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 ( < 0.001), and the percentage of freezing time in contextual fear test decreased ( < 0.001). Surgery triggers neuroinflammation, manifested as the elevated levels of the inflammatory cytokines IL-1β ( < 0.001) and IL-6 ( < 0.001), the increased expression of the transcription factor RORγt ( = 0.0181, POD1;  = 0.0073, POD5)and major inflammatory cytokines IL-17A ( = 0.0215, POD1;  = 0.0071, POD5), and the increased average fluorescence intensity of Iba1 ( < 0.001, POD1;  < 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 ( = 0.0148) was close to the baseline level on POD5 ( = 0.1846), and they performed better in behavioral tests. The levels of IL-1β ( < 0.001) and IL-6 ( = 0.0035) inflammatory factors in hippocampus decreased on POD1 and the average fluorescence intensity of Iba1 decreased ( = 0.0024, POD1;  < 0.001, POD5), representing the neuroinflammation was significantly improved. Besides, the levels of RORγt mRNA ( = 0.0231, POD1;  = 0.0251, POD5) and IL-17A mRNA ( = 0.0208, POD1;  = 0.0071, POD5) in hippocampus as well as the expression of IL-17A ( = 0.0057, POD1;  < 0.001, POD5) and IL-17RA ( = 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.