Food and Behaviour Research

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Causal relationships among the gut microbiome, short-chain fatty acids and metabolic diseases

Sanna S, van Zuydam NR, Mahajan A, Kurilshikov A, Vich Vila A, V├Ása U, Mujagic Z, Masclee AAM, Jonkers DMAE, Oosting M, Joosten LAB, Netea MG, Franke L, Zhernakova A, Fu J, Wijmenga C, McCarthy MI (2019) Nat Genet.  2019 Feb.  doi: 10.1038/s41588-019-0350-x. [Epub ahead of print] 

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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 causality3, we found that the host-genetic-driven increase in gutproduction of the SCFA butyrate was associated with improved insulin response after an oral glucose-tolerance test (P = 9.8 × 10-5), 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.