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Sanna, Serena; van Zuydam, Natalie R; Mahajan, Anubha; Kurilshikov, Alexander; Vich Vila, Arnau; Võsa, Urmo; Mujagic, Zlatan; Masclee, Ad A M; Jonkers, Daisy M A E; Oosting, Marije; Joosten, Leo A B; Netea, Mihai G; Franke, Lude; Zhernakova, Alexandra; Fu, Jingyuan; Wijmenga, Cisca; McCarthy, Mark I
Nature genetics, 04/2019, Volume: 51, Issue: 4Journal Article
Microbiome-wide association studies on large population cohorts have highlighted associations between the gut microbiome and complex traits, including type 2 diabetes (T2D) and obesity . However, the causal relationships remain largely unresolved. We leveraged information from 952 normoglycemic individuals for whom genome-wide genotyping, gut metagenomic sequence and fecal short-chain fatty acid (SCFA) levels were available , then combined this information with genome-wide-association summary statistics for 17 metabolic and anthropometric traits. Using bidirectional Mendelian randomization (MR) analyses to assess causality , we found that the host-genetic-driven increase in gut production of the SCFA butyrate was associated with improved insulin response after an oral glucose-tolerance test (P = 9.8 × 10 ), whereas abnormalities in the production or absorption of another SCFA, propionate, were causally related to an increased risk of T2D (P = 0.004). These data provide evidence of a causal effect of the gut microbiome on metabolic traits and support the use of MR as a means to elucidate causal relationships from microbiome-wide association findings.
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