Age‑related loss of intestinal alkaline phosphatase (IAP) activity permits increased translocation of lipopolysaccharide (LPS) and altered bile acid pools into the circulation. This microbial‑derived endotoxin load engages microglial TLR4, triggering NF‑κB‑mediated pro‑inflammatory cytokine release and complement‑dependent synapse elimination, a mechanism that parallels the indoleacetic acid‑deficiency pathway described in recent fecal transplant studies[1]. Simultaneously, age‑shifted bile acid metabolism reduces signaling through the fibroblast growth factor 19 (FGF19)–FGFR4 axis, diminishing hepatocyte‑derived repression of hepatic CYP7A1 and further elevating cytotoxic secondary bile acids that directly impair vascular endothelial senescence[2].

We hypothesize that restoring IAP function—either through recombinant IAP supplementation or dietary phosphoserine enrichment—will simultaneously (a) decrease circulating LPS, (b) rebalance primary/secondary bile acid ratios toward gut‑protective species, and (c) attenuate microglial TLR4 activation, thereby rescuing synaptic density and improving cognitive performance in aged mice. This predicts a synergistic interaction with rapamycin: mTORC1 inhibition enhances Paneth cell antimicrobial peptide secretion, which together with IAP‑mediated LPS detoxification should more effectively normalize gut barrier integrity than either intervention alone.

Testable predictions

1. Aged mice treated with oral recombinant IAP will show a ≥30 % reduction in plasma LPS‑binding protein and a shift in fecal bile acid profile toward increased cholic acid and decreased deoxycholic acid relative to vehicle controls[3].
2. Microglial isolation from IAP‑treated aged brains will exhibit reduced TLR4 surface expression and lowered IL‑1β mRNA (≥40 % decrease) compared with untreated aged counterparts[4].
3. Synaptic marker density (synaptophysin‑positive puncta) in the hippocampus will be restored to ≥80 % of young adult levels after 4 weeks of IAP treatment, as quantified by confocal microscopy[5].
4. Combining low‑dose rapamycin (0.5 mg kg⁻¹ day⁻¹) with IAP will produce a greater than additive improvement in Morris water maze performance (escape latency reduced by an additional 25 % beyond either monotherapy).
5. Administering heat‑inactivated IAP or a TLR4 antagonist will abolish the cognitive benefits, confirming that the effect depends on endogenous LPS detoxification and microglial TLR4 signaling.

Falsifiability If IAP supplementation fails to lower plasma LPS, does not shift bile acid ratios, or does not rescue synaptic loss and cognition despite adequate dosing, the central claim that intestinal IAP deficiency drives microglia‑mediated synapse loss via microbial translocation is refuted. Likewise, if rapamycin adds no further benefit over IAP alone, the proposed synergistic barrier‑immune mechanism would be unsupported.