Bacillus safensis from Sauerkraut Alleviates Acute Lung Injury Induced by Methicillin-Resistant Staphylococcus aureus through the Regulation of M2 Macrophage Polarization via Its Metabolite Esculin

Sauerkraut contains various fermentative microorganisms that produce active metabolites, enhancing immunity and resistance to infections. However, its effects on methicillin-resistant Staphylococcus aureus (MRSA)-induced acute lung injury (ALI) remain unclear. Using RAW264.7 cells and a mouse model, we demonstrated that Bacillus safensis SK14 (BS SK14), an understudied fermentative bacterium, has an immunomodulatory effect on MRSA-induced ALI. BS SK14 significantly reduced the inflammatory responses. Supplementation with live BS SK14 or its culture supernatant increased survival rates, reduced lung damage, and attenuated inflammation in ALI model mice. LC–MS/MS analysis identified esculin as the key metabolite responsible for these effects. BS SK14 produces esculin via the gut–lung axis, inhibiting the TLR2–MyD88–NF-κB pathway, reducing Keap1 levels, and activating the Nrf2–ARE pathway. This decreased MRSA-induced M1 polarization and increased M2 polarization, enhancing antioxidant and anti-inflammatory activities in mice. Collectively, these results reveal that BS SK14 and its metabolite esculin exert therapeutic effects on MRSA-induced ALI through a multifactorial strategy.