TY - JOUR
T1 - Causal relationships among the gut microbiome, short-chain fatty acids and metabolic diseases
AU - Sanna, Serena
AU - van Zuydam, Natalie R
AU - Mahajan, Anubha
AU - Kurilshikov, Alexander
AU - Vich Vila, Arnau
AU - Võsa, Urmo
AU - Mujagic, Zlatan
AU - Masclee, Ad A M
AU - Jonkers, Daisy M A E
AU - Oosting, Marije
AU - Joosten, Leo A B
AU - Netea, Mihai G
AU - Franke, Lude
AU - Zhernakova, Alexandra
AU - Fu, Jingyuan
AU - Wijmenga, Cisca
AU - McCarthy, Mark I
PY - 2019/4
Y1 - 2019/4
N2 - 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.
AB - 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.
U2 - 10.1038/s41588-019-0350-x
DO - 10.1038/s41588-019-0350-x
M3 - Letter
C2 - 30778224
SN - 1061-4036
VL - 51
SP - 600
EP - 605
JO - Nature Genetics
JF - Nature Genetics
IS - 4
ER -