Natural Products as Protective Modulators of Environmental Pollutant Toxicity Through the Gut-X Axis.

Environmental pollutants, including heavy metals, endocrine-disrupting chemicals, particulate matter, persistent organic pollutants, pesticides, and micro/nanoplastics, perturb the gut microbiome and intestinal barrier and propagate oxidative, inflammatory, metabolic, and epigenetic injury through interconnected gut-organ axes. This narrative review reframes the gut-X axis as a mechanistic platform for evaluating natural products as protective agents against pollutant toxicity. We summarize pollutant-induced dysbiosis, barrier dysfunction, microbial-metabolite disruption, and immunometabolic reprogramming, then examine evidence for natural products and microbiota-active interventions, including polyphenols, flavonoids, triterpenoids, medicinal-plant constituents, polysaccharides, dietary fibers, and probiotic-derived strategies. Particular attention is given to antioxidant and anti-inflammatory signaling, restoration of epithelial integrity, modulation of short-chain fatty acids and bile acids, suppression of TLR4/NF-κB and NLRP3 signaling, and regulation of immune-cell metabolism. The available literature contains stronger mechanistic evidence than direct pollutant-specific intervention studies; therefore, established protective mechanisms are distinguished from evidence that remains indirect or preclinical. The review identifies the gut-X axis as a promising route through which natural products may reduce systemic consequences of environmental exposure and highlights priorities for pollutant-specific animal studies, human cohorts, pharmacokinetic characterization, combination strategies, and integrated multi-omics and in silico approaches.