Sepsis-Induced Gut Dysbiosis Mediates the Susceptibility to Sepsis-Associated Encephalopathy in Mice

Abstract

The bidirectional interactions between the gut microbiota and sepsis-associated encephalopathy (SAE) are not well characterized. We found that the gut microbiota was more severely disturbed in SAE-susceptible (SES) mice than in SAE-resistant (SER) mice after sepsis modeling.

The Microbiota-Gut-Brain Axis in Sepsis-Associated Encephalopathy

“…Demonstrating a role of the microbiota in dictating these poor neurological outcomes during sepsis, fecal microbiota transplantation (FMT) from mice resistant to SAE (sepsis-induced encephalopathy resistant [SER] mice) was protective in recipient SES mice, validating a role for gut microbes in SAE. This role of the microbiota was further substantiated by transfer of the SES phenotype induced by CLP to normally resistant (SER) mice via FMT ( 8 ). Mechanistically, the bacterial metabolite IPA was found to be enriched in the feces from SER mice, suggesting that IPA may protect against CNS deficits seen in SAE.…”

“…In the article by Fang et al ( 8 ), induction of sepsis via cecal ligation and puncture (CLP) was used to study a potential role of the MGB axis in controlling disease progression. In their model, a subset of animals developed significant neurological deficits, as determined by a composite score of pinna reflex, corneal reflex, righting reflex, tail flexion reflex, and escape response, with lower scores (<6) associated with poor prognosis, including mortality.…”

“…In their model, a subset of animals developed significant neurological deficits, as determined by a composite score of pinna reflex, corneal reflex, righting reflex, tail flexion reflex, and escape response, with lower scores (<6) associated with poor prognosis, including mortality. Mice that were susceptible to SAE (sepsis-induced encephalopathy susceptible [SES] mice) had an intestinal microbiota that was enriched for the Gram-negative Enterobacteriaceae family, which is known to promote inflammation and lead to sepsis ( 8 ). Demonstrating a role of the microbiota in dictating these poor neurological outcomes during sepsis, fecal microbiota transplantation (FMT) from mice resistant to SAE (sepsis-induced encephalopathy resistant [SER] mice) was protective in recipient SES mice, validating a role for gut microbes in SAE.…”

“…Indeed, administration of IPA could protect mice against CLP-induced SAE and death, which was thought to be mediated in part by inhibiting the activation of the NLRP3 (NOD-, LRR- and pyrin domain-containing protein 3) inflammasome in microglia. Additionally, in in vitro studies where primary microglia were isolated from the cortex of neonatal mice pretreated with IPA and exposed to the bacterial endotoxin lipopolysaccharide (LPS), IPA reduced proinflammatory cytokine production and apoptosis ( 8 ). Finally, since the aryl hydrocarbon (AhR) can negatively regulate activity of the NLRP3 inflammasome, the authors discovered that pretreatment with an AhR antagonist could inhibit the beneficial impacts of IPA on microglia in vitro .…”

“…While this study by Fang et al ( 8 ) is novel and exciting, providing mechanistic insights into the role of the gut microbiome in regulating SAE, limitations exist. First, the effect of IPA on ameliorating survival and neurological scores in mice is partial, suggesting that other mechanisms are also contributing to the impacts of SAE.…”