Propionic acid ameliorates cognitive function through immunomodulatory effects on Th17 cells in perioperative neurocognitive disorders.

BACKGROUND: Elderly patients undergoing surgery are prone to cognitive decline known as perioperative neurocognitive disorders (PND). Several studies have shown that the microglial activation and the decrease of short-chain fatty acids (SCFAs) in gut induced by surgery may be related to the pathogenesis of PND. The purpose of this study was to determine whether microglia and short-chain fatty acids were involved in cognitive dysfunction in aged rats.

METHODS: Male wild-type Wistar rats aged 11-12 months were randomly divided into control group (Ctrl: Veh group), propionic acid group (Ctrl: PA group), exploratory laparotomy group (LP: Veh group) and propionic acid + exploratory laparotomy group (LP: PA group) according to whether exploratory laparotomy (LP) or PA pretreatment for 21 days was performed. The motor ability of the rats was evaluated by open field test on postoperative day 3 (POD3), and then the cognitive function was evaluated by Y-maze test and fear conditioning test. The expression of IL-1β, IL-6, RORγt and IL-17A mRNA in hippocampus was detected by RT-qPCR, the expression of IL-17A and IL-17RA in hippocampus was detected by Western blot, and the activation of microglia was detected by immunofluorescence.

RESULTS: The PND rat model was successfully established by laparotomy. Compared with Ctrl: Veh group, the body weight of LP: Veh group decreased, the percentage of spontaneous alternations in Y maze decreased ( P  < 0.001), and the percentage of freezing time in contextual fear test decreased ( P  < 0.001). Surgery triggers neuroinflammation, manifested as the elevated levels of the inflammatory cytokines IL-1β ( P  < 0.001) and IL-6 ( P  < 0.001), the increased expression of the transcription factor RORγt ( P  = 0.0181, POD1; P  = 0.0073, POD5)and major inflammatory cytokines IL-17A ( P  = 0.0215, POD1; P  = 0.0071, POD5), and the increased average fluorescence intensity of Iba1 ( P  < 0.001, POD1; P  < 0.001, POD5). After PA preconditioning, the recovery of rats in LP: PA group was faster than that in LP: Veh group as the body weight lost on POD1 ( P  = 0.0148) was close to the baseline level on POD5 ( P  = 0.1846), and they performed better in behavioral tests. The levels of IL-1β ( P  < 0.001) and IL-6 ( P  = 0.0035) inflammatory factors in hippocampus decreased on POD1 and the average fluorescence intensity of Iba1 decreased ( P  = 0.0024, POD1; P  < 0.001, POD5), representing the neuroinflammation was significantly improved. Besides, the levels of RORγt mRNA ( P  = 0.0231, POD1; P  = 0.0251, POD5) and IL-17A mRNA ( P  = 0.0208, POD1; P  = 0.0071, POD5) in hippocampus as well as the expression of IL-17A ( P  = 0.0057, POD1; P  < 0.001, POD5) and IL-17RA ( P  = 0.0388) decreased.

CONCLUSION: PA pretreatment results in reduced postoperative neuroinflammation and improved cognitive function, potentially attributed to the regulatory effects of PA on Th17-mediated immune responses.