2025 Gut Microbiota International Grant Winner

Bile acids (BAs) play a central role in human physiology, acting as signaling molecules in a complex communication system involving the liver, intestine, and gut microbiota. BAs function as ligands for nuclear receptors (primarily FXR and LXR) and membrane receptors like TGR5, which are important targets for studying metabolic diseases such as nonalcoholic fatty liver disease.

The investigator team recently identified a previously undescribed family of BAs produced by the host in a microbiota-dependent manner: the methylcysteamine (BA-MCY) conjugates (Nature, in press). These BAs are synthesized in the intestine by the enzyme VNN1/Vanin 1. Importantly, BA-MCYs invert BA function in the hepatobiliary system: whereas free BAs function as FXR agonists, which negatively regulate BA production, the BA-MCYs function as FXR antagonists and promote BA biosynthesis. We further showed that BA-MCY supplementation decreased liver lipid accumulation in a mouse model of hypercholesterolemia. The discovery of BA-MCYs as endogenous FXR antagonists thus offers significant new opportunities for treating metabolic diseases, given that inhibition of specifically intestinal FXR signaling can reduce obesity, insulin resistance, hypercholesterolemia, and fatty liver disease.

BA-MCY levels were reduced in microbiota-deficient mice and restored by human fecal microbiota transplantation. Moreover, we have shown that microbiota can deactivate BA-MCYs by hydrolysis. These results indicating that the abundance of the host-derived BA-MCYs is strongly regulated by microbial transformations, providing the basis for this application.

The central goal of this application is to investigate the roles of the microbiota in the regulation of BA-MCY metabolism and the resulting functional impact on metabolic homeostasis and immune responses. In Aim 1 we will investigate the role of the microbiota in BA-MCY metabolism. We will first identify microbiota and microbial genes involved in deactivation of BA-MCYs via hydrolysis, based on the hypothesis that a subset of microbial bile salt hydrolases ((BSHs) is capable of hydrolyzing BAMCYs. Next we will investigate the role of the microbiota in oxidative deactivation of BA-MCYs by conversion into the corresponding sulfoxides, the BA-MCYOs, which have no FXR agonist or antagonist activity. In Aim 2 we will then investigate how BA-MCYs regulate metabolic homeostasis and inflammation and how depletion of BA-MCY by gut microbiota impact host physiology. We will begin with an in-depth characterization of the effects of BA-MCYs on metabolic homeostasis and innate and adaptive immune responses, including the underlying molecular and cellular mechanisms that regulate these effects. This will provide a basis to determine how microbial BA-MCY metabolism regulates BA-MCY-dependent physiology, specifically in the context of fat metabolism, obesity, and tissue inflammation.

Taken together, our research will help uncover the complex interplay between gut microbiota, BA signaling, and host physiology, potentially leading to novel therapeutic strategies for metabolic and immune disorders.