Intestinal permeability (zonulin, leaky gut)

Intestinal permeability refers to the regulated paracellular passage of molecules across the intestinal epithelium, governed by tight junction complexes — claudins, occludin, ZO-1, and junctional adhesion molecules sealing the space between enterocytes. Pathologically elevated permeability (leaky gut) allows bacterial lipopolysaccharide (LPS) to translocate into systemic circulation, triggering TLR4-mediated endotoxemia and cytokine release (IL-1β, IL-6, TNF-α) linked to inflammaging. Zonulin, identified as prehaptoglobin-2, is the only characterised endogenous tight-junction modulator: luminal gliadin or bacterial signals activate CXCR3, transactivate EGFR via PAR2, and drive PKCα-mediated ZO-1 phosphorylation and actin rearrangement. In healthy aging, Qi et al. (2017, n=37) found serum zonulin ~22% higher in older versus young adults, correlated with TNF-α and IL-6, consistent with barrier decline as part of the inflammaging loop. The functional gold standard is the urinary lactulose-mannitol ratio (LMR): paracellularly excluded lactulose relative to freely absorbed mannitol; a 2.5–4 h collection window minimises variability. Commercial serum zonulin ELISAs carry a critical caveat: Scheffler et al. (2018) and Ajamian et al. (2019) independently showed widely used kits detect complement C3 and properdin rather than prehaptoglobin-2. Intervention data for barrier-targeted strategies — prebiotics, short-chain fatty acids, dietary exclusion — remain limited to small trials; no agent is approved for longevity indications as of 2026.