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

Serena Sanna, Natalie R van Zuydam, Anubha Mahajan, Alexander Kurilshikov, Arnau Vich Vila, Urmo Võsa, Zlatan Mujagic, Ad A M Masclee, Daisy M A E Jonkers, Marije Oosting, Leo A B Joosten, Mihai G Netea, Lude Franke, Alexandra Zhernakova, Jingyuan Fu, Cisca Wijmenga, Mark I McCarthy

Research output: Contribution to journalLetterAcademicpeer-review

215 Citations (Scopus)
6 Downloads (Pure)

Abstract

Microbiome-wide association studies on large population cohorts have highlighted associations between the gut microbiome and complex traits, including type 2 diabetes (T2D) and obesity1. 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 available2, 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 gut production 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.

Original languageEnglish
Pages (from-to)600-605
Number of pages6
JournalNature Genetics
Volume51
Issue number4
Early online date18-Feb-2019
DOIs
Publication statusPublished - Apr-2019

Cite this