- Sepsis induces gut dysbiosis and disrupted tryptophan metabolism, activating AhR and causing Th17/Treg imbalance with IL-17A and IL-1β driven hippocampal injury.
- Fecal microbiota transplantation remodelled gut microbiota, partially normalised metabolites, and alleviated cognitive, anxiety and depression like behaviours and neuroinflammation.
- AhR inhibition (CH-223191) reduced neuronal injury in vitro, implicating AhR modulation as a therapeutic strategy for SAE, effect reversed by exogenous IL-1β.
Microb Pathog. 2026 Sep 6:108815. doi: 10.1016/j.micpath.2026.108815. Online ahead of print.
ABSTRACT
BACKGROUND: Sepsis-associated encephalopathy (SAE) is a diffuse brain dysfunction secondary to sepsis; however, its pathogenesis remains poorly defined. This study characterizes gut-microbiota-brain axis dysbiosis and aberrant tryptophan metabolism in SAE, providing a multi-dimensional framework to understand the underlying pathways.
METHODS: SAE was induced in rats via cecal ligation and puncture, with Sham and fecal microbiota transplantation (FMT) groups as controls. Cognitive and emotional functions were assessed using the open field and novel object recognition tests. Gut microbiota and metabolite profiles were analyzed through 16S rDNA sequencing and untargeted metabolomics. Hippocampal neuroinflammation and neuronal apoptosis were quantified via ELISA, TUNEL staining, Western blot, and flow cytometry. In vitro CD4+ T cell cultures and AhR inhibitor (CH-223191) interventions were performed to verify the mechanism of tryptophan metabolite-mediated immune regulation via the AhR pathway.
RESULTS: SAE rats exhibited cognitive deficits, anxiety- and depression-like behaviors, hippocampal neuronal injury, and elevated pro-inflammatory cytokines (IL-17A, IL-1β, TNF-α), alongside gut dysbiosis and disrupted tryptophan metabolism. FMT effectively restructured gut microbiota, partially reversed metabolic abnormalities, alleviated neurobehavioral deficits, and attenuated neuroinflammation. In vitro analyses demonstrated that SAE-associated microbial metabolites upregulated AhR expression, inducing a Th17/Treg imbalance. Inhibiton of AhR signaling (via CH-223191-mediated blockade of aberrant signaling) mitigated neuronal injury, an effect reversed by exogenous IL-1β.
CONCLUSION: This study delineates a gut-brain axis mechanism in which sepsis-induced dysbiosis perturbs tryptophan metabolism and AhR signaling, driving a Th17/Treg imbalance that mediates IL-17A/IL-1β-driven hippocampal injury. These findings validate FMT and AhR modulation as potential therapeutic strategies for SAE.
PMID:42702263 | DOI:10.1016/j.micpath.2026.108815
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