The gut-brain axis drives cognitive aging not just through inflammation but through a specific loss of microbial tryptophan metabolites that normally sustain vagal‑hippocampal signaling. Aged microbiota show depleted Bifidobacterium pseudolongum and related tryptophan‑catabolizing strains, leading to falling levels of indole‑3‑acetic acid (IAA) and downstream aryl hydrocarbon receptor (AHR) ligands in the hippocampus (Aged microbiota reduces Bifidobacterium pseudolongum). Simultaneously, overgrowth of pro‑inflammatory species such as P. goldsteinii elevates ligands that activate myeloid GPR84, which dampens vagal afferent tone to the hippocampus (Gut microbes may drive memory decline during aging by disrupting vagal brain signaling). We hypothesize that the combined deficit of AHR‑activating tryptophan metabolites and excess GPR84 signaling creates a bistable state where vagal signaling is insufficient to maintain hippocampal synaptic plasticity, thereby accelerating memory loss. This state is self‑reinforcing because reduced vagal output lowers acetylcholine release in the gut, which further impairs barrier integrity and promotes LPS translocation, fueling more inflammaging (Circadian misalignment desynchronizes host‑microbiota rhythms).

Novel mechanistic insight: the hippocampus expresses AHR in microglia and neurons; AHR activation by microbial IAA derivatives promotes a neuroprotective phenotype that suppresses complement‑mediated synapse engulfment. When AHR signaling falls, microglia shift to a phagocytic state that indiscriminately tags synapses for removal, a process exacerbated by vagal hypofunction because cholinergic anti‑inflammatory signaling normally restrains microglial activation. Thus, the axis operates as a metabolite‑gated switch: sufficient tryptophan‑derived AHR ligands keep microglia in a surveillance mode, while their loss lets GPR84‑driven vagal inhibition tip microglia into a destructive mode.

Testable predictions: (1) Oral administration of indole‑3‑propionic acid (IPA), a stable tryptophan metabolite that activates AHR, to aged mice will restore hippocampal AHR/CYP1A1 signaling, reduce microglial synapse engulfment, and improve spatial memory even without altering overall microbiota composition. (2) Co‑administration of a GPR84 antagonist will synergize with IPA, producing greater memory rescue than either treatment alone, because vagal afferent signaling will be disinhibited while microglial activation is suppressed. (3) Conversely, germ‑free aged mice colonized with a tryptophan‑catabolizing deficient microbiota will fail to show memory improvement after vagal stimulation, proving that the metabolite, not merely the nerve, is essential.

Experimental design: Young (3 mo) and aged (24 mo) C57BL/6 mice receive either vehicle, IPA (10 mg/kg/day), GPR84 antagonist (GLPG1205, 5 mg/kg/day), or both for 8 weeks. Behavioral assessment includes Morris water maze and novel object recognition. Hippocampal tissue is assayed for AHR target gene expression (CYP1A1, TIPARP), microglial morphology (Iba1 staining), synapse markers (PSD‑95, synaptophysin), and vagal activity (choline acetyltransferase in the dorsal motor nucleus). Fecal metabolites are quantified by LC‑MS to confirm IPA delivery.

Falsifiability: If IPA fails to elevate hippocampal AHR signaling or improve memory despite reaching the brain, or if GPR84 blockade does not enhance vagal‑dependent acetylcholine release, the hypothesis that microglial phenotype is governed by this metabolite‑vagal balance would be refuted. Conversely, positive outcomes would support the notion that targeting the tryptophan‑AHR‑GPR84 node can uncouple peripheral dysbiosis from central cognitive decline, offering a precise lever within the messy gut‑brain feedback loop.