Steamed Panax notoginseng Saponins Ameliorate Cyclophosphamide-Induced Anemia by Attenuating Gut-Liver Injury and Activating the cAMP/PI3K/AKT Signaling Pathway.

Background

Steamed Panax notoginseng saponins (SPNSs) can alleviate cyclophosphamide-induced anemia. However, the hepatointestinal effects of SPNSs and their role in ameliorating cyclophosphamide-induced anemia remain unexplored.

Objective

To elucidate the hepatointestinal effects of SPNSs and their role in ameliorating cyclophosphamide-induced anemia.

Methods

Blood samples were collected and analyzed on days 7 and 14. Liver tissues and small intestinal villi structures were observed via HE staining. Liver and colon content metabolites were detected by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Liver proteins were analyzed by using an Orbitrap Astral mass spectrometer. Colon content microbiota composition was assessed via metagenomics. Signaling pathway protein expression was analyzed via Western blotting (WB).

Results

SPNSs significantly increased the red blood cell (RBC) count and hemoglobin (HGB) level by day 14 and alleviated hepatointestinal damage. Hepatic metabolomics revealed: the most abundant metabolites were fatty acids and stachyose on day 7 and amino acid and arachidonic acid derivatives on day 14. KEGG analysis implicated cAMP signaling. Proteomics revealed upregulated immune-related proteins and enhanced PI3K pathway activity (WB-validated). Colon content metabolomics showed increased daidzein, 3-(2,5-dimethoxyphenyl) propanoic acid, γ-CEHC, and adenosine in SPNS groups on day 14. Metagenomics indicated differential abundances of Heminiphilus faecis, Phocaeicola sartorii, and s-bacterium_J10.2018 on day 14. Multiomics integration demonstrated significant correlations between hepatic metabolites, hematopoietic proteins, colon content metabolites, and probiotic bacteria.

Conclusions

SPNS alleviates cyclophosphamide-induced hepato-intestinal injury in anemic mice by modulating the gut microbiota and enhancing hepato-intestinal immune defense. Additionally, SPNSs ameliorate anemia in cyclophosphamide-treated mice by activating the cAMP/PI3K/AKT pathway, promoting hepatocyte proliferation, and increasing hematopoietic protein expression.