Mechanistic modeling approach relating human gut microbial community to physiologically-relevant biomarkers
Kirill Peskov*, Yuri Kosinsky*, Anna Popenko, Aleksndr Tyakht, Dmitry Alexeev; *Current affiliation: Modeling & Simulation, Novartis Pharma LLC, Moscow, Russia
Russian Institute of Physico-Chemical Medicine, Moscow, Russia
Objectives: The adult human gut houses a microbial community which contains a large number of bacterial species. It is well-known now that the actual composition of this community has a significant influence on human vital functions and may be an important determinant of various pathologies (e.g., obesity, inflammation). However, the mechanisms controlling the assembly of gut microbiota and its relationship with host human tissues remain poorly understood. This paper represents a first attempt in developing an integrated quantitative understanding of factors relating gut microbiota to measures of physiologically-significant blood plasma biomarkers.
Methods: Based on the results of Turnbaugh. et al., 2009, showing that the human gut microbial community is typically formed by two bacterial phyla (Fermicutes and Bacteroides), we developed various sub-models describing generalized metabolic peculiarities of these bacteria, their sensitivity to various nutrients, and processing of endpoint metabolites such as short-chain fatty acids. Individual sub-models were integrated to provide a unified model of microbiota relationships with host tissues. Model predictions were verified against experimental data from the literature, on qualitative and quantitative gut microbial composition, biochemical characterization of particular bacteria, and results of gnotobiotic mice colonization by various microbial cultures.
Results: All individual sub-models provided adequate descriptions of isolated interactions. The integrated model provided good descriptions of literature-reported changes in butyrate, acetate and propionate in response to different bacterial composition (in accordance to the data published by Mahowald et al., 2009). It was shown that different steady-state ratios of short-chain fatty acids produced by one or another microbial composition can be considered as risk factors for obesity.
Conclusions: A mechanistic model of the relationship between human gut microbial community and host tissues was developed. The model can be used to evaluate the potential effect of various compositions of microbial community to the steady state ratios of short-chain fatty acids and in silico testing of possible therapies related to interventions and changes in gut microbial composition.
 Turnbaugh P. et al. (2009) Nature, 457: 480-484
 Mahowald M. et al. (2009) PNAS, 106: 5859-5864