The pyruvate-GPR31 axis promotes transepithelial dendrite formation in human intestinal dendritic cells

Area of Science:

• Immunology
• Microbiology
• Gastroenterology

Background:

• Gut microbial metabolites are crucial signaling molecules for intestinal immune cells.
• G-protein-coupled receptors (GPCRs) mediate the translation of gut luminal signals into host immune responses.
• The precise mechanisms of gut microbe-GPCR interactions influencing human physiology remain incompletely understood.

Purpose of the Study:

• To investigate the role of the GPCR GPR31, activated by the bacterial metabolite pyruvate, in human intestinal immunity.
• To elucidate how GPR31 activation on specific immune cells impacts the uptake of luminal antigens.
• To understand the functional consequences of gut microbe-GPCR signaling in the human gut.

Main Methods:

• Utilized human induced pluripotent stem cell-derived type 1 conventional dendritic cells (cDC1s).
• Employed a monolayer human gut organoid co-culture system to model the intestinal environment.
• Investigated the formation of transepithelial dendrites (TED) and antigen uptake by cDC1s in response to pyruvate.

Main Results:

• GPR31 is specifically expressed on cDC1s in the human intestinal lamina propria.
• cDC1s form transepithelial dendrites (TED) towards pyruvate on the luminal side.
• GPR31 activation by pyruvate enhances cDC1 antigen uptake via TED formation, including dietary compounds and bacterial particles.

Conclusions:

• GPR31 activation by the gut bacterial metabolite pyruvate enhances cDC1 function in the human intestine.
• Transepithelial dendrite (TED) formation is a key mechanism for cDC1s to sense and respond to luminal metabolites.
• GPCRs play a vital role in modulating the human gut immune system based on local metabolic cues.