The prospective Kiel Inflammatory Bowel Disease (IBD) Family Cohort Study (KINDRED cohort) was initiated in 2013 to systematically and extensively collect data and biosamples from index IBD patients and their relatives, a population at high risk for IBD development. Regular follow-ups were conducted to collect updated health and lifestyle information, to obtain new biosamples, and to capture the incidence of IBD during development. By combining microbial data collected at successive time points with extensive anthropometric, medical, nutritional, and social information, this study aimed to characterize the factors influencing the microbiota in health and disease via detailed ecological analyses. Using a microbial dysbiosis metric based on the German KINDRED cohort, we identified strong and generalizable gradients within and across different external IBD cohorts for validation. These community gradients correspond strongly with IBD pathologies, physiological manifestations of inflammation (e.g. Bristol stool score, ASCA IgA, ASCA IgG), and genetic risk for IBD. Anthropometric and medical factors influencing fecal transit time strongly modify bacterial communities. Various Enterobacteriaceae (e.g. Klebsiella sp.) and opportunistic Clostridia pathogens (e.g. C. XIVa clostridioforme), characterize in combination with ectopically colonizing oral taxa (e.g. Veillonella sp. Cand. Saccharibacteria sp. Fusobacterium nucleatum) the distinct and chaotic IBD-specific communities. Weak community and physiological changes are further traceable in a small number of individuals, who developed IBD in the study's runtime. Our findings demonstrate broad-scale ecological patterns which indicate drastic state transitions of communities in IBD patients. These patterns appear to be universal across cohorts and influence physiological signs of inflammation, display increased resilience, but show only limited heritability/intrafamily transmission.

Population-based biobanking is an essential element of medical research that has grown substantially over the last two decades, and many countries are currently pursuing large national biobanking initiatives. The rise of individual biobanks is paralleled by various networking activities in the field at both the national and international level, such as BBMRI-ERIC in the EU. A significant contribution to population-based biobanking comes from large cohort studies and national repositories, including the United Kingdom Biobank (UKBB), the CONSTANCES project in France, the German National Cohort (NAKO), LifeLines in the Netherlands, FinnGen in Finland, and the All of Us project in the U.S. At the same time, hospital-based biobanking has also gained importance in medical research. We describe some of the scientific questions that can be addressed particularly well by the use of population-based biobanks, including the discovery and calibration of biomarkers and the identification of molecular correlates of health parameters and disease states. Despite the tremendous progress made so far, some major challenges to population-based biobanking still remain, including the need to develop strategies for the long-term sustainability of biobanks, the handling of incidental findings, and the linkage of sample-related and sample-derived data to other relevant resources.

Aberrant CD4+ T cell reactivity against intestinal microorganisms is considered to drive mucosal inflammation in inflammatory bowel diseases. The disease-relevant microbial species and the corresponding microorganism-specific, pathogenic T cell phenotypes remain largely unknown. In the present study, we identified common gut commensal and food-derived yeasts, as direct activators of altered CD4+ T cell reactions in patients with Crohn's disease (CD). Yeast-responsive CD4+ T cells in CD display a cytotoxic T helper cell (TH1 cell) phenotype and show selective expansion of T cell clones that are highly cross-reactive to several commensal, as well as food-derived, fungal species. This indicates cross-reactive T cell selection by repeated encounter with conserved fungal antigens in the context of chronic intestinal disease. Our results highlighted a role of yeasts as drivers of aberrant CD4+ T cell reactivity in patients with CD and suggest that both gut-resident fungal commensals and daily dietary intake of yeasts might contribute to chronic activation of inflammatory CD4+ T cell responses in patients with CD.

Inflammatory bowel disease (IBD) is associated with dysbiotic microbiomes. However, whether microbiomes of family members of IBD patients harbour microbial disease signatures of IBD is unknown. Here, we generate shotgun metagenomic data of an IBD family cohort and treatment-naive IBD cases, which we combine with published IBD metagenomes, to perform a meta-analysis of IBD-microbiome associations. Our study reveals microbial shifts that are specific to IBD or IBD subtypes (Crohn’s disease and ulcerative colitis). We find that IBD cohorts share signatures of association with disease irrespective of geography, and we report novel species-level identifications of microbial taxa that are universal markers of Crohn’s disease. We further demonstrate that the microbiome of healthy family members at high risk for IBD represent transitional states between the microbiome of unrelated healthy controls and IBD cases, and harbor diversity, compositional and ecological features that are also observed among IBD microbiomes. Overall, our study provides valuable insights into the intricate relationship between the gut microbiome and IBD, with implications for better predicting disease onset among individuals with high susceptibility for IBD. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This study was financed through the EU Horizon miGut-Health project (Personalised blueprint of chronic inflammation in health-to-disease transition; Grant agreement ID: 101095470, AF, MG) and the DFG-sequencing grant Identification of early fine-scale microbial signatures in inflammatory bowel disease (project 433152305, CB, AF, WL). Microbiome sequencing and data analysis received infrastructure support from the DFG Excellence Cluster 2167 (Precision Medicine in Chronic Inflammation (PMI)) and the DFG Research Unit 5042 miTarget. MR was supported by the Bruhn foundation for the advancement of medical research. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Ethics committee of the Medical Faculty of Kiel University gave ethical approval for this work (AZ A117/13 & AZ A103/14) I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Data and material of the IBD-FC cohort are available upon the submission of a research proposal to https://portal.popgen.de/. Data of the ITM cohort will be uploaded to ENA upon acceptance of this manuscript at a peer-reviewed journal.

The significance of human biorepositories for modern medical research, particularly for comprehensive population-based genetic analyses, is constantly growing. While large and centralized institutions are usually considered best suited to meet the increasing demand for high-quality “biobanks,” most medical research institutions still host rather heterogeneous and fragmented biobanking activities, undertaken by clinical departments with oftentimes rather different scientific scope. Undoubtedly, most clinicians and medical researchers would appreciate infrastructural support in terms of the storage and handling of their biosamples, but they are also likely to expect access to their samples avoiding extensive formal requirements. We report on the establishment of the PopGen 2.0 Network (P2N), an overarching alliance of initially seven biobanks from Northern Germany which adopted a joint but lean governance structure and use-and-access policy for their samples and data. In addition, the members of P2N have pursued an intense collaboration on ethical, legal and social issues and maintain a common IT infrastructure. The implementation of P2N has substantially improved the prospects of biobank-based research at the participating institutions. The network may thus serve as a role model for similar initiatives geared at linking pre-existing biorepositories for the benefit of research quality, efficiency, and transparency.

Purpose The aim of the present study was to derive overall and sex-specific dietary patterns associated with inflammatory biomarkers in a general population sample from Northern Germany. Methods The present analysis included 1158 participants (477 men, 681 women, mean age: 53.1 years; mean body mass index: 26.2 kg/m(2)) of the Food Chain Plus (FoCus) cohort in Kiel, Germany. Participants completed a semi-quantitative food frequency questionnaire and provided blood samples. Reduced rank regression with C-reactive protein (CRP) and Interleukin 6 (IL-6) as response variables was used to derive dietary patterns. After a mean follow-up of 1.7 years, a second blood sample was obtained in a subsample of 112 individuals. Multiple regression models were used to examine the association between dietary patterns at baseline and inflammatory biomarkers at follow-up. Results The overall pattern characterised by high intakes of soft drinks, meat, potatoes and sauce, and low intakes of other cereals (except pasta/rice), wine, nuts, seeds, vegetarian dishes, vegetable oil, and fish was positively associated with CRP (OR 2.20; 95% CI 1.12, 4.35) and IL-6 (OR 3.14; 95% CI 1.26, 7.87) at follow-up. In men, the dietary pattern was higher in soft drinks, processed meat and low in cereals and plant-based fats. In women, the pattern was characterised by soft drinks, meat, vegetables and low in other cereals, wine, nuts, and seeds. The association between sex-specific patterns with inflammatory biomarkers was weaker for CRP. Conclusion We identified dietary patterns positively associated with established biomarkers of chronic low-grade inflammation.

The association of complex dietary patterns with circulating selenoprotein P (SELENOP) levels in humans is unknown. In a general population sample, we aimed to identify a dietary pattern explaining inter-individual variation in circulating SELENOP concentrations and to study this pattern in relation to prevalent diabetes, metabolic syndrome (MetS), MRI-determined total volumes of visceral (VAT) and subcutaneous (SAT) abdominal adipose tissue, and liver signal intensity/fatty liver disease.

In addition to well-established risk factors like older age, female gender, and adiposity, oxidative stress may play a role in the pathophysiology of gallstone disease. Since vitamin E exerts important anti-oxidative functions, we hypothesized that circulating vitamin E levels might be inversely associated with prevalence of gallstone disease. In a cross-sectional study, we measured plasma levels of α- and γ-tocopherol using high performance liquid chromatography in a community-based sample (582 individuals; median age 62 years; 38.5% women). Gallstone disease status was assessed by ultrasound. Multivariable-adjusted logistic regression models were used to estimate the association of circulating α- and γ-tocopherol/cholesterol ratio levels with prevalent gallstone disease. Lower probabilities of having gallstone disease were observed in the top (compared to the bottom) tertile of the plasma α-tocopherol/cholesterol ratio in multivariable-adjusted models (OR (Odds Ratio): 0.31; 95% CI (Confidence Interval): 0.13–0.76). A lower probability of having gallstone disease was also observed for the γ-tocopherol/cholesterol ratio, though the association did not reach statistical significance (OR: 0.77; 95% CI: 0.35–1.69 for 3rd vs 1st tertile). In conclusion, our observations are consistent with the concept that higher vitamin E levels might protect from gallstone disease, a premise that needs to be further addressed in longitudinal studies.

Digitalization is currently permeating virtually all sectors of modern societies, including biomedical research and medical care. At the same time, biobanks engaged in the long-term storage of biological samples that are fit for purpose have become key drivers in both fields. The present article highlights some of the challenges and opportunities that biobanking is facing in the current proverbial "era of digitalization."

Little is known about the distribution and determinants of circulating vitamin E levels in a German population. In this cross-sectional study we assessed the distribution of both α- and γ-tocopherol levels, identified their clinical and biochemical correlates, and assessed their relationships with a priori and a posteriori derived dietary patterns. Plasma α- and γ-tocopherol concentrations were measured using high performance liquid chromatography (HPLC) with fluorescence detection in 641 individuals (mean-age: 61 years; 40.6% women). Correlates of both markers were determined using linear regression with backward selection. Using a validated food-frequency questionnaire (FFQ), an a priori defined vitamin E-rich dietary pattern was constructed, and three a posteriori derived dietary patterns were identified by principal component analysis. Each pattern was related to α- and γ-tocopherol levels using linear regression. Median concentrations of α- and γ-tocopherol were 31.54 μmol/L and 1.35 µmol/L, respectively. 57.6% of participants had α-tocopherol levels >30 µmol/L. Triglycerides, high density lipoprotein (HDL)- and low density lipoprotein (LDL)-cholesterol, and vitamin E supplementation were identified as correlates of vitamin E levels. After excluding supplement users, a dietary pattern rich in meat, bread, fats, potatoes, and sugar/confectionery was inversely related to α-tocopherol levels (β, −0.032, SE = 0.016; p = 0.047). Prospective studies are warranted to evaluate the actual impact of the reported findings in terms of nutrition and health outcomes.

Selenoprotein P (SELENOP) has been previously related to various metabolic traits with partially conflicting results. The identification of SELENOP-associated metabolites, using an untargeted metabolomics approach, may provide novel biological insights relevant to disentangle the role of SELENOP in human health.

ObjectiveAssociation studies of selenoprotein P (SELENOP) with cardiometabolic traits in humans are relatively scarce and, in part, conflicting. A general population sample from Northern Germany was evaluated for cross‐sectional associations of circulating SELENOP concentrations with metabolic syndrome (MetS), total volumes of MRI‐determined visceral (VAT) and subcutaneous (SAT) abdominal adipose tissue, liver signal intensity, and fatty liver disease (FLD).MethodsNine hundred and five participants received comprehensive clinical and molecular phenotyping along with measurement of serum SELENOP; 584 individuals received MRI.ResultsMultivariable‐adjusted restricted cubic regression splines displayed statistically significant inverse relations of SELENOP levels with MetS, VAT, and SAT (P < 0.0001 for all). Compared with the second quartile of SELENOP distribution, the MetS odds ratios for the first, third, and fourth quartiles were 1.62 (95% confidence interval [CI]: 1.08‐2.43), 0.85 (95% CI: 0.57‐1.26), and 0.41 (95% CI: 0.27‐0.62), respectively. Furthermore, participants in the second, third, and fourth SELENOP quartiles had significantly lower VAT and SAT volumes as compared to those in the first biomarker quartile. A J‐shaped relation was observed for SELENOP levels and liver signal intensity/FLD (P = 0.01).ConclusionsThe findings suggest inverse associations of circulating SELENOP concentrations with several metabolic traits, to be further investigated in longitudinal studies.

Aim: Selenoprotein P, a selenium-rich hepatokine, serves as main carrier for selenium from the liver to peripheral organs. Data on the associations of selenoprotein P with cardiometabolic traits in humans are still relatively scarce and in part conflicting.

We aimed to relate circulating α- and γ-tocopherol levels to a broad spectrum of adiposityrelated traits in a cross-sectional Northern German study. Anthropometric measures were obtained, and adipose tissue volumes and liver fat were quantified by magnetic resonance imaging in 641 individuals (mean age 61 years; 40.6% women). Concentrations of α- and γ-tocopherol were measured using high performance liquid chromatography. Multivariable-adjusted linear and logistic regression were used to assess associations of circulating α- and γ-tocopherol/cholesterol ratio levels with visceral (VAT) and subcutaneous adipose tissue (SAT), liver signal intensity (LSI), fatty liver disease (FLD), metabolic syndrome (MetS), and its individual components. The α- tocopherol/cholesterol ratio was positively associated with VAT (β scaled by interquartile range (IQR): 0.036; 95%Confidence Interval (CI): 0.0003; 0.071) and MetS (Odds Ratio (OR): 1.83; 95% CI: 1.21–2.76 for 3rd vs. 1st tertile), and the γ-tocopherol/cholesterol ratio was positively associated with VAT (β scaled by IQR: 0.066; 95% CI: 0.027; 0.104), SAT (β scaled by IQR: 0.048; 95% CI: 0.010; 0.087) and MetS (OR: 1.87; 95% CI: 1.23–2.84 for 3rd vs. 1st tertile). α- and γ-tocopherol levels were positively associated with high triglycerides and low high density lipoprotein cholesterol levels (all Ptrend < 0.05). No association of α- and γ-tocopherol/cholesterol ratio with LSI/FLD was observed. Circulating vitamin E levels displayed strong associations with VAT and MetS. These observations lay the ground for further investigation in longitudinal studies.

Background/Objectives: Fatty liver disease (FLD) is an important intermediate trait along the cardiometabolic disease spectrum and strongly associates with type 2 diabetes. Knowledge of biological pathways implicated in FLD is limited. An untargeted metabolomic approach might unravel novel pathways related to FLD. Subjects/Methods: In a population-based sample ( n =555) from Northern Germany, liver fat content was quantified as liver signal intensity using magnetic resonance imaging. Serum metabolites were determined using a non-targeted approach. Partial least squares regression was applied to derive a metabolomic score, explaining variation in serum metabolites and liver signal intensity. Associations of the metabolomic score with liver signal intensity and FLD were investigated in multivariable-adjusted robust linear and logistic regression models, respectively. Metabolites with a variable importance in the projection >1 were entered in in silico overrepresentation and pathway analyses. Results: In univariate analysis, the metabolomics score explained 23.9% variation in liver signal intensity. A 1-unit increment in the metabolomic score was positively associated with FLD ( n =219; odds ratio: 1.36; 95% confidence interval: 1.27–1.45) adjusting for age, sex, education, smoking and physical activity. A simplified score based on the 15 metabolites with highest variable importance in the projection statistic showed similar associations. Overrepresentation and pathway analyses highlighted branched-chain amino acids and derived gamma-glutamyl dipeptides as significant correlates of FLD. Conclusions: A serum metabolomic profile was associated with FLD and liver fat content. We identified a simplified metabolomics score, which should be evaluated in prospective studies.

Coenzyme Q10 (CoQ10) is a lipophilic redox molecule that is present in membranes of almost all cells in human tissues. CoQ10 is, amongst other functions, essential for the respiratory transport chain and is a modulator of inflammatory processes and gene expression. Rare monogenetic CoQ10 deficiencies show noticeable symptoms in tissues (e.g. kidney) and cell types (e.g. neurons) with a high energy demand. To identify common genetic variants influencing serum CoQ10 levels, we performed a fixed effects meta-analysis in two independent cross-sectional Northern German cohorts comprising 1300 individuals in total. We identified two genome-wide significant susceptibility loci. The best associated single nucleotide polymorphism (SNP) was rs9952641 (P value = 1.31 × 10 -8, β = 0.063, CI0.95 [0.041, 0.085]) within the COLEC12 gene on chromosome 18. The SNP rs933585 within the NRXN-1 gene on chromosome 2 also showed genome wide significance (P value = 3.64 × 10 -8, β = -0.034, CI0.95 [-0.046, -0.022]). Both genes have been previously linked to neuronal diseases like Alzheimer's disease, autism and schizophrenia. Among our 'top-10' associated variants, four additional loci with known neuronal connections showed suggestive associations with CoQ10 levels. In summary, this study demonstrates that serum CoQ10 levels are associated with common genetic loci that are linked to neuronal diseases.

Reduced glomerular filtration rate defines chronic kidney disease and is associated with cardiovascular and all-cause mortality. We conducted a meta-analysis of genome-wide association studies for estimated glomerular filtration rate (eGFR), combining data across 133,413 individuals with replication in up to 42,166 individuals. We identify 24 new and confirm 29 previously identified loci. Of these 53 loci, 19 associate with eGFR among individuals with diabetes. Using bioinformatics, we show that identified genes at eGFR loci are enriched for expression in kidney tissues and in pathways relevant for kidney development and transmembrane transporter activity, kidney structure, and regulation of glucose metabolism. Chromatin state mapping and DNase I hypersensitivity analyses across adult tissues demonstrate preferential mapping of associated variants to regulatory regions in kidney but not extra-renal tissues. These findings suggest that genetic determinants of eGFR are mediated largely through direct effects within the kidney and highlight important cell types and biological pathways.