"Heat-dissipating, lung-moistening, and constipation-relieving" effects of Siraitiae Fructus total saponins regulated through gut-lung axis.

Abstract

BACKGROUND: Siraitiae Fructus (SF), a well-known medicinal and edible herb, is traditionally used for heat-dissipation, lung-moistening, and constipation relief. However, the active substances and mechanisms responsible for these effects remain incompletely understood. Our previous study has shown that Siraitiae Fructus total saponins (SFTS) are the effective components in SF. PURPOSE: To systematically investigate the multi-target mechanisms of SFTS and its characteristic compound, Mogroside V (MV). METHODS: A novel model of allergic asthma with comorbid functional constipation (AFC) and gut microbiota depletion, AMPK inhibitor administration, and MyD88 knockout mice were employed in this study. RESULTS: SFTS alleviated asthma and constipation symptoms by modulating gut microbiota and SCFAs, suppressing the TLR4/MyD88/NF-κB pathway, activating the AMPK pathway, and rebalancing Th1/Th2 and Th17/Treg ratios. Collectively, SFTS restored immune homeostasis and physiological function in the lung and gut. This study further identified the TLR4/MyD88/NF-κB pathway as a critical mechanism for overall effects, while AMPK activation specifically mediated constipation relief. Predictably, SFTS showed broader efficacy than MV. CONCLUSION: This study is the first to employ a pulmonary-gastrointestinal comorbidity model to reveal the multi-target and multi-pathway mechanisms of SFTS. These findings fill a critical gap in the understanding of the multi-mechanism of SF, providing a novel theoretical foundation for its clinical application and product development.