Key receptor reveals how gut cells detect harmful invaders

The human gut is home to helpful microbes, called the microbiota, that produce molecules known as metabolites. These metabolites are increasingly recognized for their role in supporting our health.

A group of proteins in our body, known as G protein-coupled receptors (GPCRs), can sense these metabolites and trigger important immune responses and other pathways. However, it is still unclear which metabolites cause these reactions and what kind of immune responses they create.

Now, researchers at Osaka University have discovered that a receptor, called GPR31, is active on a specific type of immune cells found in the gut, known as type 1 conventional dendritic cells (cDC1s ). These cells, located in parts of the intestine such as the ileum, can activate CD8⁺ T cells, which are key players in the immune system and destroy harmful bacteria, viruses and even some cancer cells.

The team’s conclusions, published in Proceedings of the National Academy of Sciencesled them to investigate whether the GPR31 receptor detects bacterial metabolites and activates the immune system. The article is titled “The pyruvate-GPR31 axis promotes transepithelial dendrite formation in human intestinal dendritic cells.”

When they tested how the different metabolites affected the cDC1 cells, they saw an increase in the expression of genes linked to membranes, dendrites and filopodia: small cell extensions that help the cell interact with its environment, in the presence of pyruvate. This change disappeared when GPR31 was blocked.

“Critically, we were able to observe under the microscope that dendrites in humans responded to metabolites; dendrites protruded when GPR31 was activated and retracted when we inhibited GPR31,” explains lead author Eri Oguro-Igashira.

Dendrites, when extended, help dendritic cells sample the gut for foreign substances. When they encounter something dangerous, they activate immune cells such as T cells.

The researchers created a model that showed that these extensions can pass through the intestinal lining and are attracted to areas with more metabolites, specifically pyruvate. In the presence of pyruvate and GPR31, cDC1 cells were better at detecting antigens and bacteria, such as E. coli, and activating CD8.⁺ T cells.

This study is the first to show that GPR31 plays a key role in the immune response to intestinal infections in humans and that this process is supported by metabolites produced by helpful gut bacteria.

“Our research shows that targeting this pathway could be valuable for developing new mucosal drugs and vaccines,” says lead author Kiyoshi Takeda. “Probiotics that produce pyruvate could also help boost our immune response to intestinal infections.”