The human body is almost always facing the oxidative stress caused by foodborne aldehydes such as glyoxal (GO) and methylglyoxal (MGO), 4-hydroxyhexenal (HHE), and 4-hydroxynonenal (HNE). When these aldehydes build up, they can cause a range of harm. However, a probiotic,Clostridium butyricum, can increase nuclear factor erythroid-2 related factor 2 (Nrf2) and may have the potential to relieve oxidative stress. IfC. butyricumis indeed resistant to aldehydes, the advantages (accessibility, convenience, and safety) will be of great significance compared with drugs. Unfortunately, whetherC. butyricumcan play a role in alleviating toxic effects of foodborne aldehydes in the intestine (the first line of defense against food-derived toxin) was unclear. To investigate these, we measured the viability, ROS, autophagy, and inflammatory cytokine expression of Caco-2 which were co-cultured withC. butyricumand stimulated by the four aldehydes via Nrf2 pathway (Staphylococcus aureusandEnterococcus faeciumas controls). Then, we explored the link amongC. butyricum, NLRP6, and Nrf2 signaling pathways when facing the stimuli. In the present study, we demonstrated thatClostridium butyricumrelieved the oxidative stress induced by the aldehydes in Caco-2. Most interestingly, we found a "complementary" relationship between NLRP6 and Nrf2 inC. butyricumtreatment under aldehyde stress. Our research not only makes a contribution to the popularization ofC. butyricumas a probiotic-rich food instead of medicines but also sheds new light on the application of subsequent microecological formulation ofC. butyricum.