interval (95% CI): 1.47–2.56] with high statistical heterogeneity (I2 = 82%) and overall moderate risk of bias. Stratified analyses indicated a significant risk increase in non-cardia (OR: 2.20, 95% CI: 1.44–3.36, I2 = 77%) with a similar non-significant trend in cardia regions (OR: 1.77, 95% CI: 0.72–4.36, I2 = 66%). There was no GC increase with longer durations of PPI exposure (<1 year: OR: 2.29, 95% CI: 2.13–2.47, I2 = 0%; 1–3 years: OR: 1.46, 95% CI: 0.53–4.01, I2 = 35%; >3 years: OR: 2.08, 95% CI: 0.56–7.77, I2 = 61%). Conclusion: We found a twofold increased GC risk among PPI users, but this association does not confirm causation and studies are highly heterogeneous. PPI should only be prescribed when strictly indicated.

Despite advances in the modeling and understanding of colorectal cancer development, the dynamics of the progression from benign adenomatous polyp to colorectal carcinoma are still not fully resolved. To take advantage of adenoma size and prevalence data in the National Endoscopic Database of the Clinical Outcomes Research Initiative (CORI) as well as colorectal cancer incidence and size data from the Surveillance Epidemiology and End Results (SEER) database, we construct a two-type branching process model with compartments representing adenoma and carcinoma cells. To perform parameter inference we present a new large-size approximation to the size distribution of the cancer compartment and validate our approach on simulated data. By fitting the model to the CORI and SEER data, we learn biologically relevant parameters, including the transition rate from adenoma to cancer. The inferred parameters allow us to predict the individualized risk of the presence of cancer cells for each screened patient. We provide a web application which allows the user to calculate these individual probabilities at https://ccrc-eth.shinyapps.io/CCRC/. For example, we find a 1 in 100 chance of cancer given the presence of an adenoma between 10 and 20mm size in an average risk patient at age 50. We show that our two-type branching process model recapitulates the early growth dynamics of colon adenomas and cancers and can recover epidemiological trends such as adenoma prevalence and cancer incidence while remaining mathematically and computationally tractable.

Colonoscopy-based screening provides protection against colorectal cancer (CRC), but the optimal starting age and time intervals of screening colonoscopies are unknown. We aimed to determine an optimal screening schedule for the US population and its dependencies on the objective of screening (life years gained or incidence, mortality, or cost reduction) and the setting in which screening is performed. We used our established open-source microsimulation model CMOST to calculate optimized colonoscopy schedules with one, two, three or four screening colonoscopies between 20 and 90 years of age. A single screening colonoscopy was most effective in reducing life years lost from CRC when performed at 55 years of age. Two, three and four screening colonoscopy schedules saved a maximum number of life years when performed between 49–64 years; 44–69 years; and 40–72 years; respectively. However, for maximum incidence and mortality reduction, screening colonoscopies needed to be scheduled 4–8 years later in life. The optimum was also influenced by adenoma detection efficiency with lower values for these parameters favoring a later starting age of screening. Low adherence to screening consistently favored a later start and an earlier end of screening. In a personalized approach, optimal screening would start earlier for high-risk patients and later for low-risk individuals. In conclusion, our microsimulation-based approach supports colonoscopy screening schedule between 45 and 75 years of age but the precise timing depends on the objective of screening, as well as assumptions regarding individual CRC risk, efficiency of adenoma detection during colonoscopy and adherence to screening.

Background Human immunodeficiency virus (HIV) severely damages the epithelial cells of the gut lining leading to an inflamed leaky gut, translocation of microbial products, and dysbiosis resulting in systemic immune activation. Also, microbiota composition and maternal gut function can be altered in pregnancy through changes in the immune system and intestinal physiology. The aim of this study was to investigate the gut microbiota in HIV-infected and HIV-uninfected pregnant women and to compare and identify the association between gut microbial composition and adverse birth outcomes. Results A total of 94 pregnant women (35 HIV-infected and 59 HIV-uninfected controls) were recruited in Harare from 4 polyclinics serving populations with relatively poor socioeconomic status. Women were of a median age of 28 years (interquartile range, IQR: 22.3–32.0) and 55% of women were 35 weeks gestational age at enrolment (median 35.0 weeks, IQR: 32.5–37.2). Microbiota profiling in these participants showed that species richness was significantly lower in the HIV-infected pregnant women compared to their HIV-uninfected peers and significant differences in β-diversity using Bray–Curtis dissimilarity were observed. In contrast, there was no significant difference in α-diversity between immune-compromised (CD4 +  < 350 cells/µL) and immune-competent HIV-infected women (CD4 +  ≥ 350 cells/µL) even after stratification by viral load suppression. HIV infection was significantly associated with a reduced abundance of Clostridium, Turicibacter, Ruminococcus, Parabacteroides, Bacteroides, Bifidobacterium, Treponema, Oscillospira, and Faecalibacterium and a higher abundance of Actinomyces, and Succinivibrio. Low infant birth weight (< 2500 g) was significantly associated with high abundances of the phylum Spirochaetes, the families Spirochaeteceae, Veillonellaceae, and the genus Treponema. Conclusion The results reported here show that the species richness and taxonomy composition of the gut microbiota is altered in HIV-infected pregnant women, possibly reflecting intestinal dysbiosis. Some of these taxa were also associated with low infant birth weight.

Extraintestinal manifestations (EIMs) in patients with inflammatory bowel disease (IBD) are frequently observed. Little is known about the efficacy of anti–tumor necrosis factor (TNF) in EIM management. We assessed the effect of 3 anti-TNF agents (infliximab, adalimumab, and certolizumab pegol) on EIM evolution.MethodsData on 1249 patients from the Swiss IBD Cohort Study (SIBDCS) were analyzed. All EIMs were diagnosed by relevant specialists. Response was classified into improvement, stable disease, and clinical worsening based on the physician's interpretation.ResultsOf the 366 patients with at least 1 EIM, 213 (58.2%) were ever treated with an anti-TNF. A total of 299 treatments were started for 355 EIMs. Patients with EIM were significantly more often treated with anti-TNF compared with those without EIM (58.2% versus 21.0%, P < 0.001). Infliximab was the most frequently used drug (63.2%). In more than 71.8%, a clinical response of the underlying EIM to anti-TNF therapy was observed. In 92 patients (43.2%), anti-TNF treatments were started for the purpose of treating EIM rather than IBD. Response rates to anti-TNF were generally good and best for psoriasis, aphthous stomatitis, uveitis, and peripheral arthritis. In 11 patients, 14 EIM occurred under anti-TNF treatment.ConclusionsAnti-TNF was frequently used among patients with EIM. In more than 40%, anti-TNF treatments are started to treat EIM rather than IBD. Given the good response rates, anti-TNF seems to be a valuable option in the treatment of EIM, whereas appearance of EIM under anti-TNF does not seem to be a source of considerable concern.

The Roux-en-Y gastric bypass (RYGB) remains the most effective treatment for morbidly obese patients to lower body weight and improve glycemic control. There is recent evidence that the mycobiome (fungal microbiome) can aggravate disease severity in a number of diseases including inflammatory bowel disease (IBD), irritable bowel syndrome (IBS) and hepatitis; moreover, a dysbiotic fungal microbiota has been reported in the obese. We characterized fungal and bacterial microbial composition in fecal samples of 16 morbidly obese patients before and three months after RYGB surgery and compared with nine healthy controls. We found that RYGB surgery induced a clear alteration in structure and composition of the gut fungal and bacterial microbiota. Beta diversity analysis revealed significant differences in bacterial microbiota between obese patients before surgery and healthy controls (P < 0.005) and a significant, unidirectional shift in RYGB patients after surgery (P < 0.001 vs. before surgery). In contrast, there was no significant difference in fungal microbiota between groups but individually specific changes after RYGB surgery. Interestingly, RYGB surgery induced a significant reduction in fungal alpha diversity namely Chao1, Sobs, and Shannon diversity index (P<0.05, respectively) which contrasts the trend for uniform changes in bacteria towards increased richness and diversity post-surgery. We did not observe any inter-kingdom relations in RYGB patients but in the healthy control cohort and there were several correlations between fungi and bacteria and clinical parameters (P<0.05, respectively) that warrant further research. Our study identifies changes in intestinal fungal communities in RYGB patients that are distinct to changes in the bacterial microbiota.