Benjamin H Singer, Robert P Dickson, Scott J Denstaedt, Michael W Newstead, Kwi Kim, Nicole R Falkowski, John R Erb-Downward, Thomas M Schmidt, Gary B Huffnagle, Theodore J Standiford

Sepsis causes both brain dysfunction and neuroinflammation. It is unknown whether neuroinflammation in sepsis is initiated by dissemination of bacteria to the brain and sustained by persistent infection, or whether neuroinflammation is a sterile process resulting solely from circulating inflammatory mediators. To determine if gut bacteria translocate to the brain during sepsis, and are associated with neuroinflammation. Murine sepsis was induced using cecal ligation and puncture and sepsis survivor mice were compared to sham and unoperated controls. Brain tissue of patients who died of sepsis was compared to patients who died on non-infectious causes. Bacterial taxa were characterized by 16S rRNA gene sequencing in both murine and human brain specimens, compared among sepsis and non-sepsis groups, and correlated with levels of S100A8, a marker of neuroinflammation using PERMANOVA. Viable gut-associated bacteria were enriched in the brains of mice 5 days after surviving abdominal sepsis (p<0.01), and undetectable by 14 days. The community structure of brain-associated bacteria correlated with severity of neuroinflammation (p<0.001). Furthermore, bacterial taxa detected in brains of humans who die of sepsis were distinct from those who died of non-infectious causes (p<0.001), and correlated with S100A8/A9 expression (p<0.05). While bacterial translocation is associated with acute neuroinflammation in murine sepsis, bacterial translocation did not result in chronic cerebral infection. Post-mortem analysis of patients who die of sepsis suggests a role for bacteria in acute brain dysfunction in sepsis. Further work is needed to determine if modifying gut-associated bacterial communities modulates brain dysfunction after sepsis.