Differential effects of the microbial metabolite acetate on murine microglia in in vitro sepsis and trauma models

Short chain fatty acids (SCFAs) including acetate, produced by gut microbiota, are key signaling molecules and impact microglial maturation and metabolism. Microglia play a dual role in maintaining homeostasis and neuroinflammation when activated. Despite evidence suggesting acetate's anti-inflammatory effects on lipopolysaccharide (LPS)-stimulated microglia, no studies have examined its impact on mechanically stretched microglia, a model for traumatic brain injury (TBI).

We investigated the effects of acetate at physiological doses and a frequently used higher experimental concentration in in vitro sepsis and TBI models in EOC20 mouse microglial cells. The impact of acetate was assessed using assays of cell death, cytokine production and inducible nitric oxide synthase (iNOS) expression.

In LPS-stimulated microglia, acetate did not reduce pro-inflammatory cytokine secretion or intracellular iNOS expression. Surprisingly, in moderate mechanically stretched microglia, physiological doses of acetate (100 µM and 300 µM) significantly reduced tumor necrosis factor-alpha (TNFα) production without affecting cell viability. Additionally, stretch injury increased nuclear localization of NF-κB that was attenuated with physiological doses of sodium acetate.

Acetate exerted anti-inflammatory effects in microglial stretch but not LPS stimulation. Further studies are warranted to elucidate acetate's regulatory role in sterile etiologies of neuroinflammation and its therapeutic potential for TBI.