Intestinal immune responses driven by gut microbial metabolite-GPCR signaling and advances in human in vitro models

Intestinal metabolites produced by gut microbiota have an important function as signaling molecules for host intestinal immune cells and mediate their effects via G protein-coupled receptors (GPCRs). Recently, an increasing number of novel gut microbial metabolite–GPCR axes have been identified, revealing dynamic and intricate interactions between the microbiota, their metabolites, and the host immune system. These discoveries have highlighted the importance of metabolic communication in regulating intestinal immune homeostasis and the development of various inflammatory and infectious diseases. At the same time, significant advances have been made in developing sophisticated human in vitro models, including organoid and co-culture systems, which have enabled the more precise elucidation of these axes and their underlying mechanisms, overcoming previous technical limitations associated with animal models or traditional cell lines. In this review, we focus on the pyruvate–GPR31 axis, which we have characterized as a key mechanism for maintaining intestinal homeostasis, and provide an overview of immune responses mediated by gut microbial metabolite–GPCR signaling. We also highlight recent progress in the development of innovative co-culture models—particularly those utilizing human cells—that have proven valuable in dissecting the functional impact of gut microbial metabolites on the human immune system.