Microcystin-LR (MC-LR) and polystyrene nanoplastics (PSNPs) are ubiquitous co-pollutants in freshwater systems known to individually impair feeding in aquatic organisms, yet their combined ecological risks are inadequately defined. Here, we demonstrated that MC-LR exposure induced feeding abnormalities in zebrafish Danio rerio, and this effect was severely aggravated by co-exposure with PSNPs. Mechanistic studies revealed that PSNPs acted as a carrier, markedly enhancing the bioaccumulation of MC-LR in intestinal tissues. This process initially disrupted gut microbiota structure (reduction in beneficial bacteria like Bacteroidetes and Cetobacterium) and tryptophan metabolism, leading to suppressed synthesis of intestinal serotonin (5-HT). The deficiency in gut-derived 5-HT, in turn, provoked peripheral metabolic disturbances (hypoglycemia and hyperlipidemia) and an imbalance of appetite-regulating hormones (ghrelin, cholecystokinin, peptide YY, and glucagon-like peptide). These peripheral signals converged to dysregulate key hypothalamic neuropeptides (agouti-related protein, pro-opiomelanocortin, neuropeptide Y, and orexin), ultimately contributing to abnormal feeding behavior. Our study elucidates a complete pathway along the microbiota-gut-brain axis and identifies reduced gut-derived 5-HT as the critical hub linking pollutant exposure to neurobehavioral deficits, offering a novel perspective for assessing the ecological risks of complex pollutants.
