Sepsis-induced immune dysregulation and dysbiosis impairs cognitive abilities

• Published in: The Journal of immunology (1950) 2021-05, Vol.206 (1_Supplement), p.112-112.04
• Main Authors: Giridharan, Vijayasree Vayalanellore, Generoso, Jaqueline S, Lee, Juneyoung, Petronilho, Fabricia, Dal-Pizzol, Felipe, Morales, Rodrigo, Barichello, Tatiana
• Format: Article
• Language: English
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.206.Supp.112.04

Sepsis is a life-threatening organ dysfunction caused by a dysregulated host response to microbial infection. More than 50% of sepsis survivors suffer from long-term cognitive deficits. Recently the disruption of gut microbiota at both compositional and functional levels was reported in sepsis patients. In this context, we aimed to explore if experimental sepsis-induced immune dysregulation and dysbiosis accelerates Alzheimer’s disease (AD) pathology. Male, 50-day-old APP/PS1 mice were subjected to cecal ligation and perforation (CLP) surgery for sepsis induction. Longitudinally, at 3, 30, and 120 days after sepsis or sham surgery, feces were collected for 16S rRNA sequencing and short-chain fatty acid (SCFA) evaluation. The brain was removed to measure Aβ expression and inflammatory cytokines levels. Cognition was tested using novel object recognition (NOR) task at 30 and 120 days after sepsis. Alpha and beta diversity analyses revealed higher disruption of intestinal communities at 30 and 120 days after sepsis. The levels of SCFA, such as acetic acid, butyric acid, isovaleric acid, and isobutyric acid, decreased in sepsis mice. At 30 days, IFN-γ, IL1-α, IL-12 (p40), eotaxin, and TNF-α were increased; at 120 days, anti-inflammatory cytokines IL-6, IL-10, and IL-13 were decreased in the hippocampus of sepsis mice as compared to control. At 120 days after sepsis, the AD pathological marker, Aβ expression, was elevated in the sepsis group. Further, at 30 and 120 days, the sepsis group demonstrated a significant cognitive decline. Sepsis-induced dysbiosis precedes overt cognitive impairment in APP/PS1 mice. Therefore gut microbiota can be targeted to impact outcomes from sepsis-related long-term cognitive decline positively.