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

By Serena Sanna, Natalie R. van Zuydam, A. Mahajan, A. Kurilshikov, A. Vich Vila, Urmo Võsa, Z. Mujagic, A. Masclee, D. Jonkers, M. Oosting and 7 more. Nature Genetics, 2019

1,283 citations recorded by the source corpus.

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. Mendelian randomization analyses using genotyping data, gut metagenomic sequence and fecal short-chain-fatty-acid levels from 952 individuals combined with GWAS data show evidence of a causal effect of the gut microbiome on metabolic traits.

Subfields: General Health Professions, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/1c6ce10bc7c9676f9506eaa8f595a029ac38be90

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Citations in the corpus

Gut Microbiota and Short Chain Fatty Acids: Implications in Glucose Homeostasis (2022, background): “, 2019 [107] Healthy individuals selected on the basis of SCFAs and genome, fecal metagenomic sequences.”
The role of short-chain fatty acids in the interplay between gut microbiota and diet in cardio-metabolic health (2021, background): “SCFAs are the most well-studied gut bacteriaderived metabolites and they have been suggested as potential disease-mitigating factors and/or disease preventing in CMD, including T2D, obesity, and CVD, among others.(14,64) SCFAs will be explained in detail in the below sections.”
SCFA: mechanisms and functional importance in the gut (2020, background): “As discussed in this review, the gut microbial metabolites SCFA are well known to exert a wide beneficial impact to the host((167,168)).”
The Controversial Role of Human Gut Lachnospiraceae (2020, background): “MD Substantial amounts of propionate entering into the mitochondrial tricarboxylic acid (TCA) cycle bypass the first four TCA enzymes, causing a shift in the cycle with a potential toxic effect [78,79].”
Role of gut microbiota in type 2 diabetes pathophysiology (2020, methodology): “Indeed, new approaches, such as Transkingdom Network Analysis [122] and novel application of Mendelian Randomization methods [129], have been recently developed and validated to answer which microbes and microbial genes/pathways are in control of host physiological processes.”
The Role of Short-Chain Fatty Acids From Gut Microbiota in Gut-Brain Communication (2020, background): “Despite differences in the identification of specific microbiome features responsible for these effects, a shift in the microbiome composition away from species able to produce butyrate was one consistent finding in type 2 diabetes subjects (187).”
Short-chain fatty acids: linking diet, the microbiome and immunity (2024, positive): “Metagenomic studies combined with metabolomics show that the abundance of Eubacterium rectale , Bacteroides pectinophilus and Roseburia intestinalis , and levels of the butyrate-producing 4-aminobutanoate degradation V pathway, correlate with butyrate levels and increased insulin responsiveness 42 .”