Researchers have identified that GPR31, a receptor present in certain immune cells within the human gut, is crucial for reacting to bacterial metabolites and initiating immune responses. In particular, when the metabolite pyruvate is present, these immune cells extend dendrites to explore the gut environment, identify pathogens, and activate T cells via GPR31. This finding could pave the way for creating new medications, vaccines, and probiotics that improve gut immunity by focusing on this pathway.
The human gut is inhabited by beneficial microbes collectively known as the microbiota, which produce various molecules called metabolites. Researchers are increasingly acknowledging the importance of these metabolites for our health. A group of proteins in our body, called G protein-coupled receptors (GPCRs), can sense these metabolites and initiate vital immune responses and other biological pathways. Nonetheless, the specific metabolites that drive these reactions and the types of immune responses they trigger remain largely unclear.
Recently, researchers from Osaka University made a significant discovery regarding GPR31, a receptor active in a specialized type of immune cell in the gut known as conventional type 1 dendritic cells (cDC1s). These cells, found in areas like the ileum of the gut, are responsible for activating CD8+ T cells. These T cells are essential for the immune system, as they eliminate harmful bacteria, viruses, and even some cancer cells.
The team documented their findings in the Proceedings of the National Academy of Sciences (PNAS) and sought to determine whether GPR31 responds to bacterial metabolites and activates the immune system. Upon testing the effects of various metabolites on cDC1 cells, they observed an increase in the expression of genes related to dendrite membranes and filopodia—small extensions that facilitate interaction with the environment—when exposed to pyruvate. This response diminished when GPR31 was inhibited.
Lead author Eri Oguro-Igashira mentions, “Importantly, we could see under the microscope that dendrites in humans were responsive to these metabolites; they extended when GPR31 was activated and retracted when we blocked GPR31.”
The extended dendrites help dendritic cells survey the gut for foreign materials. Upon detecting a threat, they activate immune cells like T cells. The researchers developed a model illustrating that these extensions can penetrate the gut lining and are attracted to areas with higher metabolite concentrations, particularly pyruvate. With both pyruvate and GPR31 present, cDC1 cells exhibited improved abilities to detect antigens and bacteria, such as E. coli, enhancing the activation of CD8+ T cells.
This research is the first to demonstrate that GPR31 is instrumental in the human immune response to gut infections and that this process is bolstered by metabolites from beneficial gut bacteria.
Senior author Kiyoshi Takeda notes, “Our research indicates that targeting this pathway has potential for the development of new drugs and mucosal vaccines. Probiotics that produce pyruvate could also enhance our immune response to gut infections.”
