@article{591519e1b6674bcca09ebd6f2d1ffdce,
title = "Causal relationships among the gut microbiome, short-chain fatty acids and metabolic diseases",
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.",
keywords = "GENOME-WIDE ASSOCIATION, MENDELIAN RANDOMIZATION, GENETIC-VARIANTS, CYTOKINE PRODUCTION, COMMON VARIANTS, HOST GENETICS, BUTYRATE, GLUCOSE, MODEL, PROPIONATE",
author = "Serena Sanna and \{van Zuydam\}, \{Natalie R.\} and Anubha Mahajan and Alexander Kurilshikov and Vila, \{Arnau Vich\} and Urmo Vosa and Zlatan Mujagic and Masclee, \{Ad A. M.\} and Jonkers, \{Daisy M. A. E.\} and Marge Oosting and Joosten, \{Leo A. B.\} and Netea, \{Mihai G.\} and Lude Franke and Alexandra Zhernakova and Jingyuan Fu and Cisca Wijmenga and Mark McCarthy",
note = "Funding Information: We thank the participants and staff of the LL-DEEP cohort for their collaboration, the UMCG Genomics Coordination center, the UG Center for Information Technology and their sponsors BBMRI-NL and TarGet for storage and compute infrastructure. We are also grateful to M. J. Bonder for help in formatting summary statistics; to R. K. Weersma and Y. Li for discussions; and to K. Mc Intyre for editing the manuscript. Part of this work was conducted by using the UK Biobank resource under application no. 9161. This project was funded by IN-CONTROL CVON grant CVON2012-03 to M.G.N., A.Z., L.A.B.J. and J.F.; Top Institute Food and Nutrition (TiFN, Wageningen, the Netherlands) grant TiFN GH001 to C.W.; the Netherlands Organization for Scientific Research (NWO) grants NWO-VENI 016.176.006 to M.O., NWO-VIDI 864.13.013 to J.F. and NWO-VIDI 016.Vidi.178.056 to A.Z.; NWO Spinoza Prizes SPI 92-266 to C.W. and SPI 94-212 to M.G.N.; European Research Council (ERC) starting grant ERC no. 715772 to A.Z.; FP7/2007-2013/ERC Advanced Grant (agreement 2012-322698) to C.W.; ERC Consolidator Grant ERC no. 310372 to M.G.N.; Tripartite Immunometabolism consortium (TrIC)–Novo Nordisk Foundation grant NNF15CC0018486 to M.I.M.; and Wellcome grants 090532, 098381, 106130 and 203141 to M.I.M. A.Z. is also supported by a Rosalind Franklin Fellowship from the University of Groningen. M.I.M. is supported as a Wellcome Senior Investigator and a National Institute of Health Research Senior Investigator. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The views expressed in this article are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health. Publisher Copyright: {\textcopyright} 2019, The Author(s), under exclusive licence to Springer Nature America, Inc.",
year = "2019",
month = apr,
doi = "10.1038/s41588-019-0350-x",
language = "English",
volume = "51",
pages = "600--605",
journal = "Nature Genetics",
issn = "1061-4036",
publisher = "Nature Research",
number = "4",
}