There is a growing interest to understand if and how gut microbiome is causally linked to the pathogenesis and/or progression of diseases. While in vitro cell line models are commonly used for studying specific aspects of the host-microbe interaction, gnotobiotic murine models are considered the preferred platform for studying causality in microbiome research. Nevertheless, findings from animal studies provide limited opportunity for delineating various areas of interest to the human gut microbiome research. Gut-on-chips are biomimetics recapitulating intestinal physiology which enable investigation of bidirectional effects of the host and microbiome. We posit that they could advance causal and ecological gut microbiome research in three major areas: 1) diet- and drug-microbiome interaction; 2) microbiome-targeted therapeutics pharmacoecology; and 3) mechanistic studies of gut microbiome and microbiome-targeted intervention in extra-intestinal pathologies.