Age‑associated copy‑number variations (CNVs) accumulate in human colonic crypts, yet their functional impact on distal organs remains untested. We hypothesize that intestinal CNVs disrupt epithelial barrier integrity by altering dosage of tight‑junction and mucin genes, thereby increasing luminal bacterial translocation. This breach elevates systemic levels of microbial‑associated molecular patterns (MAMPs) such as LPS and peptidoglycan, which chronically activate innate immune cells in the lamina propria. Persistent MAMP exposure creates a selective pressure favoring the expansion of hematopoietic clones harboring mutations in epigenetic regulators (e.g., TET2, DNMT3A) that confer heightened inflammatory cytokine production—a process paralleling clonal hematopoiesis of indeterminate potential (CHIP). These myeloid‑derived clones release IL‑1β, IL‑6, and TNF‑α into the circulation, compromising blood‑brain barrier permeability and priming microglia and astrocytes toward a neurotoxic phenotype. Consequently, gut‑derived somatic instability initiates a cascade: epithelial CNV → barrier leak → MAMP‑driven immune clonal expansion → peripheral neuroinflammation → accelerated cognitive decline.

Key predictions that render this hypothesis falsifiable:

1. Individuals with high intestinal CNV burden (detected via deep sequencing of colon biopsies or stool‑derived epithelial DNA) will exhibit elevated serum LPS/LBP levels and a higher prevalence of CHIP mutations compared with age‑matched controls with low CNV load.
2. Longitudinally, the rate of CNV accumulation in intestinal epithelium will predict subsequent increases in clonal hematopoietic variant allele frequency and inversely correlate with changes in hippocampal volume or memory performance over a 2‑year interval.
3. Experimental restoration of intestinal barrier function—using a targeted butyrate prodrug or a tight‑junction‑enhancing peptide—will reduce MAMP translocation, attenuate the expansion of TET2‑mutant myeloid clones in peripheral blood, and lower CSF inflammatory markers in aged mice harboring induced intestinal CNVs.
4. Conversely, inducing specific CNVs (e.g., focal deletion of the occludin gene) in mouse intestinal stem cells will increase barrier permeability, drive splenic myeloid clonal expansion, and exacerbate neuroinflammatory responses to a sub‑threshold LPS challenge, an effect rescued by bone‑marrow transplantation from wild‑type donors.

By placing intestinal genomic instability at the apex of the gut‑brain axis, this model redirects focus from brain‑centric somatic mutation studies to the epithelium that separates the host from its microbiota. Validating the link between intestinal CNVs, peripheral clonal immunity, and neurodegeneration would uncover a mechanistic nexus amenable to interventions targeting barrier repair, microbial metabolite modulation, or selective suppression of inflammatory hematopoietic clones—offering a bottom‑up strategy to mitigate cognitive aging.