REPROGRAMMING IMMUNITY: A META-ANALYSIS OF LIFESTYLE, NUTRITION, AND MICROBIOME INTERVENTIONS

Abstract

Chronic low-grade inflammation is implicated in the pathogenesis of metabolic, cardiovascular, renal, and age-related diseases. Non-pharmacologic interventions-spanning lifestyle modification, nutritional strategies, and microbiome-directed therapies-have been proposed as upstream modulators of inflammatory physiology, yet cross-domain quantitative syntheses remain scarce. This systematic review and meta-analysis evaluated whether lifestyle, nutrition, microbiome-directed, and hybrid interventions reduce circulating inflammatory biomarkers relative to control conditions in adult populations. A systematic search of PubMed/MEDLINE, Embase, Scopus, Web of Science, and Cochrane CENTRAL (January 2011–April 2026) identified randomized or controlled intervention studies reporting C-reactive protein (CRP/hs-CRP), interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), or lipopolysaccharide (LPS) endpoints. Fifteen studies met strict eligibility criteria. Random-effects meta-analyses were conducted using Hedges’ g with inverse-variance weighting. All four biomarker families showed pooled effects favoring intervention. CRP/hs-CRP yielded the most robust estimate (k = 11; Hedges’ g = −0.51, 95% CI [−0.81, −0.20]; I² = 73.4%). IL-6 (k = 6; g = −1.76, 95% CI [−3.18, −0.33]; I² = 96.3%), TNF-α (k = 4; g = −1.50, 95% CI [−2.61, −0.38]; I² = 91.2%), and LPS (k = 2; g = −0.75, 95% CI [−1.45, −0.04]; I² = 68.0%) showed large effects with considerable heterogeneity. Microbiome-directed interventions constituted the dominant evidence base. Non-pharmacologic interventions are associated with reduced inflammatory biomarker burden in adults, with the most stable evidence for CRP-family outcomes. These findings support a biomarker-centered interpretation of immune recalibration and highlight the need for domain-balanced trials with standardized inflammatory outcome reporting.