Short-chain fatty acids attenuate sepsis-induced gut dysbiosis and hippocampal neuroinflammation via NLRP6 inflammasome activation in mice

Oct 29, 2025International journal of surgery (London, England)

Short-chain fatty acids reduce gut imbalance and brain inflammation caused by sepsis through activating a protective immune sensor in mice

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Abstract

SCFA supplementation resulted in a 1.8-fold increase in intestinal tight junction proteins in septic mice (p<0.01).

Sepsis-induced hippocampal neuroinflammation was characterized by microglial proliferation and astrocyte activation.
Mice with sepsis exhibited gut dysbiosis, with increased Firmicutes/Proteobacteria and decreased microbial diversity.
Reduced levels of gut microbiota-derived were observed in septic mice.
activity was significantly increased in colonic tissues following SCFA supplementation.
Cognitive deficits in septic mice were improved with SCFA treatment, as indicated by reduced escape latency in maze tests.

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BACKGROUND: (SAE) is a critical complication of sepsis, yet the mechanisms linking gut dysbiosis to hippocampal neuroinflammation remain poorly understood. Our previous work identified sepsis-induced hippocampal neuroinflammation; here, we investigated the role of gut microbiota-derived (SCFAs) and signaling in this process.

METHODS: Sepsis was induced in C57BL/6 mice via cecal ligation and puncture (CLP). Gut microbiota composition, SCFA levels, intestinal barrier integrity, and NLRP6 inflammasome activity were analyzed. Colon organoids and NLRP6-silenced CT26 cells were employed to validate SCFA-NLRP6 interactions. Hippocampal neuroinflammation (microglial/astrocytic activation, cytokine levels) and cognitive function (Morris Water Maze, Barnes Maze) were assessed post-SCFA treatment.

RESULTS: CLP-induced sepsis triggered hippocampal neuroinflammation, characterized by microglial proliferation (IBA-1 +), astrocyte activation (GFAP +), and neuronal dysfunction (reduced c-Fos). Septic mice showed gut dysbiosis (increased Firmicutes/Proteobacteria, decreased α-diversity), reduced SCFA levels, and impaired intestinal barrier integrity (decreased ZO-1/occludin expression, p<0.05). SCFA supplementation restored gut microbiota homeostasis (β-diversity: p = 0.019 vs. CLP), enhanced intestinal tight junction proteins (ZO-1:1.8-fold increase, p<0.01), and activated NLRP6 inflammasomes in colonic tissues (NLRP6:2.1-fold increase, caspase-1:1.6-fold increase, p<0.01). NLRP6 knockdown abolished SCFA-mediated IL-18 secretion (p<0.001). Behaviorally, SCFAs ameliorated cognitive deficits in septic mice (escape latency: CLP = 48s vs. SCFA + CLP = 32s, p<0.01) and correlated with hippocampal c-Fos restoration (R2 = 0.839 for propionate, p = 0.01).

CONCLUSIONS: Sepsis disrupts the gut-brain axis by impairing intestinal barrier integrity and NLRP6 inflammasome function, exacerbating hippocampal neuroinflammation. SCFAs mitigate these effects via NLRP6-dependent mechanisms, highlighting their therapeutic potential for SAE. This study provides the first evidence linking SCFA-mediated NLRP6 activation to neuroprotection in sepsis, offering novel insights for targeting the gut microbiota in critical care.

Key numbers

1.8×

Increase in ZO-1 Protein Level

SCFA supplementation increased ZO-1 expression significantly.

32 seconds

Escape Latency Improvement

CLP mice took 48 seconds to escape vs. 32 seconds with .

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Short-chain fatty acids attenuate sepsis-induced gut dysbiosis and hippocampal neuroinflammation via NLRP6 inflammasome activation in mice

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