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 Vosa, Zlatan Mujagic, Ad A. M. Masclee, Daisy M. A. E. Jonkers, Marge Oosting, Leo A. B. Joosten, Mihai G. Netea, Lude Franke, Alexandra Zhernakova, Jingyuan Fu, Cisca Wijmenga*, Mark McCarthy*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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 obesity(1). 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(2), 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(3), 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 x 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
DOIs
Publication statusPublished - Apr 2019

Keywords

  • GENOME-WIDE ASSOCIATION
  • MENDELIAN RANDOMIZATION
  • GENETIC-VARIANTS
  • CYTOKINE PRODUCTION
  • COMMON VARIANTS
  • HOST GENETICS
  • BUTYRATE
  • GLUCOSE
  • MODEL
  • PROPIONATE

Cite this