The discovery of gut microbial metabolites as modulators of host susceptibility to acetaminophen-induced hepatotoxicity.

The mammalian gut microbiota plays diverse and essential roles in modulating host physiology. Key mediators determining the outcome of the microbiota-host interactions are the small molecule metabolites produced by the gut microbiota. The liver is the organ massively exposed to gut microbial metabolites, and it serves as the nexus, maintaining healthy interactions between the gut microbiota and host. At the same time, the liver is the primary target of harmful gut microbial metabolites. This review provides an up-to-date list of gut microbial metabolites identified to increase or decrease host susceptibility to APAP-induced liver injury. Signaling pathways and molecular factors involved in the progression of APAP-induced hepatotoxicity are well-established, and we propose that the mouse model of APAP-induced hepatotoxicity serves as an excellent system for uncovering gut microbial metabolites of previously unknown function. Moreover, we envision that gut microbial metabolites identified to alter APAP-induced hepatotoxicity likely have broader implications in other liver diseases. Significance Statement This review provides an overview of recent discoveries from investigating whether and how the gut microbiota modulates the host susceptibility to APAP-induced liver injury. It focuses on the roles of gut bacterial small molecule metabolites as mediators of the interaction between the gut microbiota and the liver. It also illustrates the utility of APAP-induced liver injury as a model to identify gut microbial metabolites with biological function.