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Background & Aims: A genome-wide significant association between anti–Helicobacter pylori (H pylori) IgG titers and Toll-like receptor (TLR1/6/10) locus on 4p14 was demonstrated for individuals of European ancestry, but not uniformly replicated. We re-investigated this association in an updated genome-wide association study (GWAS) meta-analysis for populations with low gastric cancer incidence, address potential causes of cohort heterogeneity, and explore functional implications of genetic variation at the TLR1/6/10 locus. Methods: The dichotomous GWAS (25% individuals exhibiting highest anti–H pylori IgG titers vs remaining 75%) included discovery and replication sampls of, respectively, n = 15,685 and n = 9676, all of European ancestry. Longitudinal analysis of serologic data was performed on H pylori–eradicated subjects (n = 132) and patients under surveillance for premalignant gastric lesions (n = 107). TLR1/6/10 surface expression, TLR1 mRNA, and cytokine levels were measured in leukocyte subsets of healthy subjects (n = 26) genotyped for TLR1/6/10 variants. Results: The association of the TLR1/6/10 locus with anti–H pylori IgG titers (rs12233670; β = −0.267 ± SE 0.034; P = 4.42 × 10−15) presented with high heterogeneity and failed replication. Anti–H pylori IgG titers declined within 2–4 years after eradication treatment (P = 0.004), and decreased over time in patients with premalignant gastric lesions (P < 0.001). Variation at the TLR1/6/10 locus affected TLR1-mediated cytokine production and TLR1 surface expression on monocytes (P = 0.016) and neutrophils (P = 0.030), but not mRNA levels. Conclusions: The association between anti–H pylori IgG titers and TLR1/6/10 locus was not replicated across cohorts, possibly owing to dependency of anti–H pylori IgG titers on therapy, clearance, and antibody decay. H pylori–mediated immune cell activation is partly mediated via TLR1 signaling, which in turn is affected by genetic variation.

Pancreatic necroses are a major challenge in the treatment of patients with pancreatitis, causing high morbidity. When indicated, these lesions are usually drained endoscopically using plastic or metal stents. However, data on factors associated with the occurrence of failure or adverse events during stent therapy are scarce. We retrospectively analyzed all adverse events and their associated features which occurred in patients who underwent a first-time endoscopic drainage of pancreatic necrosis from 2009 to 2019. During the observation period, a total of 89 eligible cases were identified. Adverse events occurred in 58.4% of the cases, of which 76.9% were minor (e.g., stent dislocation, residual lesions, or stent obstruction). However, these events triggered repeated interventions (63.5% vs. 0%, p < 0.001) and prolonged hospital stays (21.0 [11.8–63.0] vs. 14.0 [7.0–31.0], p = 0.003) compared to controls without any adverse event. Important factors associated with the occurrence of adverse events during endoscopic drainage therapy were positive necrosis cultures (6.1 [2.3–16.1], OR [95% CI], p < 0.001) and a larger diameter of the treated lesion (1.3 [1.1–1.5], p < 0.001). Superinfection of pancreatic necrosis is the most significant factor increasing the likelihood of adverse events during endoscopic drainage. Therefore, control of infection is crucial for successful drainage therapy, and future studies need to consider superinfection of pancreatic necrosis as a possible confounding factor when comparing different therapeutic modalities.

The human body is colonized by a multitude of different microbes that are collectively referred to as the human microbiome. Gut microbes account for the largest proportion of these. They constitute a barrier against foreign pathogens, carry out important metabolic functions and regulate the immune system, thereby making them essential for the maintenance of health. The most important determinants of the gut microbiome structure in the general population include exocrine pancreatic function, genetics, nutrition, age, sex, and obesity. Changes in the gut microbiome have also been linked to a variety of diseases not limited to gastrointestinal disorders. Typical microbiome changes in disease include a loss of diversity and beneficial bacteria or an increase in opportunistic pathogens. This may result in a proinflammatory and unstable microbiome. Knowledge about the microbiome is rapidly increasing and microbiome modulation therapies have already been implemented in clinical practice. Therefore, basic knowledge about the microbiome is essential for all medical professionals in order for them to advise and treat their patients properly.Der menschliche Körper wird von einer Vielzahl von Mikroorganismen besiedelt, die zusammen das humane Mikrobiom bilden. Das Darmmikrobiom macht hiervon den größten Anteil aus. Es stellt eine wichtige Barriere gegen die Ansiedlung von pathogenen Erregern dar, übernimmt wichtige Stoffwechselfunktionen und wirkt regulativ auf das Immunsystem ein. Das macht es essenziell für die Erhaltung der Gesundheit. Die wichtigsten Determinanten der Mikrobiomzusammensetzung in der Allgemeinbevölkerung sind exokrine Pankreasfunktion, Genetik, Ernährung, Alter, Geschlecht und Adipositas. Darüber hinaus werden Veränderungen des Darmmikrobioms mit einer Vielzahl verschiedener, nicht nur gastrointestinaler, Erkrankungen in Verbindung gebracht. Typische Mikrobiomveränderungen beim Kranken sind beispielsweise ein Verlust mikrobieller Diversität und gesundheitsförderlicher Bakterien oder eine Zunahme potenziell pathogener Erreger. Dies kann zu einem proinflammatorischen und instabilen Mikrobiom führen. Der Wissensstand rund um das Thema Mikrobiom nimmt mit rasanter Geschwindigkeit zu, und auf eine Modulation des Mikrobioms zielende Therapien haben inzwischen in unterschiedlichsten Indikationen ihren Weg in die Praxis gefunden. Grundkenntnisse über das Darmmikrobiom sind daher für alle Behandelnden essenziell, um in diesem sich schnell entwickelnden Feld die Übersicht zu behalten und Patientinnen und Patienten adäquat beraten zu können.

Gallstone disease affects up to twenty percent of the population in western countries and is a significant contributor to morbidity and health care expenditure. Intestinal microbiota have variously been implicated as either contributing to gallstone formation or to be affected by cholecystectomy. We conducted a large-scale investigation on 404 gallstone carriers, 580 individuals post-cholecystectomy and 984 healthy controls with similar distributions of age, sex, body mass index, smoking habits, and food-frequency-score. All 1968 subjects were recruited from the population-based Study-of-Health-in-Pomerania (SHIP), which includes transabdominal gallbladder ultrasound. Fecal microbiota profiles were determined by 16S rRNA gene sequencing. No significant differences in microbiota composition were detected between gallstone carriers and controls. Individuals post-cholecystectomy exhibited reduced microbiota diversity, a decrease in the potentially beneficial genus Faecalibacterium and an increase in the opportunistic pathogen Escherichia/Shigella. The absence of an association between the gut microbiota and the presence of gallbladder stones suggests that there is no intestinal microbial risk profile increasing the likelihood of gallstone formation. Cholecystectomy, on the other hand, is associated with distinct microbiota changes that have previously been implicated in unfavorable health effects and may not only contribute to gastrointestinal infection but also to the increased colon cancer risk of cholecystectomized patients.

Purpose Exocrine pancreatic function is critically involved in regulating the gut microbiota composition. At the same time, its impairment acutely affects human metabolism. How these 2 roles are connected is unknown. We studied how the exocrine pancreas contributes to metabolism via modulation of gut microbiota. Design Fecal samples were collected in 2226 participants of the population-based Study of Health in Pomerania (SHIP/SHIP-TREND) to determine exocrine pancreatic function (pancreatic elastase enzyme-linked immunosorbent assay) and intestinal microbiota profiles (16S ribosomal ribonucleic acid gene sequencing). Plasma metabolite levels were determined by mass spectrometry. Results Exocrine pancreatic function was associated with changes in the abundance of 28 taxa and, simultaneously, with those of 16 plasma metabolites. Mediation pathway analysis revealed that a significant component of how exocrine pancreatic function affects the blood metabolome is mediated via gut microbiota abundance changes, most prominently, circulating serotonin and lysophosphatidylcholines. Conclusion These results imply that the effect of exocrine pancreatic function on intestinal microbiota composition alters the availability of microbial-derived metabolites in the blood and thus directly contributes to the host metabolic changes associated with exocrine pancreatic dysfunction.

Objective The intestinal microbiome affects the prevalence and pathophysiology of a variety of diseases ranging from inflammation to cancer. A reduced taxonomic or functional diversity of the microbiome was often observed in association with poorer health outcomes or disease in general. Conversely, factors or manifest diseases that determine the long-term stability or instability of the microbiome are largely unknown. We aimed to identify disease-relevant phenotypes associated with faecal microbiota (in-)stability. Design A total of 2564 paired faecal samples from 1282 participants of the population-based Study of Health in Pomerania (SHIP) were collected at a 5-year (median) interval and microbiota profiles determined by 16S rRNA gene sequencing. The changes in faecal microbiota over time were associated with highly standardised and comprehensive phenotypic data to determine factors related to microbiota (in-)stability. Results The overall microbiome landscape remained remarkably stable over time. The greatest microbiome instability was associated with factors contributing to metabolic syndrome such as fatty liver disease and diabetes mellitus. These, in turn, were associated with an increase in facultative pathogens such as Enterobacteriaceae or Escherichia/Shigella. Greatest stability of the microbiome was determined by higher initial alpha diversity, female sex, high household income and preserved exocrine pancreatic function. Participants who newly developed fatty liver disease or diabetes during the 5-year follow-up already displayed significant microbiota changes at study entry when the diseases were absent. Conclusion This study identifies distinct components of metabolic liver disease to be associated with instability of the intestinal microbiome, increased abundance of facultative pathogens and thus greater susceptibility toward dysbiosis-associated diseases.

Pancreatic fluid collections (PFCs) are a common complication associated with pancreatic injury. Drainage of a PFC is usually indicated if a patient becomes symptomatic with complications such as bacterial superinfection, septicaemia, fistulas, biliary obstruction or gastric outlet obstruction. Endoscopic ultrasound guided drainage is a well-established minimally invasive procedure to insert stents into a fluid collection, most prominently plastic double pigtail stents (DPSs) and lumen-apposing metal stents (LAMS). Both, DPSs and LAMSs have advantages and disadvantages that need to be considered before treatment. However, the main factors leading to failure of currently available stent systems are the relatively short patency period and bacterial superinfection. In this study, we subjected two broadly used pancreatic stents, a DPS and a LAMS Hot AXIOS stent, which were retrieved from the same patient, to a systematic morphological analysis by scanning electron microscopy in order to identify factors related to stent topography and geometry and potentially involved in stent failure. Results of this work will provide essential information for future innovations regarding the stent design for drainage of PFCs.

Syntaxins are SNARE proteins and may play a role in epithelial sodium channel (ENaC) trafficking. The aim of the present study was to investigate the effects of syntaxin 2 (STX2), syntaxin 3 (STX3), and syntaxin 4 (STX4) on rat (rENaC) and human ENaC (hENaC). Co-expression of rENaC and STX3 or STX4 in Xenopus laevis oocytes increased amiloride-sensitive whole-cell currents (ΔIami) on average by 50% and 135%, respectively, compared to oocytes expressing rENaC alone. In contrast, STX2 had no significant effect on rENaC. Similar to its effect on rENaC, STX3 stimulated hENaC by 48%. In contrast, STX2 and STX4 inhibited hENaC by 51% and 44%, respectively. Using rENaC carrying a FLAG tag in the extracellular loop of the β-subunit, we demonstrated that the stimulatory effects of STX3 and STX4 on ΔIami were associated with an increased expression of the channel at the cell surface. Co-expression of STX3 or STX4 did not significantly alter the degree of proteolytic channel activation by chymotrypsin. STX3 had no effect on the inhibition of rENaC by brefeldin A, and the stimulatory effect of STX3 was preserved in the presence of dominant negative Rab11. This indicates that the stimulatory effect of STX3 is not mediated by inhibiting channel retrieval or by stimulating fusion of recycling endosomes. Our results suggest that the effects of syntaxins on ENaC are isoform and species dependent. Furthermore, our results demonstrate that STX3 increases ENaC expression at the cell surface, probably by enhancing insertion of vesicles carrying newly synthesized channels.

The human body is inhabited by diverse microorganisms. Together, this so-called microbiome exerts important metabolic functions and contributes to the maintenance of health. At the same time, shifts in the microbiome composition may lead to disease.Review of the current literature about the role of the microbiome in diseases of the pancreas.Literature search in PubMed and Embase.The exocrine pancreas is a major factor determining the composition and stability of the intestinal microbiome even in healthy people without pancreatic disease. Inflammatory diseases of the pancreas such as acute or chronic pancreatitis lead to reduced microbial diversity, loss of gut barrier stabilizing bacteria and an increase in facultative pathogens like Escherichia or Enterococcus. Even pancreatic cancer tissue harbours microbiota and mice models have shown that the growth of pancreatic cancer can be inhibited by microbiota ablation.Inflammatory diseases of the pancreas lead to gut microbiome dysbiosis and tumor microbiota probably play a role in the development of pancreatic cancer. Until now, however, there is no proof that therapeutic microbiota modulation in individuals with pancreatic disease can improve mortality or quality of life. At this point, the analysis of the microbiome in pancreatic disease should only be performed in scientific studies.HINTERGRUND: Der menschliche Körper wird von einer Vielzahl von Mikroorganismen besiedelt. Dieses sogenannte Mikrobiom übernimmt oder beeinflusst wichtige Stoffwechselfunktionen und trägt zur Aufrechterhaltung der Gesundheit bei. Gleichzeitig können Veränderungen im Mikrobiom zu krankhaften Zuständen führen.Übersicht über den gegenwärtigen Wissensstand zur Rolle des Mikrobioms bei Erkrankungen des Pankreas.Literaturrecherche in PubMed und Embase.Das exokrine Pankreas ist bei Gesunden ohne Pankreaserkrankung ein bedeutender Faktor für die Zusammensetzung und Stabilität des Darmmikrobioms. Entzündliche Erkrankungen des Pankreas wie die akute oder chronische Pankreatitis führen zu einem Verlust an mikrobieller Diversität. Bakterien, welche die Darmbarriere stabilisieren, nehmen ab, während sich fakultative Pathogene wie Escherichia oder Enterococcus vermehren. Auch im Pankreaskarzinomgewebe lassen sich Mikrobiota nachweisen und im Mausmodell kann das Wachstum des Pankreaskarzinoms durch Mikrobiotaablation inhibiert werden.Entzündliche Erkrankungen des Pankreas führen zu einer Dysbiose des Darmmikrobioms und das Pankreaskarzinom wird in seiner Entstehung wahrscheinlich durch ein eigenes Tumormikrobiom beeinflusst. Bislang fehlt allerdings der Nachweis, dass durch therapeutische Modulation des Mikrobioms bei Erkrankungen des Pankreas eine Verbesserung der Mortalität oder Lebensqualität erreichbar ist. Die Analyse des Mikrobioms bei Pankreaserkrankungen sollte daher derzeit nur in Studien durchgeführt werden.

ObjectiveIn acute pancreatitis (AP), bacterial translocation and subsequent infection of pancreatic necrosis are the main risk factors for severe disease and late death. Understanding how immunological host defence mechanisms fail to protect the intestinal barrier is of great importance in reducing the mortality risk of the disease. Here, we studied the role of the Treg/Th17 balance for maintaining the intestinal barrier function in a mouse model of severe AP.DesignAP was induced by partial duct ligation in C57Bl/6 or DEREG mice, in which regulatory T-cells (Treg) were depleted by intraperitoneal injection of diphtheria toxin. By flow cytometry, functional suppression assays and transcriptional profiling we analysed Tregactivation and characterised T-cells of the lamina propria as well as intraepithelial lymphocytes (IELs) regarding their activation and differentiation. Microbiota composition was examined in intestinal samples as well as in murine and human pancreatic necrosis by 16S rRNA gene sequencing.ResultsThe prophylactic Treg-depletion enhanced the proinflammatory response in an experimental mouse model of AP but stabilised the intestinal immunological barrier function of Th17 cells and CD8+/γδTCR+IELs. Tregdepleted animals developed less bacterial translocation to the pancreas. Duodenal overgrowth of the facultative pathogenic taxaEscherichia/Shigellawhich associates with severe disease and infected necrosis was diminished in Tregdepleted animals.ConclusionTregsplay a crucial role in the counterbalance against systemic inflammatory response syndrome. In AP, Treg-activation disturbs the duodenal barrier function and permits translocation of commensal bacteria into pancreatic necrosis. Targeting Tregsin AP may help to ameliorate the disease course.

Helicobacter (H.) pylori is the most important cause for peptic ulcer disease and a risk factor for gastric carcinoma. How colonization with H. pylori affects the intestinal microbiota composition in humans is unknown. We investigated the association of H. pylori infection with intestinal microbiota composition in the population-based cohort Study-of-Health-in-Pomerania (SHIP)-TREND. Anti-H. pylori serology and H. pylori stool antigen tests were used to determine the H. pylori infection status. The fecal microbiota composition of 212 H. pylori positive subjects and 212 matched negative control individuals was assessed using 16S rRNA gene sequencing. H. pylori infection was found to be significantly associated with fecal microbiota alterations and a general increase in fecal microbial diversity. In infected individuals, the H. pylori stool antigen load determined a larger portion of the microbial variation than age or sex. The highest H. pylori stool antigen loads were associated with a putatively harmful microbiota composition. This study demonstrates profound alterations in human fecal microbiota of H. pylori infected individuals. While the increased microbiota diversity associated with H. pylori infection as well as changes in abundance of specific genera could be considered to be beneficial, others may be associated with adverse health effects, reflecting the complex relationship between H. pylori and its human host.

The gut microbiota-dependent metabolite trimethylamine-N-oxide (TMAO) is linked to an increased risk for cardiovascular diseases. Trimethylamine (TMA), which is subsequently oxidized to TMAO in the liver, is formed by intestinal bacteria via distinct biochemical routes from dietary precursors that are enriched in animal product-based foods. To get a full picture of the entire process of the diet > gut microbiota > TMAO axis, we quantified potential TMA-forming gut bacteria and plasma metabolites using gene-targeted assays and targeted metabolomics on a subsample (n = 425) of a German population-based cohort study. We specifically compared persons reporting daily meat intake with those that rarely or never consume meat. While meat intake did not predict TMAO plasma levels in our study, two major bacterial TMA-forming pathways were linked to the metabolite’s concentration. Furthermore, advancing age was strongly associated with TMAO. Construction of a structural equation model allowed us to disentangle the different routes that promote higher TMAO levels with increasing age, demonstrating, for the first time, a functional role of gut microbiota in the process, where specific food items augmented abundances of TMA-forming bacteria that were associated with higher TMAO plasma concentrations. Analyses stratified by age showed an association between carotid intima-media thickness and TMAO only in individuals >65 of age, indicating that this group is particularly affected by the metabolite. IMPORTANCE Many cohort studies have investigated the link between diet and plasma TMAO levels, reporting incongruent results, while gut microbiota were only recently included into analyses. In these studies, taxonomic data were recorded that are not a good proxy for TMA formation, as specific members of various taxa exhibit genes catalyzing this reaction, demanding function-based technologies for accurate quantification of TMA-synthesizing bacteria. Using this approach, we demonstrated that abundances of the main components leading to TMAO formation, i.e., TMA precursors and TMA-forming bacteria, are uncoupled and not governed by the same (dietary) factors. Results emphasize that all levels leading to TMA(O) formation should be considered for accurate risk assessment, rejecting the simple view that diets rich in TMA precursors directly lead to increased plasma levels of this hazardous compound. The results can assist in developing strategies to reduce TMAO levels, specifically in the elderly, who are prone to TMAO-associated diseases.

The gut microbiota synthesize hundreds of molecules, many of which influence host physiology. Among the most abundant metabolites are the secondary bile acids deoxycholic acid (DCA) and lithocholic acid (LCA), which accumulate at concentrations of around 500 μM and are known to block the growth of Clostridium difficile

In this work, we introduce an entirely data-driven and automated approach to reveal disease-associated biomarker and risk factor networks from heterogeneous and high-dimensional healthcare data. Our workflow is based on Bayesian networks, which are a popular tool for analyzing the interplay of biomarkers. Usually, data require extensive manual preprocessing and dimension reduction to allow for effective learning of Bayesian networks. For heterogeneous data, this preprocessing is hard to automatize and typically requires domain-specific prior knowledge. We here combine Bayesian network learning with hierarchical variable clustering in order to detect groups of similar features and learn interactions between them entirely automated. We present an optimization algorithm for the adaptive refinement of such group Bayesian networks to account for a specific target variable, like a disease. The combination of Bayesian networks, clustering, and refinement yields low-dimensional but disease-specific interaction networks. These networks provide easily interpretable, yet accurate models of biomarker interdependencies. We test our method extensively on simulated data, as well as on data from the Study of Health in Pomerania (SHIP-TREND), and demonstrate its effectiveness using non-alcoholic fatty liver disease and hypertension as examples. We show that the group network models outperform available biomarker scores, while at the same time, they provide an easily interpretable interaction network., Author summary High-dimensional and heterogeneous healthcare data, such as electronic health records or epidemiological study data, contain much information on yet unknown risk factors that are associated with disease development. The identification of these risk factors may help to improve prevention, diagnosis, and therapy. Bayesian networks are powerful statistical models that can decipher these complex relationships. However, high dimensionality and heterogeneity of data, together with missing values and high feature correlation, make it difficult to automatically learn a good model from data. To facilitate the use of network models, we present a novel, fully automated workflow that combines network learning with hierarchical clustering. The algorithm reveals groups of strongly related features and models the interactions among those groups. It results in simpler network models that are easier to analyze. We introduce a method of adaptive refinement of such models to ensure that disease-relevant parts of the network are modeled in great detail. Our approach makes it easy to learn compact, accurate, and easily interpretable biomarker interaction networks. We test our method extensively on simulated data as well as data from the Study of Health in Pomerania (SHIP-Trend) by learning models of hypertension and non-alcoholic fatty liver disease.

Contains fulltext : 231681.pdf (Publisher’s version ) (Closed access) To study the effect of host genetics on gut microbiome composition, the MiBioGen consortium curated and analyzed genome-wide genotypes and 16S fecal microbiome data from 18,340 individuals (24 cohorts). Microbial composition showed high variability across cohorts: only 9 of 410 genera were detected in more than 95% of samples. A genome-wide association study of host genetic variation regarding microbial taxa identified 31 loci affecting the microbiome at a genome-wide significant (P

INTRODUCTION: Exocrine pancreatic function is a critical host factor in determining the intestinal microbiota composition. Diseases affecting the exocrine pancreas could therefore influence the gut microbiome. We investigated the changes in gut microbiota of patients with chronic pancreatitis (CP). METHODS: Patients with clinical and imaging evidence of CP (n = 51) were prospectively recruited and compared with twice the number of nonpancreatic disease controls matched for distribution in age, sex, body mass index, smoking, diabetes mellitus, and exocrine pancreatic function (stool elastase). From stool samples of these 153 subjects, DNA was extracted, and intestinal microbiota composition was determined by bacterial 16S ribosomal RNA gene sequencing. RESULTS: Patients with CP exhibited severely reduced microbial diversity (Shannon diversity index and Simpson diversity number, P < 0.001) with an increased abundance of facultative pathogenic organisms (P < 0.001) such as Enterococcus (q < 0.001), Streptococcus (q < 0.001), and Escherichia.Shigella (q = 0.002). The CP-associated changes were independent of exocrine pancreatic insufficiency. Short-chain fatty acid producers, considered protective for epithelia such as Faecalibacterium (q < 0.001), showed reduced abundance in patients with CP. Of 4 additional patients with CP previously treated with antibiotics (ceftriaxone and metronidazole), 3 patients were characterized by distinct Enterococcus overgrowth. DISCUSSION: CP is associated with marked gut microbiota dysbiosis, greatly reduced diversity, and increased abundance of opportunistic pathogens, specifically those previously isolated from infected pancreatic necrosis. Taxa with a potentially beneficial role in intestinal barrier function are depleted. These changes can increase the probability of complications from pancreatitis such as infected fluid collections or small intestinal bacterial overgrowth (see Graphical Abstract, Supplementary Digital Content 1, http://links.lww.com/CTG/A383).

The intestinal microbiome is implicated as an important modulating factor in multiple inflammatory,1,2 neurologic,3 and neoplastic diseases.4 Recent genome-wide association studies yielded inconsistent, underpowered and rarely replicated results such that the role of human host genetics as a contributing factor to microbiome assembly and structure remains uncertain.5–11 Nevertheless, twin-studies clearly suggest host-genetics as driver of microbiome composition.11 In a genome-wide association analysis of 8,956 German individuals, we identified 32 genetic loci to be associated with single bacteria and overall microbiome composition. Further analyses confirm the identified associations of ABO histo-blood groups and FUT2 secretor status with Bacteroides and Faecalibacterium. Mendelian randomization analysis suggests causative and protective effects of gut microbes, with clade-specific effects on inflammatory bowel disease. This holistic investigative approach of the host, its genetics, and its associated microbial communities as a ‘metaorganism’ broadens our understanding of disease aetiology and emphasizes the potential for implementing microbiota in disease treatment and management.

To study the effect of host genetics on gut microbiome composition, the MiBioGen consortium curated and analyzed genome-wide genotypes and 16S fecal microbiome data from 18,340 individuals (24 cohorts). Microbial composition showed high variability across cohorts: only 9 out of 410 genera were detected in more than 95% samples. A genome-wide association study (GWAS) of host genetic variation in relation to microbial taxa identified 31 loci affecting microbiome at a genome-wide significant (P−8) threshold. One locus, the lactase (LCT) gene locus, reached study-wide significance (GWAS signal P=1.28×10−20), and it showed an age-dependent association with Bifidobacterium abundance. Other associations were suggestive (1.95×10−10−8) but enriched for taxa showing high heritability and for genes expressed in the intestine and brain. A phenome-wide association study and Mendelian randomization identified enrichment of microbiome trait loci in the metabolic, nutrition and environment domains and suggested the microbiome has causal effects in ulcerative colitis and rheumatoid arthritis.

Background and aim Malnutrition is a frequent complication of chronic pancreatitis. Adequate nutritional support is imperative, but there is still uncertainty about the optimal nutritional treatment. This work systematically compiles evidence from randomized controlled trials investigating dietary interventions in chronic pancreatitis and, in a further step, contrasts those findings with existing dietary recommendations. Methods The literature search (PubMed and Cochrane Central Register of Controlled Trials) included English and German full-text articles, which had been published in peer-reviewed journals. Two independent reviewers identified and selected studies. For meta-analysis, forest plots with 95% confidence intervals were generated using a random-effects model. Results Eleven randomized controlled trials fulfilled all selection criteria. In these trials, the following dietary interventions were tested: antioxidant treatment (n = 6), vitamin D supplementation (n = 3), supplementation with oral nutritional supplements (n = 1), and symbiotics supplementation (n = 1). Studies were of good methodological quality (mean Jadad score of 3.6) but heterogeneous in terms of interventions and study populations. Only for vitamin D, there was convincing evidence for efficacy of supplementation. We found no effect for antioxidant treatment on pain relief (standardized mean difference = -0.12; 95% confidence interval -0.73 to 0.48) and limited generalizability for interventions with oral nutritional supplements and symbiotics. Conclusions Nutritional management in chronic pancreatitis remains challenging. As well-designed randomized controlled trials are scarce, in large part, recommendations can only be based on low-level evidence studies or expert opinion. For now, consumption of a balanced diet remains the cornerstone recommendation for prevention, whereas more goal-directed interventions are indicated for specific nutrient deficiencies.

Objectives: To investigate the relation between exocrine pancreatic function and secretin-stimulated magnetic resonance cholangiopancreatography (sMRCP) fluid volumes and its concordance to pancreatic elastase using a case-control approach. Methods: Navigator-triggered T2-weighted 3D-turbo-spin-echo sMRCP was performed on a 1·5-T-system in 977 subjects including volunteers without a history of pancreatitis (group: A n=917) and chronic pancreatic disorder patients without (group: B, n=32) and with diagnosis of exocrine pancreatic insufficiency (EPI) (group: C, n=28). After intravenous administration of 1 unit/kg secretin duodenal filling was graded (0-3) and quantified as sMRCP fluid volume. According to pancreatic elastase ELISA subjects were grouped as severe (

Wurde durch die Entdeckung von Helicobacter plyori das Konzept des sterilen Magens ein erstes Mal revidiert, muss durch die Anwendung molekularbiologischer Verfahren und die Ergebnisse tierexperimenteller Arbeiten auch der Einfluss anderer Bakterien auf Erkrankungen des Magens und des Duodenums angenommen werden. Unverandert ist die Unterscheidung zwischen transienten und residenten Bakterien und ihre detaillierte Rolle im Zusammenspiel der gesamten mikrobiellen Gemeinschaft nicht in allen Einzelheiten verstanden. Dieser Review vermittelt einen Uberblick zum derzeitigen Kenntnisstand uber Helicobacter pylori und andere Bakterien des oberen Gastrointestinaltrakts in Zusammenhang mit gastroduodenalen Erkrankungen.

Obesity and type 2 diabetes (T2D) are metabolic disorders that are linked to microbiome alterations. However, their co-occurrence poses challenges in disentangling microbial features unique to each condition. We analyzed gut microbiomes of lean non-diabetic (n = 633), obese non-diabetic (n = 494), and obese individuals with T2D (n = 153) from German population and metabolic disease cohorts. Microbial taxonomic and functional profiles were analyzed along with medical histories, serum metabolomics, biometrics, and dietary data. Obesity was associated with alterations in microbiome composition, individual taxa, and functions with notable changes in Akkermansia, Faecalibacterium, Oscillibacter, and Alistipes, as well as in serum metabolites that correlated with gut microbial patterns. However, microbiome associations were modest for T2D, with nominal increases in Escherichia/Shigella. Medications, including antihypertensives and antidiabetics, along with dietary supplements including iron, were significantly associated with microbiome variation. These results differentiate microbial components of these interrelated metabolic diseases and identify dietary and medication exposures to consider in future studies.

ObjectiveIgG4-related disease (IgG4-RD) is a heterogeneous, multiorgan condition of unclear aetiology that can cause organ failure. Difficulty recognising IgG4-RD contributes to diagnostic delays. We sought to identify key IgG4-RD phenotypes.MethodsWe used two cross-sectional studies assembled by an international, multispecialty network of IgG4-RD specialists who submitted 765 cases to derive and replicate phenotypic groups. Phenotype groups of disease manifestations and key covariate distributions across the identified groups were measured using latent class analysis.ResultsIn the derivation cohort (n=493), we identified four groups with distinct manifestations: Group 1 (31%), Pancreato-Hepato-Biliary disease; Group 2 (24%), Retroperitoneal Fibrosis and/or Aortitis; Group 3 (24%), Head and Neck-Limited disease and Group 4 (22%), classic Mikulicz syndrome with systemic involvement. We replicated the identification of four phenotype groups in the replication cohort. Compared with cases in Groups 1, 2 and 4, respectively, cases in Group 3 were more likely to be female (OR 11.60 (95% CI 5.39 to 24.98), 10.35 (95% CI 4.63 to 23.15) and 9.24 (95% CI 3.53 to 24.20)) and Asian (OR 6.68 (95% CI 2.82 to 15.79), 7.43 (95% CI 2.97 to 18.56) and 6.27 (95% CI 2.27 to 17.29)). Cases in Group 4 had a higher median serum IgG4 concentration (1170 mg/dL) compared with groups 1–3 (316, 178 and 445 mg/dL, respectively, pConclusionWe identified four distinctive IgG4-RD phenotypes according to organ involvement. Being Asian or female may predispose individuals to head and neck-limited disease. These phenotypes serve as a framework for identifying IgG4-RD and studying its aetiology and optimal treatment.

We read with interest the study by Simren et al 1 addressing the correlation between GI symptoms and functional GI disorders (eg, irritable bowel syndrome (IBS)) and the comment by Hadizadeh et al 2 reporting abdominal pain sensation to be associated with an altered faecal microbiota composition. Hadizadeh et al 2 propose from their study on 159 individuals that their results may allow to develop novel tools for diagnosis and management of IBS and dyspepsia. We tried to replicate their findings in the population-based Study of Health in Pomerania (SHIP-Trend)3 using stool samples from 906 volunteers to analyse faecal microbiota composition and diversity by 16S rRNA gene sequencing as previously described.4 Twenty participants were excluded for incomplete phenotypic data or antibiotic treatment at sample collection. Of the remaining 886 individuals (age: 51 years (40–61), median (first to third quartiles); female: 56.4%), 172 (19.4%) reported abdominal pain or discomfort for at least 3 days per month during the last 3 months (cases), whereas 714 did not (controls). To estimate …