Tao-He-Cheng-Qi decoction protects against sepsis-associated acute lung injury by modulating gut microbiota and succinate-associated pulmonary macrophage polarization.

ETHNOPHARMACOLOGICAL RELEVANCE: Sepsis-associated acute lung injury (SA-ALI) has high mortality and limited therapies.Tao-He-Cheng-Qi decoction protects against sepsis-associated acute lung injury by modulating gut microbiota and succinate-associated pulmonary macrophage polarization.

AIM OF THE STUDY: To evaluate the protective effects of THCQ pretreatment against LPS-induced SA-ALI and examine associated changes in gut microbiota, succinate levels, SUCNR1-PKA-CREB signaling and macrophage polarization.

MATERIALS AND

METHODS

A murine SA-ALI model was induced by intraperitoneal LPS. Lung injury, inflammatory cytokines (IL-1β, TNF-α), and M1/M2 polarization were assessed. Gut microbiota was analyzed by 16S rRNA sequencing. Succinate levels, SUCNR1, and PKA-CREB signaling were measured. Microbiota dependence was tested using antibiotic depletion, fecal microbiota transplantation (FMT) from THCQ-treated donors, exogenous succinate, and macrophage depletion with clodronate liposomes.

RESULTS

THCQ pretreatment attenuated lung injury, reduced IL-1β and TNF-α levels, and shifted pulmonary macrophage polarization toward an M2-like phenotype. These effects were accompanied by altered gut microbiota composition, a lower abundance ratio of bacterial families grouped in the exploratory succinate-metabolism analysis, reduced serum and pulmonary succinate levels, lower SUCNR1 expression, and increased PKA/CREB phosphorylation. Antibiotic treatment attenuated the protective responses to THCQ, while FMT from THCQ-treated donors reproduced improvements in lung injury. Exogenous succinate attenuated THCQ-mediated protection. Clo-Lipo treatment reduced the proportions of alveolar and interstitial macrophages and markedly attenuated the protective effects of THCQ.

CONCLUSION

THCQ treatment protects against SA-ALI and suppresses M1-like macrophage polarization. These effects are accompanied by changes in gut microbiota composition, reduced succinate levels, and altered SUCNR1-PKA-CREB signaling. Together, the findings support a role for gut microbiota-metabolism-immune interactions in the protective effects of THCQ.