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The intestinal microbiome is implicated as an important modulating factor in multiple inflammatory, neurologic, and neoplastic diseases. 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. Nevertheless, twin-studies clearly suggest host-genetics as driver of microbiome composition. 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.

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