1,25(OH)2 D3 protected against LPS-induced acute lung injury through modulation of gut microbiota

This study investigated whether gut and lung microbiota mediated the effects of 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] against acute lung injury (ALI). We evaluated the impact of various 1,25(OH)2D3 doses on lipopolysaccharide (LPS)-induced ALI and characterized microbial changes in both intestinal and pulmonary communities. Correlation between lung and gut microbiota was assessed. To further explore the role of intestinal flora, a depletion model was established using antibiotics (ABX). Our results indicated that 1,25(OH)2D3 alleviated LPS-induced ALI, as evidenced by reduced pathological damage, down-regulated expression of proinflammatory cytokines (IL-1 beta, IL-6, TNF-alpha), increased levels of anti-inflammatory cytokine (IL-10), and suppressed TLR4/NF-kappa B and JNK pathways. LPS reduced alpha diversity and altered beta diversity and composition of intestinal microbes, which were partially reversed by 1,25(OH)2D3 intervention. Notably, 1,25(OH)2D3 enhanced gut microbiota diversity and elevated the relative abundance of Muribaculaceae and Lachnospiraceae genus. Importantly, depletion of gut flora with ABX eliminated the anti-inflammatory effects of 1,25(OH)2D3, including its inhibition of LPS-induced cytokine expressions and pathway activation. Although LPS did not significantly affect the diversity of lung microbiota, it seemed to change its composition and induced a significant correlation between intestinal and pulmonary microbial communities, which was attenuated by 1,25(OH)2D3. In conclusion, our findings suggested that the protective effects of 1,25(OH)2D3 against LPS-induced ALI might be partially mediated by gut microbiota, highlighting a potential mechanism for vitamin D's immunomodulatory activity in inflammatory lung disease. (c) 2025 Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.