Metagenome-wide association studies: fine-mining the microbiome

Metagenome-wide association studies (MWAS) have enabled the high-resolution investigation of associations between the human microbiome and several complex diseases, including type 2 diabetes, obesity, liver cirrhosis, colorectal cancer and rheumatoid arthritis. The associations that can be identified by MWAS are not limited to the identification of taxa that are more or less abundant, as is the case with taxonomic approaches, but additionally include the identification of microbial functions that are enriched or depleted. In this Review, we summarize recent findings from MWAS and discuss how these findings might inform the prevention, diagnosis and treatment of human disease in the future. Furthermore, we highlight the need to better characterize the biology of many of the bacteria that are found in the human microbiota as an essential step in understanding how bacterial strains that have been identified by MWAS are associated with disease.

[1]  B. Becher,et al.  Innate lymphoid cells regulate intestinal epithelial cell glycosylation , 2014, Science.

[2]  H. Neu,et al.  Inactivation of digoxin by Eubacterium lentum, an anaerobe of the human gut flora. , 1982, Transactions of the Association of American Physicians.

[3]  Georg Schett,et al.  The pathogenesis of rheumatoid arthritis. , 2011, The New England journal of medicine.

[4]  Kyongbum Lee,et al.  Prediction and quantification of bioactive microbiota metabolites in the mouse gut , 2014, Nature Communications.

[5]  J. Wallace,et al.  Hydrogen Sulfide Protects from Colitis and Restores Intestinal Microbiota Biofilm and Mucus Production , 2015, Inflammatory bowel diseases.

[6]  Qiang Feng,et al.  Metagenomic analysis of faecal microbiome as a tool towards targeted non-invasive biomarkers for colorectal cancer , 2015, Gut.

[7]  P. Brubaker,et al.  Direct and indirect mechanisms regulating secretion of glucagon-like peptide-1 and glucagon-like peptide-2. , 2003, Canadian journal of physiology and pharmacology.

[8]  P. Schloss,et al.  Dynamics and associations of microbial community types across the human body , 2014, Nature.

[9]  Benjamin P. Westover,et al.  Glycan Foraging in Vivo by an Intestine-Adapted Bacterial Symbiont , 2005, Science.

[10]  J. Clemente,et al.  The Impact of the Gut Microbiota on Human Health: An Integrative View , 2012, Cell.

[11]  F. Ginhoux,et al.  Anticancer immunotherapy by CTLA-4 blockade relies on the gut microbiota , 2015, Science.

[12]  Jenny Sauk,et al.  Disease-Specific Alterations in the Enteric Virome in Inflammatory Bowel Disease , 2015, Cell.

[13]  B. Roe,et al.  A core gut microbiome in obese and lean twins , 2008, Nature.

[14]  M. Lamkanfi,et al.  Dietary modulation of the microbiome affects autoinflammatory disease , 2014, Nature.

[15]  Katherine H. Huang,et al.  A framework for human microbiome research , 2012, Nature.

[16]  P. Turnbaugh,et al.  Predicting and Manipulating Cardiac Drug Inactivation by the Human Gut Bacterium Eggerthella lenta , 2013, Science.

[17]  Ruben E. Valas,et al.  Genomic insights to SAR86, an abundant and uncultivated marine bacterial lineage , 2011, The ISME Journal.

[18]  B. Olle,et al.  Medicines from microbiota , 2013, Nature Biotechnology.

[19]  F. Bushman,et al.  The human gut virome: inter-individual variation and dynamic response to diet. , 2011, Genome research.

[20]  E. Mardis,et al.  An obesity-associated gut microbiome with increased capacity for energy harvest , 2006, Nature.

[21]  Hamidreza Chitsaz,et al.  Candidate phylum TM6 genome recovered from a hospital sink biofilm provides genomic insights into this uncultivated phylum , 2013, Proceedings of the National Academy of Sciences.

[22]  David F. Smith,et al.  Microbial glycan microarrays define key features of host-microbial interactions. , 2014, Nature chemical biology.

[23]  Jun Yu,et al.  Gut mucosal microbiome across stages of colorectal carcinogenesis , 2015, Nature Communications.

[24]  S. Bordenstein,et al.  Rethinking heritability of the microbiome , 2015, Science.

[25]  C. Mathers,et al.  Cancer incidence and mortality worldwide: Sources, methods and major patterns in GLOBOCAN 2012 , 2015, International journal of cancer.

[26]  C. Huttenhower,et al.  Expansion of intestinal Prevotella copri correlates with enhanced susceptibility to arthritis , 2013, eLife.

[27]  Qiang Feng,et al.  The oral and gut microbiomes are perturbed in rheumatoid arthritis and partly normalized after treatment , 2015, Nature Medicine.

[28]  S. Hazen,et al.  Non-lethal Inhibition of Gut Microbial Trimethylamine Production for the Treatment of Atherosclerosis , 2015, Cell.

[29]  L. Ursell,et al.  Genetically dictated change in host mucus carbohydrate landscape exerts a diet-dependent effect on the gut microbiota , 2013, Proceedings of the National Academy of Sciences.

[30]  M. Blaser,et al.  The human microbiome: at the interface of health and disease , 2012, Nature Reviews Genetics.

[31]  Jens Roat Kultima,et al.  Identification and assembly of genomes and genetic elements in complex metagenomic samples without using reference genomes , 2014, Nature Biotechnology.

[32]  V. Tremaroli,et al.  Dynamics and Stabilization of the Human Gut Microbiome during the First Year of Life. , 2015, Cell host & microbe.

[33]  M. Meyerson,et al.  Fusobacterium nucleatum potentiates intestinal tumorigenesis and modulates the tumor-immune microenvironment. , 2013, Cell host & microbe.

[34]  Amy M. Sheflin,et al.  Stool Microbiome and Metabolome Differences between Colorectal Cancer Patients and Healthy Adults , 2013, PloS one.

[35]  Harry J. Flint,et al.  The gut microbiota, bacterial metabolites and colorectal cancer , 2014, Nature Reviews Microbiology.

[36]  A. Viale,et al.  Periodontal disease and the oral microbiota in new-onset rheumatoid arthritis. , 2012, Arthritis and rheumatism.

[37]  Eric C. Martens,et al.  Human gut Bacteroidetes can utilize yeast mannan through a selfish mechanism , 2015, Nature.

[38]  Robert W. Li,et al.  Lowbush Wild Blueberries have the Potential to Modify Gut Microbiota and Xenobiotic Metabolism in the Rat Colon , 2013, PloS one.

[39]  Peter J. Turnbaugh,et al.  The microbial pharmacists within us: a metagenomic view of xenobiotic metabolism , 2016, Nature Reviews Microbiology.

[40]  F. Bäckhed,et al.  The gut microbiota — masters of host development and physiology , 2013, Nature Reviews Microbiology.

[41]  P. Hugenholtz,et al.  Genome sequences of rare, uncultured bacteria obtained by differential coverage binning of multiple metagenomes , 2013, Nature Biotechnology.

[42]  P. Bork,et al.  Richness of human gut microbiome correlates with metabolic markers , 2013, Nature.

[43]  Elhanan Borenstein,et al.  Extensive Strain-Level Copy-Number Variation across Human Gut Microbiome Species , 2015, Cell.

[44]  Jun Wang,et al.  Disentangling type 2 diabetes and metformin treatment signatures in the human gut microbiota , 2015, Nature.

[45]  Klaus Ley,et al.  Bacterial colonization factors control specificity and stability of the gut microbiota , 2013, Nature.

[46]  V. Holers,et al.  When and where does inflammation begin in rheumatoid arthritis? , 2014, Current opinion in rheumatology.

[47]  Katherine H. Huang,et al.  Structure, Function and Diversity of the Healthy Human Microbiome , 2012, Nature.

[48]  J. Clemente,et al.  Gut Microbiota from Twins Discordant for Obesity Modulate Metabolism in Mice , 2013, Science.

[49]  W. D. de Vos,et al.  Differential Modulation by Akkermansia muciniphila and Faecalibacterium prausnitzii of Host Peripheral Lipid Metabolism and Histone Acetylation in Mouse Gut Organoids , 2014, mBio.

[50]  Jens Roat Kultima,et al.  An integrated catalog of reference genes in the human gut microbiome , 2014, Nature Biotechnology.

[51]  A. Jemal,et al.  Global Cancer Statistics , 2011 .

[52]  P. Bork,et al.  Accurate and universal delineation of prokaryotic species , 2013, Nature Methods.

[53]  R. Reimer,et al.  Prebiotic fiber increases hepatic acetyl CoA carboxylase phosphorylation and suppresses glucose-dependent insulinotropic polypeptide secretion more effectively when used with metformin in obese rats. , 2012, The Journal of nutrition.

[54]  Rustem F. Ismagilov,et al.  Rapid fucosylation of intestinal epithelium sustains host-commensal symbiosis in sickness , 2014, Nature.

[55]  Qiang Feng,et al.  Gut microbiome development along the colorectal adenoma–carcinoma sequence , 2015, Nature Communications.

[56]  E. Segal,et al.  Personalized Nutrition by Prediction of Glycemic Responses , 2015, Cell.

[57]  C. Ryu,et al.  Interspecific bacterial sensing through airborne signals modulates locomotion and drug resistance , 2013, Nature Communications.

[58]  Eric Vivier,et al.  The Intestinal Microbiota Modulates the Anticancer Immune Effects of Cyclophosphamide , 2013, Science.

[59]  Allyson L. Byrd,et al.  Biogeography and individuality shape function in the human skin metagenome , 2014, Nature.

[60]  Fredrik H. Karlsson,et al.  Gut metagenome in European women with normal, impaired and diabetic glucose control , 2013, Nature.

[61]  Peer Bork,et al.  Enterotypes of the human gut microbiome , 2011, Nature.

[62]  T. R. Licht,et al.  A catalog of the mouse gut metagenome , 2015, Nature Biotechnology.

[63]  I. Amit,et al.  Host microbiota constantly control maturation and function of microglia in the CNS , 2015, Nature Neuroscience.

[64]  Falk Hildebrand,et al.  A comparative analysis of the intestinal metagenomes present in guinea pigs (Cavia porcellus) and humans (Homo sapiens) , 2012, BMC Genomics.

[65]  Otto X. Cordero,et al.  Ecology drives a global network of gene exchange connecting the human microbiome , 2011, Nature.

[66]  Na-Ri Shin,et al.  An increase in the Akkermansia spp. population induced by metformin treatment improves glucose homeostasis in diet-induced obese mice , 2013, Gut.

[67]  Fredrik H. Karlsson,et al.  Symptomatic atherosclerosis is associated with an altered gut metagenome , 2012, Nature Communications.

[68]  Po-E Li,et al.  Accurate read-based metagenome characterization using a hierarchical suite of unique signatures , 2015, Nucleic acids research.

[69]  Partho Sen,et al.  Quantifying Diet-Induced Metabolic Changes of the Human Gut Microbiome. , 2015, Cell metabolism.

[70]  P. van Endert,et al.  Pancreatic β-Cells Limit Autoimmune Diabetes via an Immunoregulatory Antimicrobial Peptide Expressed under the Influence of the Gut Microbiota. , 2015, Immunity.

[71]  S. Jonjić,et al.  Binding of the Fap2 protein of Fusobacterium nucleatum to human inhibitory receptor TIGIT protects tumors from immune cell attack. , 2015, Immunity.

[72]  Liping Zhao,et al.  Structural modulation of gut microbiota during alleviation of type 2 diabetes with a Chinese herbal formula , 2014, The ISME Journal.

[73]  J. Collins,et al.  Antibiotic Treatment Expands the Resistance Reservoir and Ecological Network of the Phage Metagenome , 2013, Nature.

[74]  Beiwen Zheng,et al.  Alterations of the human gut microbiome in liver cirrhosis , 2014, Nature.

[75]  Hermann Brenner,et al.  Colorectal cancer , 2014, The Lancet.

[76]  Andre Franke,et al.  Microbial Exposure During Early Life Has Persistent Effects on Natural Killer T Cell Function , 2012, Science.

[77]  P. Chambon,et al.  Homeostasis in Intestinal Epithelium Is Orchestrated by the Circadian Clock and Microbiota Cues Transduced by TLRs , 2013, Cell.

[78]  S. Sørensen,et al.  Gut Microbiota in Human Adults with Type 2 Diabetes Differs from Non-Diabetic Adults , 2010, PloS one.

[79]  R. Schwabe,et al.  The Microbiome and Cancer , 2021, Gut Feelings.

[80]  B. Birren,et al.  Genomic analysis identifies association of Fusobacterium with colorectal carcinoma. , 2012, Genome research.

[81]  S. Panda,et al.  A Smartphone App Reveals Erratic Diurnal Eating Patterns in Humans that Can Be Modulated for Health Benefits. , 2015, Cell metabolism.

[82]  N. Hall,et al.  Towards the Human Colorectal Cancer Microbiome , 2011, PloS one.

[83]  F. Bäckhed,et al.  Dietary Fiber-Induced Improvement in Glucose Metabolism Is Associated with Increased Abundance of Prevotella. , 2015, Cell metabolism.

[84]  Jeffrey I. Gordon,et al.  Mechanisms underlying the resistance to diet-induced obesity in germ-free mice , 2007, Proceedings of the National Academy of Sciences.

[85]  Jiang He,et al.  Prevalence and control of diabetes in Chinese adults. , 2013, JAMA.

[86]  James Kinross,et al.  The gut microbiota and host health: a new clinical frontier , 2015, Gut.

[87]  A. Benson.  Host genetic architecture and the landscape of microbiome composition: humans weigh in , 2015, Genome Biology.

[88]  Richard A. Moore,et al.  Fusobacterium nucleatum infection is prevalent in human colorectal carcinoma. , 2012, Genome research.

[89]  GwangPyo Ko,et al.  Effect of Metformin on Metabolic Improvement and Gut Microbiota , 2014, Applied and Environmental Microbiology.

[90]  M. Hattori,et al.  Treg induction by a rationally selected mixture of Clostridia strains from the human microbiota , 2013, Nature.

[91]  J. Petrosino,et al.  Microbiota Modulate Behavioral and Physiological Abnormalities Associated with Neurodevelopmental Disorders , 2013, Cell.

[92]  Angela C. Poole,et al.  Human Genetics Shape the Gut Microbiome , 2014, Cell.

[93]  Qiang Feng,et al.  A metagenome-wide association study of gut microbiota in type 2 diabetes , 2012, Nature.

[94]  C. Huttenhower,et al.  Sequencing and beyond: integrating molecular 'omics' for microbial community profiling , 2015, Nature Reviews Microbiology.

[95]  C. Huttenhower,et al.  Determining microbial products and identifying molecular targets in the human microbiome. , 2014, Cell metabolism.

[96]  J. Petrosino,et al.  The Placenta Harbors a Unique Microbiome , 2014, Science Translational Medicine.

[97]  Peer Bork,et al.  MOCAT: A Metagenomics Assembly and Gene Prediction Toolkit , 2012, PloS one.

[98]  D. Gems,et al.  Worms need microbes too: microbiota, health and aging in Caenorhabditis elegans , 2013, EMBO molecular medicine.

[99]  Jason B. Williams,et al.  Commensal Bifidobacterium promotes antitumor immunity and facilitates anti–PD-L1 efficacy , 2015, Science.

[100]  Alexandros Stamatakis,et al.  Metagenomic species profiling using universal phylogenetic marker genes , 2013, Nature Methods.

[101]  Alison S. Waller,et al.  Genomic variation landscape of the human gut microbiome , 2012, Nature.

[102]  P. Turnbaugh,et al.  Microbial ecology: Human gut microbes associated with obesity , 2006, Nature.

[103]  Lai Guan Ng,et al.  The gut microbiota influences blood-brain barrier permeability in mice , 2014, Science Translational Medicine.

[104]  Mathieu Almeida,et al.  Dietary intervention impact on gut microbial gene richness , 2013, Nature.

[105]  E. Martens,et al.  How glycan metabolism shapes the human gut microbiota , 2012, Nature Reviews Microbiology.

[106]  Philip Rosenstiel,et al.  Colonic mucosa-associated microbiota is influenced by an interaction of Crohn disease and FUT2 (Secretor) genotype , 2011, Proceedings of the National Academy of Sciences.

[107]  Jens Roat Kultima,et al.  Potential of fecal microbiota for early‐stage detection of colorectal cancer , 2014 .

[108]  H. El-Gabalawy,et al.  Pathogenesis and prevention of rheumatic disease: focus on preclinical RA and SLE , 2014, Nature Reviews Rheumatology.

[109]  Michael Snyder,et al.  Synthetic long read sequencing reveals the composition and intraspecies diversity of the human microbiome , 2015, Nature Biotechnology.

[110]  Natalia N. Ivanova,et al.  Insights into the phylogeny and coding potential of microbial dark matter , 2013, Nature.

[111]  K. Lewis,et al.  A new antibiotic kills pathogens without detectable resistance , 2015, Nature.

[112]  Jens Roat Kultima,et al.  Disentangling the effects of type 2 diabetes and metformin on the human gut microbiota , 2015, Nature.

[113]  D. Gevers,et al.  The Gut Microbiome Contributes to a Substantial Proportion of the Variation in Blood Lipids , 2015, Circulation research.

[114]  N. Nagarajan,et al.  Cloning and Variation of Ground State Intestinal Stem Cells , 2015, Nature.

[115]  Min Zhang,et al.  Individuality in gut microbiota composition is a complex polygenic trait shaped by multiple environmental and host genetic factors , 2010, Proceedings of the National Academy of Sciences.

[116]  M. Hegsted,et al.  Peptide YY and Proglucagon mRNA Expression Patterns and Regulation in the Gut , 2006, Obesity.

[117]  P. Bork,et al.  A human gut microbial gene catalogue established by metagenomic sequencing , 2010, Nature.

[118]  F. Marincola,et al.  Commensal Bacteria Control Cancer Response to Therapy by Modulating the Tumor Microenvironment , 2013, Science.

[119]  Jian Wang,et al.  Metagenome-wide analysis of antibiotic resistance genes in a large cohort of human gut microbiota , 2013, Nature Communications.

[120]  Bas E Dutilh,et al.  A bacterial driver–passenger model for colorectal cancer: beyond the usual suspects , 2012, Nature Reviews Microbiology.

[121]  Forest Rohwer,et al.  Viruses in the fecal microbiota of monozygotic twins and their mothers , 2010, Nature.