Identifying members of the intestinal microbiota that play causal roles in shaping human disease susceptibility

Were Samuel Coleridge’s ancient mariner a modern biologist trying to navigate the complex literature surrounding the intestinal microbiota, he might instead have despaired, ‘‘MWAS, MWAS, every where; Nor any causal link! ’’ In an article published recently in Nature, Surana and Kasper (2017) describe a navigational strategy for identifying causal members of the gut microbiota that shape host physiology and disease susceptibility: microbe-phenotype triangulation (MPT) (Figure 1). The intestinal microbiota consists of the trillions of microorganisms that colonize the mammalian gastrointestinal tract, including hundreds of species of bacteria. Studies in model host organisms, particularly mice, have illustrated the role of the intestinal microbiota in nearly every facet of host physiology, from immune maturation to neurodegenerative disease. In humans, the standard approach for identifying phenotype-associated microbes has been the microbe-wide association study (MWAS), which is analogous to the genome-wide association studies (GWAS) that are commonly used to identify genetic variants linked to a given phenotype. In a standard MWAS, microbial composition is compared between two populations of interest (e.g., diseased and healthy), and differentially abundant microbes are identified that correlate with the phenotype of interest (Gilbert et al., 2016). However, due to the extensive complexity, diversity, and flexibility of the human microbiota, identifying causal organisms using MWAS has remained difficult. The identification of causal microorganisms, and their functional andmechanistic roles in modulating host phenotypes, will be necessary to translate fundamental studies in the microbiota field into therapeutic advances. Thus, there has been a concerted effort over the past 10 years to develop new tools to enable identification of causal microbes in humans. The pioneering studies of Gordon, Honda, and others (Atarashi et al., 2013; Faith et al., 2014; Ridaura et al., 2013) have demonstrated that combinatorial in vivo screening of human microbial communities transplanted into germ-free mice, combined with anaerobic culture of microbes of interest, can identify causal gut microbes that impact human physiology and disease susceptibility. In their recent article, Surana and Kasper (2017) extend this trend and present a simple approach for identifying causal microbes in a mouse-model-based assay referred to as MPT. Surana and Kasper (2017) took advantage of previously characterized microbial communities derived from gnotobiotic mice colonized with either microbiota from SPF mice (MMb) or healthy human donors (HMb) (Chung et al., 2012). HMb mice were protected from dextran sodium-sulfate-induced colitis, while MMb rapidly succumbed. A standard MWAS comparing MMb and HMb identified hundreds of differentially abundant bacterial strains between the two mouse populations, whichwas beyond the experimental reach for testing causality of single microorganisms. However, co-housed mice displayed intermediate microbiota compositions and phenotypes. By comparing