Maxing Shigan decoction serves as a key component of Lianhua Qingwen in alleviating lung and gut injury by restoring gut microbiota homeostasis and inhibiting inflammation via TLR4/NF-κB and JAK2/STAT3 dual regulation.

Lianhua Qingwen (LHQW), a clinically validated herbal medicine containing Maxing Shigan Decoction (MXSGT) and others, shows broad efficacy in various respiratory disease. However, its regulatory role on the gut-lung axis, particularly the contribution of its MXSGT components, remains unexplored. This study employed a formula-disassembled approach to decipher this mechanism. Three preparations, including the complete LHQW prescription, LHQW excluding MXSGT components (LHQW-MXSGT), and MXSGT along, were administered to LPS-induced acute lung injury and DSS-induced ulcerative colitis to evaluate their therapeutic effects via the gut-lung axis. Pathological changes, mucosal barrier integrity, inflammatory cell infiltration and pro-inflammatory cytokine levels were evaluated by H&E staining, histochemical staining, immunofluorescence, ELISA, RT-qPCR and Western blot. Metagenomic analysis (16S rDNA sequencing) was conducted to examine their regulatory role of gut microbiota. Network pharmacology analysis and cellular validation was employed to explore their underlying mechanisms. Our analyses demonstrated that LHQW and MXSGT, but not LHQW-MXSGT, significantly attenuated lung/intestinal pathology damage, reduced pro-inflammatory cytokines (TNF-α, IL-1β, IL-6), and restored gut barrier proteins (ZO-1, Occludin, MUC2). LHQW/MXSGT suppressed pathogenic bacteria (Escherichia coli, Salmonella, Klebsiella pneumoniae) while enriching Akkermansia muciniphila, correlating with decreased systemic LPS. Network pharmacology and subsequent validation identified dual inhibition of TLR4/NF-κB and JAK2/STAT3 pathways as key mechanism of MXSGT. In conclusion, MXSGT serves a pivotal pharmacologically active component of LHQW for its gut-lung axis regulation, acting through gut microbiota homeostasis restoration, intestinal barrier integrity maintenance, and anti-inflammatory signaling pathways, providing compelling scientific evidence supporting LHQW's potential therapeutic application in managing diseases characterized by comorbid gut and lung inflammation.