The human gut contains beneficial microorganisms that it hosts as its residents – the microbiota – which synthesise compounds called metabolites. This knowledge is extending to these metabolites, which are being recognised for other roles supporting our health.
There are certain metabolites present in our body, to which proteins called G protein-coupled receptors (GPCRs) get bound and we get some crucial immune responses and other pathways. But it remains doubtful which metabolites produce these reactions and what type of immune responses they stimulate.
But, new research from Osaka University has revealed that one of those receptors, GPR31, is also expressed in a subset of immune cells within the intestines called conventional type 1 dendritic cells (cDC1s).
These cells are found in parts of the gut, including the ileum, and can activate something called CD8 + T cells which is a cardinal component of the immune system that destroys pathogens inclusive of bacteria, viruses and even some cancer cells.
The team’s discovery, reported in Proceedings of the National Academy of Sciences, made the investigators look for whether the GPR31 receptor serves to identify bacterial metabolites and mobilise the immune response. The title of the article is Pyruvate–GPR31 axis promotes transepithelial dendrite formation in human intestinal dendritic cells.
When they did the validation to see how different metabolites influenced cDC1 cells, they realised four genes associated with dendrite membranes and filopodia – small structures that enable the cell to communicate with the environment – whose expression augment in response to pyruvate was activated. This change was absent when GPR31 was inhibited.
To their chagrin, they could see under the microscope that in humans, dendrites respond to metabolites: ‘When the team activated GPR31, the dendrites burgeoned; and when they dampened GPR31, dendrites recoiled.’
Extended out, the dendrites enable the dendritic cells to take samples in the gut for foreign bodies. When they encounter an antibody or something hazardous they mobilise defence cells such as the T cells.
To disprove this finding, the researchers designed a model to demonstrate that these extensions can readily diffuse across the gut lining and that they are attracted to metabolite–rich regions, namely pyruvate.
When co-cultured with pyruvate and GPR31, the cDC1 cells exhibited enhanced antigen presentation and bacterial recognition such as of E.coli and T cell activation of the CD8+.
The present study is the first to demonstrate that GPR31 is attributable to immune responses to gut infections in humans and that the reaction is driven by the metabolites of beneficial bacteria residing in the gut.
“Our work may potentially indicate that cataloguing this pathway may be beneficial in creating new drugs or oral vaccines,” added senior author Kiyoshi Takeda. ‘Pyruvate producing probiotics may also enhance our immune defence to intestinal pathogens’, they highlighted.
Reference: Eri Oguro-Igashira, Murakami M, Mori R, Kuwahara R, Kihara T, Kohara M, et al. The pyruvate–GPR31 axis promotes transepithelial dendrite formation in human intestinal dendritic cells.
