A comprehensive assessment of demographic, environmental, and host genetic associations with gut microbiome diversity in healthy individuals

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Abstract

Background

The gut microbiome is an important determinant of human health. Its composition has been shown to be influenced by multiple environmental factors and likely by host genetic variation. In the framework of the Milieu Intérieur Consortium, a total of 1000 healthy individuals of western European ancestry, with a 1:1 sex ratio and evenly stratified across five decades of life (age 20–69), were recruited. We generated 16S ribosomal RNA profiles from stool samples for 858 participants. We investigated genetic and non-genetic factors that contribute to individual differences in fecal microbiome composition.

Results

Among 110 demographic, clinical, and environmental factors, 11 were identified as significantly correlated with α-diversity, ß-diversity, or abundance of specific microbial communities in multivariable models. Age and blood alanine aminotransferase levels showed the strongest associations with microbiome diversity. In total, all non-genetic factors explained 16.4% of the variance. We then searched for associations between > 5 million single nucleotide polymorphisms and the same indicators of fecal microbiome diversity, including the significant non-genetic factors as covariates. No genome-wide significant associations were identified after correction for multiple testing. A small fraction of previously reported associations between human genetic variants and specific taxa could be replicated in our cohort, while no replication was observed for any of the diversity metrics.

Conclusion

In a well-characterized cohort of healthy individuals, we identified several non-genetic variables associated with fecal microbiome diversity. In contrast, host genetics only had a negligible influence. Demographic and environmental factors are thus the main contributors to fecal microbiome composition in healthy individuals.

Trial registration

ClinicalTrials.gov identifier NCT01699893

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Most cited references 19

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The gut–liver axis and the intersection with the microbiome

Rob Knight, Michael Karin, Rohit Loomba … (2018)

In the past decade, an exciting realization has been that diverse liver diseases, ranging from non-alcoholic steatohepatitis, alcoholic steatohepatitis, and cirrhosis, to hepatocellular carcinoma, are not unrelated but fall along a spectrum. Recent work on the biology of the gut-liver communication axis has assisted in understanding the basic biology of both alcoholic and nonalcoholic fatty liver disease. Of immense importance is the massive advancement in understanding of the role of the microbiome, driven by high-throughput DNA sequencing and improved computational techniques that allow the complexity of the microbiome to be interrogated, together with improved experimental designs. Here, we review the gut-liver communications of these various forms of liver disease, explore the molecular, genetic and microbiome relationships, discuss prospects for exploiting the microbiome to determine the stage of liver disease, and to predict the effects of pharmaceutical, dietary, and other interventions at a population and individual level. We conclude that although much remains to be done in understanding the relationship between the microbiome and liver disease, rapid progress towards clinical applications is being made, especially in study designs that complement human intervention studies with mechanistic work in mice that have been humanized in multiple respects, including the genetic, immunological and microbiome characteristics of individual patients. These “avatar mice” may be especially useful for guiding new microbiome-based or microbiome-informed therapies.

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Genetic Determinants of the Gut Microbiome in UK Twins.

Julia K Goodrich, Emily R Davenport, Michelle Beaumont … (2016)

Studies in mice and humans have revealed intriguing associations between host genetics and the microbiome. Here we report a 16S rRNA-based analysis of the gut microbiome in 1,126 twin pairs, a subset of which was previously reported. Tripling the sample narrowed the confidence intervals around heritability estimates and uncovered additional heritable taxa, some of which are validated in other studies. Repeat sampling of subjects showed heritable taxa to be temporally stable. A candidate gene approach uncovered associations between heritable taxa and genes related to diet, metabolism, and olfaction. We replicate an association between Bifidobacterium and the lactase (LCT) gene locus and identify an association between the host gene ALDH1L1 and the bacteria SHA-98, suggesting a link between formate production and blood pressure. Additional genes detected are involved in barrier defense and self/non-self recognition. Our results indicate that diet-sensing, metabolism, and immune defense are important drivers of human-microbiome co-evolution.

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The effect of host genetics on the gut microbiome.

Marc Jan Bonder, Alexander Kurilshikov, Ettje Tigchelaar … (2016)

The gut microbiome is affected by multiple factors, including genetics. In this study, we assessed the influence of host genetics on microbial species, pathways and gene ontology categories, on the basis of metagenomic sequencing in 1,514 subjects. In a genome-wide analysis, we identified associations of 9 loci with microbial taxonomies and 33 loci with microbial pathways and gene ontology terms at P < 5 × 10(-8). Additionally, in a targeted analysis of regions involved in complex diseases, innate and adaptive immunity, or food preferences, 32 loci were identified at the suggestive level of P < 5 × 10(-6). Most of our reported associations are new, including genome-wide significance for the C-type lectin molecules CLEC4F-CD207 at 2p13.3 and CLEC4A-FAM90A1 at 12p13. We also identified association of a functional LCT SNP with the Bifidobacterium genus (P = 3.45 × 10(-8)) and provide evidence of a gene-diet interaction in the regulation of Bifidobacterium abundance. Our results demonstrate the importance of understanding host-microbe interactions to gain better insight into human health.

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Author and article information

Contributors

Petar Scepanovic: petar.scepanovic@epfl.ch

Flavia Hodel: flavia.hodel@epfl.ch

Stanislas Mondot: stanislas.mondot@inra.fr

Valentin Partula: v.partula@eren.smbh.univ-paris13.fr

Allyson Byrd: byrd.allyson@gene.com

Christian Hammer: hammer.christian@gene.com

Cécile Alanio: cecile.alanio@gmail.com

Jacob Bergstedt: jacoba@control.lth.se

Etienne Patin: e.patin@pasteur.fr

Mathilde Touvier: m.touvier@eren.smbh.univ-paris13.fr

Olivier Lantz: olivier.lantz@curie.fr

Matthew L. Albert: albert.matthew@gene.com

Darragh Duffy: darragh.duffy@pasteur.fr

Lluis Quintana-Murci: lluis.quintana-murci@pasteur.fr

Jacques Fellay:

ORCID: http://orcid.org/0000-0002-8240-939X

jacques.fellay@epfl.ch

Journal

Journal ID (nlm-ta): Microbiome

Journal ID (iso-abbrev): Microbiome

Title: Microbiome

Publisher: BioMed Central (London )

ISSN (Electronic): 2049-2618

Publication date (Electronic): 13 September 2019

Publication date PMC-release: 13 September 2019

Publication date Collection: 2019

Volume: 7

Electronic Location Identifier: 130

Affiliations

[1 ]ISNI 0000000121839049, GRID grid.5333.6, School of Life Sciences, , École Polytechnique Fédérale de Lausanne, ; Lausanne, Switzerland

[2 ]ISNI 0000 0001 2223 3006, GRID grid.419765.8, Swiss Institute of Bioinformatics, ; Lausanne, Switzerland

[3 ]ISNI 0000 0004 0522 0627, GRID grid.462293.8, MICALIS Institute (INRA/AgroParisTech), ; Jouy-en-Josas, France

[4 ]Sorbonne-Paris-Cité Research Center for Epidemiology and Statistics CRESS, Nutritional Epidemiology Research Team EREN (INSERM U1153/INRA U1125/CNAM/Université Paris-XIII Nord), Bobigny, France

[5 ]ISNI 0000 0001 2217 0017, GRID grid.7452.4, University of Paris-VII Denis Diderot, Sorbonne-Paris-Cité University, ; Paris, France

[6 ]ISNI 0000 0004 0534 4718, GRID grid.418158.1, Department of Cancer Immunology, , Genentech Inc., ; San Francisco, CA 94080 USA

[7 ]ISNI 0000 0004 0534 4718, GRID grid.418158.1, Department of Human Genetics, , Genentech Inc., ; San Francisco, CA 94080 USA

[8 ]ISNI 0000 0004 1936 8972, GRID grid.25879.31, Institute for Immunology, Perelman School of Medicine, , University of Pennsylvania, ; Philadelphia, PA USA

[9 ]ISNI 0000 0001 0930 2361, GRID grid.4514.4, Department of Automatic Control, LTH, , Lund University, ; Lund, Sweden

[10 ]ISNI 0000 0001 2353 6535, GRID grid.428999.7, Unit of Human Evolutionary Genetics, Department of Genomes and Genetics, , Institut Pasteur, ; Paris, France

[11 ]ISNI 0000 0001 2112 9282, GRID grid.4444.0, Centre National de la Recherche Scientifique, UMR2000, ; Paris, France

[12 ]ISNI 0000 0004 0639 6384, GRID grid.418596.7, Institut Curie, PSL Research University, Inserm U932, ; 75005 Paris, France

[13 ]Center of Clinical Investigations, CICBT1428 IGR/Curie, 75005 Paris, France

[14 ]ISNI 0000000121866389, GRID grid.7429.8, Immunobiology of Dendritic Cells laboratory (INSERM U1223/Institut Pasteur), ; Paris, France

[15 ]ISNI 0000 0001 0423 4662, GRID grid.8515.9, Precision Medicine Unit, , Lausanne University Hospital, ; Lausanne, Switzerland

Author information

Jacques Fellay http://orcid.org/0000-0002-8240-939X

Article

Publisher ID: 747

DOI: 10.1186/s40168-019-0747-x

PMC ID: 6744716

PubMed ID: 31519223

SO-VID: c45b5d03-5acb-44f3-b0f2-a8b4f119899b

License:

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

History

Date received : 20 March 2019

Date accepted : 4 September 2019

Funding

Funded by: Agence Nationale de la Recherche

Award ID: 10-LABX-69-01

Funded by: FundRef http://dx.doi.org/10.13039/501100001711, Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung;

Award ID: 31003A_175603

Award Recipient : Jacques Fellay

Custom metadata

Keywords: microbiome,gut,human,genomics,16s rrna gene sequencing,gwas,healthy,demographics,environment

Data availability:

Keywords: microbiome, gut, human, genomics, 16s rrna gene sequencing, gwas, healthy, demographics, environment

A comprehensive assessment of demographic, environmental, and host genetic associations with gut microbiome diversity in healthy individuals

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Abstract

Background

Results

Conclusion

Trial registration

Related collections

Tick microbiome

Most cited references 19

The gut–liver axis and the intersection with the microbiome

Genetic Determinants of the Gut Microbiome in UK Twins.

The effect of host genetics on the gut microbiome.

Author and article information

Contributors

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