Fucoidan from Undaria pinnatifida suppresses Enterococcus faecium-induced pro-inflammatory macrophage polarization and lung injury in mice via modulation of the gut-lung axis.

Bacterial pneumonia remains a major global health challenge, and emerging evidence highlights the gut-lung axis as an important regulator of pulmonary inflammation. This study investigated the protective effects of fucoidan isolated from Undaria pinnatifida (UPF-10) in a mouse model of Enterococcus faecium E745-induced lung inflammation. UPF-10 treatment significantly alleviated lung injury, and fibrosis, and reduced lung and thymus indices. These protective effects were closely associated with decreased neutrophil infiltration, suppression of inflammatory responses, and reduced systemic lipopolysaccharide level. Mechanistically, UPF-10 attenuated oxidative stress by activating the Nrf2 pathway and shifted macrophage polarization away from the pro-inflammatory M1 phenotype. UPF-10 preserved intestinal barrier integrity by restoring tight junction proteins and alleviating intestinal inflammation. Gut microbiota analysis showed that UPF-10 normalized E. faecium-induced microbiota dysbiosis by enriching some beneficial taxa and increasing short chain fatty acids production. Targeted serum metabolomics further showed that UPF-10 partially reversed inflammation-associated metabolic disturbances, particularly tryptophan metabolism, leading to increased circulating kynurenine level. In vitro experiments confirmed that kynurenine promoted an anti-inflammatory macrophage phenotype through activation of aryl hydrocarbon receptor. These findings suggest that UPF-10 can mitigate lung inflammation through modulation of gut-lung axis, supporting its potential as a functional food ingredient for inflammatory lung diseases.