From meta-omics to causality: experimental models for human microbiome research

Abstract

Large-scale ‘meta-omic’ projects are greatly advancing our knowledge of the human microbiome and its specific role in governing health and disease states. A myriad of ongoing studies aim at identifying links between microbial community disequilibria (dysbiosis) and human diseases. However, due to the inherent complexity and heterogeneity of the human microbiome, cross-sectional, case–control and longitudinal studies may not have enough statistical power to allow causation to be deduced from patterns of association between variables in high-resolution omic datasets. Therefore, to move beyond reliance on the empirical method, experiments are critical. For these, robust experimental models are required that allow the systematic manipulation of variables to test the multitude of hypotheses, which arise from high-throughput molecular studies. Particularly promising in this respect are microfluidics-based in vitro co-culture systems, which allow high-throughput first-pass experiments aimed at proving cause-and-effect relationships prior to testing of hypotheses in animal models. This review focuses on widely used in vivo, in vitro, ex vivo and in silico approaches to study host-microbial community interactions. Such systems, either used in isolation or in a combinatory experimental approach, will allow systematic investigations of the impact of microbes on the health and disease of the human host. All the currently available models present pros and cons, which are described and discussed. Moreover, suggestions are made on how to develop future experimental models that not only allow the study of host-microbiota interactions but are also amenable to high-throughput experimentation.

Microbiota dysbiosis: a new piece in the understanding of the carcinogenesis puzzle

“…Colonization of these animals with different species or bacterial groups enables the study of the association of these bacteria with a particular function at various stages of the animals' life cycles (Turnbaugh et al, 2007) and thereby their microorganism-host interactions (Palmer et al, 2007) or, more specifically, immunological response. Zebrafish, mice, rats and even pigs have been successfully used, with mice being the most widely used and characterized (Fritz et al, 2013).…”

“…These in vitro models allow analysis of metabolic processes in microbial digestion of certain compounds in order to understand the pharmacokinetics of certain drugs (Fritz et al, 2013) and for the study of microbiota variations that are influenced by diverse factors. The ex vivo models include cultured cells that resemble the architecture of tissue (Fritz et al, 2013).…”

“…Despite the progression in research to better understand microbial species associated with disease, existing studies are not sufficiently conclusive or statistically significant, due to both the number of cases studied and the heterogeneity of the microbiota that is influenced by many external factors (Fritz et al, 2013;Schwabe & Jobin, 2013).…”

“…Further metatranscriptomic and metabolomic studies are needed to explore the metabolic activity of the microbiome. Large-scale investigations, clinical trials, a large cohort of patients and validation through in vivo and in vitro models are required to understand the microbiome composition, variability and function in tumorigenesis (Bultman, 2014;Fritz et al, 2013;Khan et al, 2012;Schwabe & Jobin, 2013). Other limitations to consider include the standardization of both sample stability and methods for comparative data analysis between research centres (Hebert et al, 2015).…”

Anoxic Conditions Promote Species-Specific Mutualism between Gut Microbes In Silico

“…However, due to the complexity of the gut ecosystem, in vitro and gnotobiotic mouse models are limited in scope. In silico models, which can resolve complex interactions at the molecular level, are useful tools that can complement in vitro and in vivo models (12).…”