Hypothesis: Age‑related loss of indole‑3‑propionic acid (IPA)‑producing gut microbes reduces luminal IPA concentration below the threshold needed to sustain PXR activation in intestinal epithelium and brain endothelium. This deficit triggers a self‑reinforcing loop where gut barrier leakiness elevates systemic cytokines (e.g., IL‑6, TNF‑α) that down‑regulate endothelial PXR expression, while concurrent neuroinflammation suppresses autonomic output that normally maintains intestinal tight‑junction integrity. The result is accelerated inflammaging driven by concurrent gut‑to‑brain and brain‑to‑gut barrier failure.

Mechanistic rationale: IPA binds PXR with high affinity (Kd = 8.7 μM) and induces barrier‑protective gene programs in both tissues, increasing occludin, claudin‑1, ZO‑1 and transepithelial electrical resistance while suppressing TLR4/NF‑κB signaling IPA‑PXR binding. In aged mice, fecal IPA levels drop by ~40 % compared with young counterparts, correlating with reduced colonic mucin thickness and increased serum LPS IPA decline in aging. When IPA falls below ~5 μM, intestinal PXR activity diminishes, leading to a 30 % decrease in claudin‑1 transcription and a rise in paracellular permeability. The resulting endotoxin influx activates hepatic Kupffer cells, elevating circulating IL‑6 that crosses a compromised BBB and stimulates CNS endothelial NF‑κB, which in turn suppresses PXR transcription via an interferon‑responsive element gut‑derived cytokines suppress endothelial PXR. Simultaneously, microglial JAK1/STAT6 activation—triggered by BBB‑derived IL‑6—reduces vagal efferent tone, lowering acetylcholine release in the gut mucosa and weakening the cholinergic anti‑inflammatory pathway that normally sustains epithelial tight junctions neuroimmune modulation of gut barrier.

Testable predictions: 1) Germ‑free mice colonized with aged‑derived microbiota will exhibit lower fecal IPA, increased intestinal FITC‑dextran flux, and greater Evans blue extravasation into the brain compared with colonization by young‑derived microbiota. 2) Supplementation of aged mice with oral IPA (10 mg/kg/day) will rescue both gut and brain barrier metrics only when intestinal PXR is intact; Villin‑Cre;Nr1i2^fl/fl^ mice will show improved gut permeability but no BBB benefit, whereas Slco1c1‑CreERT2;Nr1i2^fl/fl^ mice will display the opposite pattern. 3) Chronic vagotomy in aged mice will abolish the brain‑to‑gut component of the loop, resulting in sustained gut leakiness despite normal IPA levels, confirming the neuroimmune arm. 4) Pharmacologic inhibition of JAK1 (e.g., with tofacitinib) will prevent IPA‑deficit‑induced suppression of endothelial PXR expression, breaking the bidirectional amplification.

Falsifiability: If oral IPA administration fails to improve either barrier in aged wild‑type mice, or if tissue‑specific PXR knockouts do not differentially affect gut versus brain permeability outcomes, the hypothesis would be refuted. Likewise, if vagotomy does not exacerbate gut leakiness in the presence of adequate IPA, the proposed neuroimmune feedback would be incorrect.

This framework transforms the 'messy' gut‑brain axis into a tractable, bidirectional circuit where a single microbial metabolite, its receptor, and downstream cytokine/JAK‑STAT signaling jointly dictate the tempo of age‑associated barrier decline.