Ecological Modeling from Time-Series Inference: Insight into Dynamics and Stability of Intestinal Microbiota
PLoS Comput Biol, 9 (12):
e1003388+ (Dec 12, 2013)DOI: 10.1371/journal.pcbi.1003388
Abstract
The intestinal microbiota is a microbial ecosystem of crucial importance to human health. Understanding how the microbiota confers resistance against enteric pathogens and how antibiotics disrupt that resistance is key to the prevention and cure of intestinal infections. We present a novel method to infer microbial community ecology directly from time-resolved metagenomics. This method extends generalized Lotka–Volterra dynamics to account for external perturbations. Data from recent experiments on antibiotic-mediated Clostridium difficile infection is analyzed to quantify microbial interactions, commensal-pathogen interactions, and the effect of the antibiotic on the community. Stability analysis reveals that the microbiota is intrinsically stable, explaining how antibiotic perturbations and C. difficile inoculation can produce catastrophic shifts that persist even after removal of the perturbations. Importantly, the analysis suggests a subnetwork of bacterial groups implicated in protection against C. difficile. Due to its generality, our method can be applied to any high-resolution ecological time-series data to infer community structure and response to external stimuli. Recent advances in DNA sequencing and metagenomics are opening a window into the human microbiome revealing novel associations between certain microbial consortia and disease. However, most of these studies are cross-sectional and lack a mechanistic understanding of this ecosystem's structure and its response to external perturbations, therefore not allowing accurate temporal predictions. In this article, we develop a method to analyze temporal community data accounting also for time-dependent external perturbations. In particular, this method combines the classical Lotka–Volterra model of population dynamics with regression techniques to obtain mechanistically descriptive coefficients which can be further used to construct predictive models of ecosystem dynamics. Using then data from a mouse experiment under antibiotic perturbations, we are able to predict and recover the microbiota temporal dynamics and study the concept of alternative stable states and antibiotic-induced transitions. As a result, our method reveals a group of commensal microbes that potentially protect against infection by the pathogen Clostridium difficile and proposes a possible mechanism how the antibiotic makes the host more susceptible to infection.