Study reveals how our gut cells detect harmful invaders

Osaka, Japan – The human gut is home to helpful microbes, called the microbiota, who produce molecules known as metabolites. These metabolites are being increasingly recognized for their role in supporting our health. A group of proteins in our body, known as G protein-coupled receptors (GPCRs), can detect these metabolites and trigger important immune responses and other pathways. However, it’s still unclear which metabolites cause these reactions and what kind of immune responses they create.

Now, researchers from Osaka University have discovered that one receptor, called GPR31, is active in a specific type of immune cell found in the gut, known as conventional type 1 dendritic cells (cDC1s). These cells, located in parts of the gut like 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 findings, published in The Proceedings of the National Academy of Sciences (PNAS), led them to investigate whether the GPR31 receptor detects bacterial metabolites and activates the immune system. When they tested how different metabolites affected cDC1 cells, they saw an increase in the expression of genes linked to dendrite membranes and filopodia—tiny cell extensions that help the cell interact with its environment, in the presence of pyruvate. This change disappeared when GPR31 was blocked.

“Critically, we could 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.

The dendrites, when extended out, help dendritic cells sample the gut for foreign substances. When they find something dangerous, they activate immune cells like T cells. The researchers created a model that showed these extensions can pass through the gut lining and that they are drawn to areas with more metabolites, specifically pyruvate. In the presence of pyruvate and GPR31, the cDC1 cells were better at detecting antigens and bacteria, like 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 gut infections in humans and that this process is supported by the metabolites produced by helpful gut bacteria.

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

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The article, “Pyruvate–GPR31 axis promotes transepithelial dendrite formation in human intestinal dendritic cells,” was published in PNAS at DOI:  https://doi.org/10.1073/pnas.2318767121

About Osaka University
Osaka University was founded in 1931 as one of the seven imperial universities of Japan and is now one of Japan's leading comprehensive universities with a broad disciplinary spectrum. This strength is coupled with a singular drive for innovation that extends throughout the scientific process, from fundamental research to the creation of applied technology with positive economic impacts. Its commitment to innovation has been recognized in Japan and around the world. Now, Osaka University is leveraging its role as a Designated National University Corporation selected by the Ministry of Education, Culture, Sports, Science and Technology to contribute to innovation for human welfare, sustainable development of society, and social transformation.
Website: https://resou.osaka-u.ac.jp/en

About Immunology Frontier Research Center (IFReC), Osaka University
IFReC was established by the support of the World Premier International Research Center Initiative (WPI) in 2007. IFReC aims to overcome immune-related diseases by clarifying the whole picture of the immune system, and has promoted globally competitive fundamental research with excellent researchers from overseas.
Website: https://www.ifrec.osaka-u.ac.jp/en