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

Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.81). 12/2011; 109(2):594-9. DOI: 10.1073/pnas.1116053109
Source: PubMed

ABSTRACT The human microbiome plays a key role in a wide range of host-related 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.

Download full-text


Available from: Peter J Turnbaugh, Jul 02, 2015
  • Source
    06/2014; 5. DOI:10.1016/j.ancene.2014.06.004
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The gut microbiota is involved in metabolic and immune disorders associated with obesity and type 2 diabetes. We previously demonstrated that prebiotic treatment may significantly improve host health by modulating bacterial species related to the improvement of gut endocrine, barrier and immune functions. An analysis of the gut metagenome is needed to determine which bacterial functions and taxa are responsible for beneficial microbiota-host interactions upon nutritional intervention. We subjected mice to prebiotic (Pre) treatment under physiological (control diet: CT) and pathological conditions (high-fat diet: HFD) for 8 weeks and investigated the production of intestinal antimicrobial peptides and the gut microbiome. HFD feeding significantly decreased the expression of regenerating islet-derived 3-gamma (Reg3g) and phospholipase A2 group-II (PLA2g2) in the jejunum. Prebiotic treatment increased Reg3g expression (by ∼50-fold) and improved intestinal homeostasis as suggested by the increase in the expression of intectin, a key protein involved in intestinal epithelial cell turnover. Deep metagenomic sequencing analysis revealed that HFD and prebiotic treatment significantly affected the gut microbiome at different taxonomic levels. Functional analyses based on the occurrence of clusters of orthologous groups (COGs) of proteins also revealed distinct profiles for the HFD, Pre, HFD-Pre and CT groups. Finally, the gut microbiota modulations induced by prebiotics counteracted HFD-induced inflammation and related metabolic disorders. Thus, we identified novel putative taxa and metabolic functions that may contribute to the development of or protection against the metabolic alterations observed during HFD feeding and HFD-Pre feeding.
    The ISME Journal 04/2014; 8(10). DOI:10.1038/ismej.2014.45 · 9.27 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Most previous studies on soil microbial communities have been focused on species abundance and diversity, but not the interactions among species. In present study, the Molecular Ecological Network Analysis tool was used to study the interactions and network organizations of fungal communities in yield-invigorating (healthy) and -debilitating (diseased) soils induced by prolonged potato monoculture, based on the relative abundances of internal transcribed spacer sequences derived using pyrosequencing. An emphasis was placed on the differences between the healthy and diseased networks. The constructed healthy and diseased networks both showed scale-free, small world and modular properties. The key topological properties and phylogenetic composition of the two networks were similar. However, major differences included: a) the healthy network had more number of functionally interrelated operational taxonomic units (OTUs) than the diseased one; b) healthy network contained 6 (4%) generalist OTUs whereas the diseased contained only 1 (0.6%) marginal generalist OTU; and c) majority (55%) of OTUs in healthy soils were stimulated by a certain set of soil variables but the majorities (63%) in diseased soils were inhibited. Based on these data, a conceptual picture was synthesized: a healthy community was a better organized or a better operated community than the diseased one; a healthy soil was a soil with variables that encouraged majority of fungi whereas a diseased soil discouraged. By comparing the topological roles of different sets of shared OTUs between healthy and diseased networks, it was found that role-shifts prevailed among the network members such as generalists/specialists, significant module memberships and the OTU sets irresponsive to soil variables in one network but responsive in the counterpart network. Soil organic matter was the key variable associated with healthy community, whereas ammonium nitrogen (NH4+–N) and Electrical conductivity (EC) were the key variables associated with diseased community. Major affected phylogenetic groups were Sordariales and Hypocreales.
    Soil Biology and Biochemistry 10/2013; 65:186–194. DOI:10.1016/j.soilbio.2013.05.025 · 4.41 Impact Factor