LAUSR

The emerging role of the gut microbiome in human pathophysiology has led to a paradigm shift in our view of complex traits, moving us from a “genetics–environment” interaction model to one that encompasses “genetics–microbes–environment.” Within this interaction, the microbial mediators are of particular interest. Moreover, the gut microbiome itself is being recognized as a complex trait, and systems genetics has been proposed as a powerful approach to gain understanding of the underlying mechanisms [1]. With respect to the role of microbes in metabolic processes in health and disease, we need to understand what they can do and how genetic determinants of gut microbes influence metabolism or vice versa. A recent proof-of-concept mendelian randomization study highlighted the causality of bacterial production of short-chain fatty acids (SCFAs) in the etiology of type 2 diabetes [2]. SCFAs are products of bacterial fermentation of dietary fibers, affecting the host’s immune fitness and metabolic homeostasis. However, metabolic interactions between host and microbes can be bidirectional and much more complicated. Bile acids (BAs) represent a class of bidirectional metabolic mediators, as their presence in the body is attributable to activities of both host and microbial enzymes (Fig 1). BAs are synthesized in relatively large quantities (approximately 1 g/day in humans) exclusively in the liver through the actions of approximately 20 enzymes encoded by genes that are controlled by distinct metabolic cues that are, in part, derived from the intestine. BAs are then efficiently maintained within the enterohepatic circulation by the actions of several specific transporter systems, i.e., they travel between the liver and the intestinal lumen, where they interact with microbiome. This interaction is 2-fold: bacteria alter BA composition by changing primary (liver-derived) species into secondary, more hydrophobic species, while at the same time, BAs have bacteriostatic actions that depend on their structure and hence, on their physicochemical characteristics [3]. In this issue of PLOS Genetics, Kemis and colleagues [4] present a study in which they performed quantitative trait locus (QTL) analyses on the fecal microbiome and plasma as well as cecal BA profiles of a Diversity Outbred (DO) mouse population, a heterogeneous population derived from eight founder strains that individually harbor distinct microbial communities and display different sensitivities to diet-induced metabolic diseases. Kemis and colleague’s study reveals several QTLs associated with variations in bacterial (16S sequencing) and BA profiles, with 17 loci defined as shared QTLs associating with both microbial and BA traits. These shared QTLs highlighted genetic effects on the gut microbes and BA via pleiotropic (QTL!microbe and QTL! BA independently) or causal effects (QTL! BA!Microbe or QTL!Microbe! BA) (Fig 1). The authors then specifically focused on a QTL near the ileal BAs transporter Solute Carrier Family 10 Member 2 (Slc10a2) that was associated with both