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Signaling between gut microbiota and brain immune cells

University of British Columbia

Neuroinflammation is a key pathophysiological feature of neurodegenerative disorders including Alzheimer’s disease. Neuroinflammation occurs when microglia, brain immune cells, become chronically activated and excessively secrete inflammatory molecules, such as reactive oxygen and nitrogen species, tumour necrosis factor (TNF)-α, and monocyte chemoattractant protein (MCP)-1. This overactivation of the brain immune system can lead to damage and death of healthy neurons. Identifying the mediators that regulate microglial activation in the central nervous system (CNS) is imperative for the development of new therapies that treat or prevent neuroinflammation. Recent evidence shows that bacteria that inhabit the gut are key players in the communication between the gut and brain and may mediate neuroinflammation. Therefore, the bacterial metabolites D-serine, trimethylamine N-oxide (TMAO), formate, and valerate, as well as the related endogenous signaling molecule Interleukin (IL)-2, were tested for their ability to modulate select microglial functions. To test this hypothesis, the cell-mediated neurotoxicity assay was used to determine the toxic effects of human microglia-like cells towards human SH-SY5Y neuronal cells. Enzyme-linked immunosorbent assays were utilized to determine the secretion levels of TNF-α and MCP-1 by microglia-like cells. The Griess assay and chemiluminescence were used to quantify the secretion of reactive nitrogen and oxygen species, respectively, by microglia-like cells and the phagocytosis assay was utilized to quantify the phagocytic activity of microglia-like cells. It was determined that formate and valerate inhibited secretion of TNF-α and MCP-1 by microglia-like cells and decreased their toxicity towards SH-SY5Y neurons. D-Serine, TMAO, and IL-2 had no effects on these parameters. D-Serine, formate, and IL-2 inhibited the secretion of reactive oxygen species by microglia-like cells, while valerate and TMAO showed no effect. D-Serine, formate and valerate modulated the phagocytic activity of microglia-like cells while TMAO and IL-2 had no effect. None of the tested compounds had any effect on the secretion of reactive nitrogen species by murine microglia. This study demonstrated that four different bacterial metabolites and the related endogenous signaling molecule IL-2 modulated select microglial functions. These data provide insight into the signaling mechanisms between gut bacteria and brain immune cells and may provide alternate therapeutic approaches for targeting neuroinflammation.

Text

2020-10-06

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/76265

Biochemistry and Molecular Biology

University of British Columbia

UBCO

http://creativecommons.org/licenses/by-nc-nd/4.0/