6PPD-Q exposure disrupts intestinal homeostasis and impairs skeletal muscle function in mice

6PPD-Q is an emerging tire-derived contaminant, but its mammalian toxicological mechanisms and inter-organ effects remain poorly understood. Because oral exposure directly interfaces with the intestine, we investigated whether 6PPD-Q disrupts intestinal homeostasis and is associated with skeletal muscle dysfunction through a microbiota-related gut-muscle axis, and whether post-exposure sodium butyrate (NaB) intervention can alleviate these alterations. Male C57BL/6 mice were orally exposed to 6PPD-Q at 0.1, 1, or 10 μg/kg/day, and NaB intervention was evaluated after high-dose exposure. Toxic effects were mainly observed at 1 and 10 μg/kg/day. 6PPD-Q accumulated predominantly in the intestine and induced villus-crypt disruption, microvillus damage, increased permeability, inflammatory activation, and oxidative imbalance. These alterations were accompanied by reduced exercise performance, smaller myofiber cross-sectional area, and impaired myogenic differentiation. Low residual 6PPD-Q levels in perfused skeletal muscle and tissue-equivalent C2C12 exposure results suggested that intestinal dysfunction may contribute to muscle impairment. 6PPD-Q also altered gut microbial composition and fecal short-chain fatty acid profiles, with reduced butyrate emerging as a candidate metabolic alteration associated with muscle dysfunction. Fecal microbiota transplantation from 6PPD-Q-exposed donors partially transferred intestinal barrier dysfunction, inflammatory and oxidative disturbances, reduced butyrate levels, and muscle-related abnormalities to recipients, whereas microbiota from NaB-treated donors attenuated these effects. Post-exposure NaB intervention partially alleviated intestinal, microbial, metabolic, and skeletal muscle alterations without substantially reducing tissue 6PPD-Q burden.These findings suggest that oral 6PPD-Q exposure disrupts intestinal homeostasis and microbiota-SCFA profiles, which may contribute to gut-muscle axis-associated skeletal muscle dysfunction in mice.