Metagenomic systems biology of the human gut microbiome reveals topological shifts associated with obesity and inflammatory bowel disease

Abstract

The human microbiome plays a key role in a wide range of hostrelated processes and has a profound effect on human health. Comparative analyses of the human microbiome have revealed substantial variation in species and gene composition associated with a variety of disease states but may fall short of providing a comprehensive understanding of the impact of this variation on the community and on the host. Here, we introduce a metagenomic systems biology computational framework, integrating metagenomic data with an in silico systems-level analysis of metabolic networks. Focusing on the gut microbiome, we analyze fecal metagenomic data from 124 unrelated individuals, as well as six monozygotic twin pairs and their mothers, and generate community-level metabolic networks of the microbiome. Placing variations in gene abundance in the context of these networks, we identify both gene-level and network-level topological differences associated with obesity and inflammatory bowel disease (IBD). We show that genes associated with either of these host states tend to be located at the periphery of the metabolic network and are enriched for topologically derived metabolic "inputs." These findings may indicate that lean and obese microbiomes differ primarily in their interface with the host and in the way they interact with host metabolism. We further demonstrate that obese microbiomes are less modular, a hallmark of adaptation to low-diversity environments. We additionally link these topological variations to community species composition. The system-level approach presented here lays the foundation for a unique framework for studying the human microbiome, its organization, and its impact on human health. W e humans are mostly microbes. Microbial communities populate numerous sites in the human anatomy and harbor over 100 trillion microbial cells (1). This complex ensemble of microorganisms, collectively known as the human microbiome, plays an essential role in our development, immunity, and nutrition, and has a tremendous impact on our health (2). Among the various body habitats, the most densely colonized is the distal gut. The normal gut flora alone consists of hundreds of bacterial species, collectively encoding an enormous gene set that is 150-fold larger than the set of human genes (3). The gut microbiome plays a key role in many essential processes, including vitamin and amino acid biosynthesis, dietary energy harvest, and immune development (4). Transferring a donor microbiota into a recipient can induce various donor phenotypes [including increased adiposity (5) and metabolic syndrome (6)] or prompt the recovery of a sick recipient (7), suggesting a promising avenue for clinical application via directed manipulation of the microbiome. Characterizing the capacity of the human microbiome, its interaction with the host, and its contribution to various disease states therefore has the potential to provide deep insight into both normal human physiology and human disease, and calls for a predictive systemslevel understandin...

Correlation detection strategies in microbial data sets vary widely in sensitivity and precision

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Energy Drink Consumption : Beneficial and Adverse Health Effects

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Generation of genome-scale metabolic reconstructions for 773 members of the human gut microbiota

“…In order to infer the metabolic repertoire of a gut metagenome data set, researchers usually map sequenced genes or organisms onto metabolic networks derived from the Kyoto Encyclopedia of Genes and Genomes (KEGG) 6 , and functional annotations from KEGG ontologies 7 . However, this approach cannot identify the contribution of each bacterial species to the metabolic repertoire of the whole gut microbiome, nor can it infer the effects of different gut microbial communities on host metabolism.…”