Gut microbiota-derived 3-indoleacetic acid confers a protection against sepsis-associated encephalopathy through microglial aryl hydrocarbon receptors.

Abstract

Background: The gut microbiota significantly contributes to the pathogenesis of central nervous system disorders. Among the bioactive molecules produced by the gut microbiota, 3-indoleacetic acid (IAA) has been shown to attenuate oxidative stress and inflammatory responses. This experiment aimed to determine the impacts of IAA on sepsis-associated encephalopathy (SAE) and the underlying mechanisms.

Methods: A total of 34 septic patients and 24 healthy controls were included in the analysis of the clinical correlation between fecal IAA and septic encephalopathy. Fecal microbiota transplantation was used to verify the role of the gut microbiota and its metabolites in SAE. Male C57BL/6 mice aged six to eight weeks, pre-treated with IAA via oral gavage, were subjected to the cecal ligation and puncture (CLP) procedures. This treatment was administered either in combination with an aryl hydrocarbon receptor (AhR) antagonist, CH223191, or a CSF1R inhibitor, PLX3397, to eliminate microglia. Both immunofluorescence staining and enzyme-linked immunosorbent assays were used to evaluate microglia activation and inflammatory cytokine secretion. Behavioral assessments were conducted to quantify neurological deficits.

Results: A decreased fecal level of IAA was observed in the patients with sepsis-associated delirium (SAD), a manifestation of SAE. A reduced IAA level was significantly associated with worsen clinical outcomes. Fecal microbiota transplantation from the SAD patients induced an SAE-like phenotype in mice, but supplementing exogenous IAA improved the SAE-like phenotype, mediated by microglia. IAA effectively binded with the aryl hydrocarbon receptor (AhR). Furthermore, IAA increased the nuclear activity of AhR in the lipopolysaccharide (LPS)-treated microglial cells, leading to reduced secretion of inflammatory cytokines. The AhR inhibitor CH223191 counteracted the protective effect of IAA against SAE in mice.

Conclusions: Gut microbiota-derived IAA confers a protection against SAE by activating AhR in microglia, improving neuronal and cognitive impairments. Thus, IAA holds the promise as a potential therapeutic agent for managing SAE.