Siraitiae Fructus Alleviate Functional Constipation and Concurrent Pulmonary Dysfunction by Modulating the TLR4/MyD88/NF‐κB Pathway and Aquaporin Expression

Siraitiae fructus (SF) is a traditional medicinal and edible herb, commonly used for heat-dissipation, lung-moistening, and constipation relief. Previous studies have confirmed that siraitiae fructus total saponins (SFTS) exhibit the same pharmacological activity as SF. This study aims to investigate the mechanism of the anti-constipation effects of SFTS and its representative ingredient (mogroside V, MV). A loperamide hydrochloride induced functional constipation rat model was used, along with biochemical analysis, histopathological analysis, 16S rRNA sequencing, short-chain fatty acids (SCFAs) analysis, and western blotting. SFTS was found to restore fecal water content, fecal morphology, gut microbiota and short-chain fatty acids. It also inhibits the TLR4/MyD88/NF-κB pathway and the AQP3 expression, while upregulating the expression of c-Kit and occludin. Additionally, SFTS promoted the secretion of MTL and GAS, decrease the release of VIP, and effectively alleviated constipation. Furthermore, SFTS suppressed the TLR4/MyD88/NF-κB and PPAR-γ/RXR-α pathway, and reduce the AQP5 expression, thereby mitigating pulmonary dysfunction induced by constipation. As expected, SFTS demonstrated broader efficacy than MV. These findings highlighted the role of SFTS and MV as edible bioactives in alleviating constipation and associated extra-intestinal inflammation, supporting their potential as functional food for gastrointestinal and systemic health.