Surgery-induced gut microbial dysbiosis promotes cognitive impairment via regulation of intestinal function and the metabolite palmitic amide

Abstract

Abstract Background Perioperative neurocognitive disorders (PND) are the most common postoperative complications with few therapeutic options. Gut microbial dysbiosis is associated with neurological diseases; however, the mechanisms by which the microbiota regulates postoperative gastrointestinal and cognitive function are incompletely understood. Methods Behavioral testing, MiSeq 16S rRNA gene sequencing, non-target metabolism, intestinal permeability detection, protein assays, and immunofluorescence staining were employed to discern the impacts of surgery on microbial profiles, intestinal barriers, serum metabolism, and the brain. Interventions in mice included fecal microbiota transplantation, the anti-inflammatory agent dexamethasone, Lactobacillus supplementation, indole propionic acid supplementation, and palmitic amide administration. Results Surgery-induced cognitive impairment occurs predominantly in aged mice, and surgery-induced alterations in the microbiota composition profile exacerbate intestinal barrier disruption in aged mice. These adverse effects can be mitigated by transferring microbiota from young donors or by bolstering the intestinal barrier function using dexamethasone, Lactobacillus, or indole propionic acid. Moreover, microbiota composition profiles can be restored by transplanting feces from young mice to aged surgical mice, improving neuropathology and cognitive function, and these effects coincide with increased intestinal permeability. Metabolomic screening identified alterations in metabolites in mouse serum after surgery, especially the increase in palmitic amide. Palmitic amide levels in serum and brain can be decreased by transplanting feces from young mice to aged surgical mice. Oral palmitic amide exacerbates cognitive impairment and neuropathological changes in mice. Conclusions Gut microbial dysbiosis in mice after surgery is a key mechanism leading to cognition dysfunction, which disrupts the intestinal barrier and metabolic abnormalities, resulting in neuroinflammation and dendritic spine loss. Intestinal barrier damage and high level of palmitic amide in old mice may be the cause of high incidence of PND in the elderly. Preoperative microbiota regulation and intestinal barrier restoration may be of therapeutic benefit in preventing PND.