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

Background Elderly patients after surgery are prone to cognitive decline known as postoperative cognitive dysfunction (POCD). Several studies have shown that the microglial activation and the decrease of short-chain fatty acids in gut induced by surgery may be related to the pathogenesis of POCD. 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) was performed and whether PA pretreatment for 21 days was performed. Among them, LP: Veh group and LP: PA group were further divided into LP1: veh group in LP5: veh group, LP1: PA group and LP5: PA group. There were 6 groups of rats with 12 rats in each group. The PND model was established by exploratory laparotomy. The motor ability of the rats was evaluated by open field test on the 3rd day after operation, and then the cognitive function was evaluated by Y maze test and conditioned fear test. The difference of PA content in intestine of LP: Veh group was detected by LC-MS/MS, the expression of IL-1β, IL-6, RORγt and IL-17 A mRNA in hippocampus was detected by RT-qPCR, the expression of IL-17 A and IL-17 R A in hippocampus was detected by WB, and the activation of microglia was detected by immunofluorescence Iba1. Results The PND rat model was successfully established by laparotomy. Compared with Ctrl: Veh group, the body weight of LP: Veh group decreased, the number of spontaneous alternations of Y maze decreased (P < 0.0001), the freezing time of conditioned fear test decreased (P < 0.0001). LC-MS/MS metabolite targeting results suggest that compared to preoperative, the concentration of PA in the intestine of rats on POD1 has significantly decreased (P = 0.0016), suggesting a possible correlation with cognitive impairment. Surgery triggers neuroinflammation, manifested as the elevated levels of the inflammatory cytokines IL-1β(P < 0.0001) and IL-6 (P < 0.0001), the increased expression of the transcription factor RORγt (P = 0.0181，POD1; P = 0.0073，POD5)and major inflammatory cytokines IL-17 A (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, and the body weight loss decreased on POD1(P = 0.0148) and was close to the baseline level on POD5(P = 0.1846). The behavioral experiment of rats in LP: PA group performed well, the number of spontaneous alternation of Y maze (P < 0.0001) and freezing time of conditioned fear test (P = 0.0012) increased significantly, and the levels of IL-1β(P < 0.0001) and IL-6(P = 0.0035) inflammatory factors in hippocampus decreased on POD1. The average fluorescence intensity of Iba1 decreased (P = 0.0024，POD1; P = 0.0001，POD5), the neuroinflammation was significantly improved, the levels of RORγt mRNA (P = 0.0231，POD1; P = 0.0251，POD5) and IL-17 A mRNA (P = 0.0208，POD1; P = 0.0071，POD5) in hippocampus decreased, the expression of IL-17 A (P = 0.0057，POD1; P = 0.0009，POD5) and IL-17 R A (P = 0.0388) decreased. Conclusion The content of PA in the intestine of PND rats decreased significantly, and PA pretreatment reduced the postoperative neuroinflammation and improved the cognitive function, which may be related to the regulation of PA on the immune function of Th17 cells.