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Key Publication: Causal relationships among the gut microbiome, short-chain fatty acids and metabolic diseases: Nature Genetics

18 February 2019

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
  • Võsa U
  • Mujagic Z
  • Masclee AAM
  • Jonkers DMAE
  • Oosting M
  • Joosten LAB
  • Netea MG
  • Franke L
  • Zhernakova A
  • Fu J
  • Wijmenga C
  • McCarthy MI


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 -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.

Last modified:20 February 2019 4.27 p.m.

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