Sepsis as a risk factor for Alzheimer’s disease pathophysiology

Abstract

AbstractBackgroundThe sepsis‐induced polymicrobial infection leads to life‐threatening organ dysfunction that accounts for high mortality and morbidity worldwide. More than half of those who survive sepsis have a worse quality of life and long‐term cognitive deficits. Significant alteration of gut microbiota has been documented in sepsis patients, impacting both compositional and functional levels. In this context, we aimed to explore the cross‐link between the gut‐brain axis on sepsis‐induced long‐term cognitive decline using Alzheimer’s disease mouse model.MethodMale, 50‐day‐old APP/PS1 mice were subjected to a gold standard sepsis model by cecal ligation and perforation (CLP) surgery to induce sepsis or sham surgery as a control group. Longitudinally, at 3, 30, and 120 days after sepsis or sham surgery, feces were collected for 16S rRNA sequencing and short‐chain fatty acids (SCFAs) evaluation. The gut was collected for histology, mucin, and amyloid‐beta (Aβ) staining. The brain was collected to measure inflammatory mediators, neuroinflammatory markers (IBA‐1 and GFAP), and soluble and insoluble Aβ. Assessment of cognition was performed using novel object recognition (NOR) at 30 and 120 days after sepsis.ResultSepsis mice demonstrated an altered microbiome measured by alpha diversity, beta diversity, and relative abundance at 30 and 120 days. In the long‐term after sepsis, SCFAs were reduced, villi length and crypt depth decreased, and fucosylated goblet cells were significantly reduced in sepsis mice demonstrating gut dysfunction. However, no positive signal for Aβ was observed in the gut. In the brain, at 30 and 120 days, proinflammatory cytokines were increased in PFC, and decreased anti‐inflammatory cytokines in the hippocampus were observed. The neuroinflammation after infection was verified by measuring the glial cell activation. Compared to the age‐matched control, sepsis mice elevated Aβ burden at 120 days after surgery. Further, after CLP surgery, long‐term mice demonstrated a significant reduction in the recognition index in the NOR task.ConclusionSepsis‐induced enteric dysbiosis, gut modulation, increased brain inflammatory cytokines, and insoluble Aβ levels negatively regulated the cognitive behavior in APP/PS1 mice. Therefore, gut microbiota can be modified to impact the sepsis‐induced long‐term cognitive decline in sepsis survivors positively.