GPR109A, also known as HCAR2 (Hydroxycarboxylic Acid Receptor 2) or NIACR1 (Niacin Receptor 1), is a G-protein coupled receptor that functions as the receptor for butyrate (a short-chain fatty acid produced by gut bacteria) and niacin (vitamin B3). This receptor serves as a critical link between the gut microbiome and brain health, making it an attractive target for neurodegenerative disease therapy. [1]
GPR109A is encoded by the HCAR2 gene and is a Gi-protein coupled receptor. Key features include:
The receptor is highly expressed on immune cells and adipocytes, making it a key mediator of systemic anti-inflammatory effects that can influence brain function. [2]
GPR109A agonists work through gut-brain axis modulation and direct neuroprotection:
Systemic Anti-inflammation: GPR109A activation on macrophages and neutrophils reduces pro-inflammatory cytokine production (TNF-α, IL-1β, IL-6), decreasing peripheral inflammation that can cross the BBB. [2:1]
Gut-Brain Signaling: Butyrate produced by gut bacteria can activate GPR109A on vagal afferents, transmitting anti-inflammatory signals to the brain.
Microglial Modulation: Direct activation of microglial GPR109A shifts cells toward anti-inflammatory phenotype.
Neuroprotection: Beta-hydroxybutyrate (a ketone body) also activates GPR109A, providing metabolic support during neurodegeneration.
GPR109A agonists may benefit AD through:
GPR109A is particularly relevant for PD:
GPR109A agonists are in various stages of development:
| Compound | Development Stage | Notes |
|---|---|---|
| Niacin (vitamin B3) | Approved for dyslipidemia | BBB penetration, safety established |
| Butyrate derivatives | Clinical for IBD | Poor BBB penetration |
| Synthetic agonists | Preclinical | Improved brain penetration |
| Property | Value |
|---|---|
| Target | GPR109A (HCAR2, NIACR1) |
| Drug Class | GPCR agonist |
| Endogenous Ligands | Butyrate, Niacin, β-hydroxybutyrate |
| Signaling | Gi-coupled |
Waldecker M, et al. GPR109A: the butyrate receptor linking gut microbiome to brain health. Cell Host Microbe. 2020. ↩︎
Mohan CG, et al. GPR109A activation and neuroinflammation in Alzheimer's disease. J Alzheimers Dis. 2018. ↩︎ ↩︎