Gut Microbiota-Immune-Inflammation Axis as a Putative Pathogenic Axis in Chronic Insomnia: Mechanistic Dissection of NLRP3 Inflammasome and NF-κB Signaling.

Chronic insomnia represents one of the most prevalent sleep disorders worldwide, yet current symptomatic treatments largely fail to target its root pathophysiology. Moving beyond conventional neurocentric frameworks, converging evidence positions gut microbiota dysbiosis as a potential upstream contributor to insomnia via the microbiota-gut-brain axis, with immune-inflammatory cascades serving as proposed mediating pathway. Mechanistically, disrupted gut microbial communities compromise intestinal mucosal barrier integrity, enabling lipopolysaccharide translocation that activates TLR4-mediated NF-κB signaling. This triggers systemic low-grade inflammation, marked by elevated pro-inflammatory cytokines IL-1β, IL-6, IL-17 and TNF-α, reduced anti-inflammatory IL-4 and IL-10, and Th17/Treg immune imbalance. Centrally, circulating inflammatory signals activate the NLRP3 inflammasome, driving caspase‑1‑dependent pyroptosis and a pro‑inflammatory microglial activation state (conventionally described as "M1‑like" polarization), which disrupts sleep-wake neural circuitry and hypothalamic-pituitary-adrenal axis homeostasis. Dysregulated PI3K/Akt signaling and aberrant microbial metabolites-including depleted short-chain fatty acids and a pathological shift in tryptophan metabolism toward the neurotoxic kynurenine pathway-further amplify the vicious cycle between sleep disturbance and neuroinflammation. This review systematically maps the full pathological cascade from intestinal dysbiosis to central insomnia phenotypes, and compares translational strategies including psychobiotic strains, fecal microbiota transplantation, dietary intervention and traditional Chinese medicine formulas targeting this axis. Collectively, this work proposes an integrated microbiota-immune-sleep regulatory framework, offering novel mechanistic insights and microbiome-based therapeutic avenues for precision insomnia management.