Organ cross talk of human microbiota and its role for health and disease in the German National Cohort

• Applicants: Professorin Dr. Sofia Forslund-Startceva; Professor Dr. André Karch; Professor Dr. Andreas Keller; Dr. Berit Lange; Professorin Dr. Annette Peters; Professor Dr. Stefan Rupf; Nicole Rübsamen, Ph.D.; Professor Dr. Till Strowig; Dr. Marius Vital
• Subject Area: Epidemiology and Medical Biometry/Statistics ; General Genetics and Functional Genome Biology ; Bioinformatics and Theoretical Biology
• Term: since 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 514199519

While there is strong evidence for an association between the human microbiome and health/disease in the human host, the causal mechanisms behind this association are only partially understood. Dependent on the disease or health status under study, similar patterns of microbiome dysbiosis have been described for various body sites associated with different organ systems. This led to the hypothesis that there exist body-wide microbiome-induced pathways linked by microbial organ cross talk. The German National Cohort (NAKO; n=200,000) is the only population-based cohort worldwide that offers biosamples specifically collected for microbiome analyses from three different body sites. The availability of these biosamples collected during the NAKO baseline examination together with the detailed and comprehensive phenotype assessment makes NAKO the perfect resource for microbiome cross talk analysis. In addition, data from the first passive follow-up of NAKO as well as from two intermediate questionnaire-based follow-ups are available, allowing for a longitudinal perspective of all analyses. We will use data and biosamples of 2,000 NAKO participants to investigate the microbial organ cross talk between the human gut (stool samples), oral cavity (saliva samples) and upper respiratory system (nasal swabs) by whole metagenome shotgun sequencing. Based on standardized platforms for biosample collection and storage, DNA extraction and whole metagenome shotgun sequencing developed by the applicants specifically for the NAKO framework, this project will be able to derive the site-specific as well as the joint composition and functional capacity of the microbiome in the human host. Microbial translocations will be studied between the three body sites to gain a comprehensive insight into the microbial dynamics based on bacterial and non-bacterial reads, and to identify microbial signatures down to rare species of the human microbiota that might shape health or disease. Compositional and functional microbiome clusters (defined as archetypes with distinct metacommunities) will be derived within and across body sites together with their respective compositional and functional patterns. Determinants of these archetypes (and the associated metacommunities) will be investigated based on NAKO phenotype data including age, nutrition, dentition functionality, sociodemographic factors, infection history, host metabolism, environmental exposure, medication (including antibiotic treatment), as well as disease status and disease pathways. Finally, we will establish procedures to take advantage of the longitudinal design of NAKO for health implications. As an initial use case we will study conditions where gradual loss of homeostasis of host-microbiome interaction results in substantial and relevant subclinical variation, focusing on the role of microbiota 1) in early cardio-metabolic diseases and 2) through the gut-brain axis, in the continuum of mood disorders.

• DFG Programme: Research Grants