This study aimed to evaluate the protective effect of ergothioneine (ERGO) on D-galactose (D-gal)-induced oxidative stress damage in rats and to explore its potential mechanisms.SD male rats were used as research subjects and were modeled by intraperitoneal injection of D-gal solution.They were randomly divided into five groups, including a blank group, a model group, an ERGO low-dose group (ERGO-L, 1.25 mg/kg), an ERGO medium-dose group (ERGO-M, 2.5 mg/kg), and an ERGO high-dose group (ERGO-H, 5.0 mg/kg).Rats received corresponding administrations once daily for 4 weeks.The levels of malondialdehyde (MDA), protein carbonyl (PC), superoxide dismutase (SOD), catalase (CAT), and reduced glutathione (GSH) in rat serum, liver, kidney, and spleen were measured by colorimetry.The composition of the gut microbiota and the content of short-chain fatty acids (SCFAs) in each group of rats were analyzed by 16S sequencing and ultra-high-performance liquid chromatography-tandem triple quadrupole mass spectrometry to evaluate the potential antioxidant mechanism.Results showed that compared with the model group, the administration groups significantly reduced the levels of MDA and PC in rat serum, liver, kidney, and spleen to varying degrees (P<0.05 or P<0.01) and significantly increased the activities of SOD and CAT and the level of GSH (P<0.05 or P<0.01).Except for the low-dose group, which had no significant reduction in IL-1β levels, all other dose groups significantly reduced the levels of IL-1β, IL-6, and TNF-α in the serum of rats with oxidative stress damage (P<0.05 or P<0.01).Compared with the model group, the contents of short-chain fatty acids (SCFAs), including butyrate, isobutyrate, and valerate, were significantly decreased in the gut of rats with oxidative damage (P<0.01).Compared with the model group, ERGO significantly increased the SCFA contents in the gut of rats with oxidative damage.ERGO administration has a significant protective effect on D-gal-induced oxidative damage in rats, and its mechanism may be achieved by reducing inflammation, regulating the gut microbiota to promote the generation of short-chain fatty acids, and direct antioxidant effects.
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