The gut microbiota and obesity: from correlation to causality

Journal name:
Nature Reviews Microbiology
Volume:
11,
Pages:
639–647
Year published:
DOI:
doi:10.1038/nrmicro3089
Published online

Abstract

The gut microbiota has been linked with chronic diseases such as obesity in humans. However, the demonstration of causality between constituents of the microbiota and specific diseases remains an important challenge in the field. In this Opinion article, using Koch's postulates as a conceptual framework, I explore the chain of causation from alterations in the gut microbiota, particularly of the endotoxin-producing members, to the development of obesity in both rodents and humans. I then propose a strategy for identifying the causative agents of obesity in the human microbiota through a combination of microbiome-wide association studies, mechanistic analysis of host responses and the reproduction of diseases in gnotobiotic animals.

At a glance

Figures

  1. Human health is influenced by interactions among the gut microbiota, the host and the environment.
    Figure 1: Human health is influenced by interactions among the gut microbiota, the host and the environment.

    Humans are supraorganisms consisting of both human cells and microbial cells, particularly the gut microbiota. The gut microbiota interacts with host genetics and the environment (mainly diet) to influence the health of the human host. On the one hand, the gut microbiota releases toxins, such as lipopolysaccharides, and beneficial metabolites, such as vitamins and short-chain fatty acids, to damage or nourish humans, respectively. On the other hand, human genetics also imposes selective pressures on the gut microbiota through innate immunity or nutrient availability. The diet and particular drugs have a greater potential to shape the structure and function of the gut microbiota than host genetics, thus influencing the health state of the supraorganism.

  2. Strategy for demonstrating the causative role of the gut microbiota in chronic diseases.
    Figure 2: Strategy for demonstrating the causative role of the gut microbiota in chronic diseases.

    In order to screen all the potential key gut microbial phylotypes that might be associated with the aetiology or development of a specific chronic disease, a microbiome-wide association study should first be carried out. Either cross-sectional or longitudinal experiments can be involved, accompanied by time series and multisite sampling to obtain measurements of both host phenotypes and the compositional and functional profiles of the gut microbiota. Multivariate statistical tools, such as principal component analysis, redundancy analysis and partial least squares models, can be used to identify candidate key members of the gut microbiota as putative causative agents. Sequence-guided isolation should then be carried out to obtain a pure culture of the key bacteria, followed by reproduction of the disease in gnotobiotic animals associated with the key bacterium and/or a defined consortium of relevant bacteria, to generate a gnotobiotic model of the disease. For those diseases for which it is difficult to obtain a pure culture of the candidate key bacteria, large-scale interventional studies can be carried out to assess whether a reduction in the levels of candidate sequences leads to an improvement in the disease phenotypes. A multi-omics covariation analysis might be used to examine the correlating patterns of changes for the candidate key players and faecal, urinary, serum and/or plasma metabolites, or even whole transcriptomic or proteomic pathways; any such correlations might be indicative of a mechanistic connection between the putative cause and the disease.

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  1. State Key Laboratory for Microbial Metabolism, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University. Ministry of Education Key Laboratory for Systems Biomedicine, Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University, 800 Dongchuan Road, Minhang Campus, Shanghai 200240, China.

    • Liping Zhao

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  • Liping Zhao

    Liping Zhao is currently a professor of microbiology and the Director of the Laboratory of Microbial Ecology and Ecogenomics, which is part of the State Key Laboratory for Microbial Metabolism in the School of Life Sciences and Biotechnology, Shanghai Jiao Tong University (SJTU), China. He is also the Director of the Laboratory of Nutritional Systems Biology, which is part of the Ministry of Education Key Laboratory for Systems Biomedicine in the Shanghai Center for Systems Biomedicine, SJTU, and Director of the SJTU-Perfect (China) Joint Research Center on Microbiota and Health. His research involves the application of molecular and genomic tools to gain a systems-level understanding of the complex microbial communities in the human and animal gut, and to be able to predictively manipulate these communities. His current focus is on the interactions between nutrition and the gut microbiota in the onset and progression of chronic diseases such as obesity and diabetes, and on how traditional Chinese medicine and medicinal foods might modulate this relationship to achieve preventive health care. Liping Zhao's homepage

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