Review
Special Issue: Systems Approach to Metabolic Disease
Linking Microbiota to Human Diseases: A Systems Biology Perspective

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Trends

The gut microbiota is altered in human metabolic diseases. Emerging data show that bacterial functions linked to colonic butyrate production are consistently associated with improved insulin sensitivity, indicating new possible therapeutic avenues.

Human metabolic diseases are often associated with decreased diversity and functional richness of the gut microbiota. Modern lifestyles characterized by the widespread use of antimicrobials and consumption of energy-dense foods, additives, and emulsifiers might contribute to loss of microbiota diversity and the increased incidence of chronic diseases.

Integration of patient stratification with microbiome functional profiling will be fundamental for the development of personalized medicine. Personal microbiome profiles will be important determinants of the effects of diet and the efficacy of therapeutic drugs.

The human gut microbiota encompasses a densely populated ecosystem that provides essential functions for host development, immune maturation, and metabolism. Alterations to the gut microbiota have been observed in numerous diseases, including human metabolic diseases such as obesity, type 2 diabetes (T2D), and irritable bowel syndrome, and some animal experiments have suggested causality. However, few studies have validated causality in humans and the underlying mechanisms remain largely to be elucidated. We discuss how systems biology approaches combined with new experimental technologies may disentangle some of the mechanistic details in the complex interactions of diet, microbiota, and host metabolism and may provide testable hypotheses for advancing our current understanding of human–microbiota interaction.

Section snippets

Gut Microbiota in Human Health and Disease

Trillions of bacteria inhabit the human gastrointestinal tract and numerous studies have suggested that this ecosystem plays a major role in host physiology by affecting several processes ranging from maturation of the immune system, regulation of host metabolism, nutrition, and transformation of bioactive molecules and drugs to behavior [1]. Due to the emergence of systems biology approaches and new computational tools, there has been increasing interest in exploring the gut microbiota (see

Host–Microbe Interactions

Host–microbe interactions are determined by the complexity of the human body and the diversity of the microbiome (Figure 1). Metagenomics analysis of various body sites has revealed specific distributions of multi-kingdom communities (i.e., bacteria, viruses, and fungi) on the human body, with distinct genetic capacities reflecting the diversity of skin microenvironments [27]. Interactions between these kingdoms are also likely to occur in the human gut and recent studies have proposed a role

Obesity

The obesity epidemic has become a major public health issue due to its links to related metabolic disorders such as T2D, CVD, and nonalcoholic fatty liver disease. Human genetics, diet, and sedentary lifestyle are risk factors for obesity while common treatments include calorie restriction, increased physical activity, antiobesity medications, and weight-loss (bariatric) surgery. Accumulating data have recently suggested that the gut microbiota may be another factor in the global obesity

New Experimental and Computational Approaches for Understanding Host–Microbe–Diet Interactions

Systems biology approaches integrating ‘omics’ techniques (Figure 2, Key Figure) can be used to unravel the mechanisms behind host–microbe interactions. Omics techniques allow the study of the collective genomes and taxonomic groups (metagenomics), transcriptomes (metatranscriptomics), proteomes (metaproteomics), and metabolomes (metabolomics) of the gut microbiota. Taxonomic and metagenomic profiling based on whole-genome shotgun sequencing can help in understanding ‘which microbes are in the

Concluding Remarks and Future Perspectives

Animal studies have indicated a direct role for the gut microbiota in the development of several diseases, such as obesity and colitis 66, 116. However, solid and consistent evidence for the contribution of the gut microbiota to human diseases is lacking due to the vast interindividual variability of the human gut microbiome [117], the potential confounding effects of diet and medications, and differences in the pipelines for gut microbiota analyses. Large prospective studies may help in

Acknowledgments

The authors thank Anna Hallén for assistance with the artwork in Figure 3.

Glossary

Bile acids
primary bile acids [e.g., cholic acid (CA) in mice and humans, chenodeoxycholic acid (CDCA) in humans, muricholic acids in mice] are synthesized from cholesterol in the liver and conjugated with glycine or taurine. The gut microbiota deconjugates and transforms primary bile acids into secondary bile acids [e.g., deoxycholic acid (DCA), lithocholic acid (LCA)].
Fecal microbiota transplantation (FMT)
a procedure in which stool samples from healthy donors are introduced to patients through

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    These authors contributed equally.

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