Gut-Mediated Systemic Toxicity of Micro- and Nanoplastics: Nanoscale Biointerface Properties, Microbiota-Metabolite Crosstalk, and Evidence Across Gut-Organ Axes

Microplastics and nanoplastics (MNPs) have been recognized as ubiquitous emerging global pollutants, which are extensively detectable in diverse environmental media and food matrices. Increasing evidence indicates that the intestine is a primary target of orally ingested MNPs and a critical initiating hub for systemic toxicity. Once ingested orally, MNPs can interact with the intestinal mucus layer and epithelial barrier, induce gut microbiota dysbiosis, remodel bile acid and short-chain fatty acid metabolism, and activate oxidative stress, inflammation, apoptosis, and immune imbalance. These gut-derived disturbances may subsequently propagate adverse signals to distal organs through the gut-liver, gut-brain, gut-kidney, gut-lung, gut-reproductive, and gut-mammary axes. Intestinal barrier dysfunction, endotoxin translocation, abnormal microbial metabolites, and microbiota-derived immune signals constitute common mediating pathways linking local intestinal injury to multi-organ toxicity. In addition, smaller particle size, surface oxidation, environmental aging, bio-corona/plastisphere formation, and co-exposure with other contaminants can further modulate the intensity and specificity of gut-organ axis disruption. Prior reviews are limited to separate analyses of single-organ toxicity or isolated gut-organ pathways. To fill this gap, this work synthesizes contemporary mechanistic and experimental evidence to establish a gut-initiated systemic toxicology framework for MNPs. We differentiate direct particle translocation from gut-derived indirect signaling, evaluate the varying robustness of supporting evidence for each gut-organ axis, and underscore nanoscale biointerface properties as key modulators of MNPs systemic toxic potency.