Integrated Multi‐Omics Elucidates the Protective Mechanism of <i>Polygonatum odoratum</i> Extract Against Cyclophosphamide‐Induced Hepatointestinal Injury via the Liver–Gut Axis and JAK/STAT3 Pathway

ABSTRACT Polygonatum odoratum is a medicinal‐food homologous plant traditionally used in its entirety for conditions such as dry‐heat cough; however, modern research predominantly focuses on isolated compounds, thereby neglecting the potential synergies of whole extracts. To address this gap, enzyme‐treated P. odoratum extract (ETP) was compared with the traditional water‐treated P. odoratum extract (WTP) using a cyclophosphamide (CTX)‐induced hepatointestinal injury model to assess its potential as a chemoprotective dietary adjunct. Compared to WTP, ETP demonstrated a more significant alleviation of CTX‐induced hepatic injury, oxidative stress, and immune dysregulation. Specifically, ETP administration reduced levels of pro‐inflammatory cytokines (interleukin‐6 [IL‐6], interleukin‐17 [IL‐17], interferon‐gamma [IFN‐γ], and C‐reactive protein [CRP]), increased anti‐inflammatory mediators (interleukin‐2 [IL‐2] and interleukin‐22 [IL‐22]), restored gut barrier integrity, and rebalanced regulatory T cell (Treg)/T helper 17 cell (Th17) homeostasis. Metabolomic analysis revealed that ETP elevated the levels of l ‐(−)‐3‐phenyllactic acid and 3β,7α‐dihydroxy‐5‐cholestenoate, thereby modulating purine, fructose, and bile acid metabolism. Gut microbiota analysis indicated that ETP reversed CTX‐induced dysbiosis, partly through a reduction in the relative abundance of Lactobacillus alongside the restoration of beneficial microbial populations. Furthermore, ETP was found to contain higher levels of terpenoids, saccharides, and flavonoids compared to WTP. Finally, molecular docking and in vivo validation suggested the potential of ETP to inhibit Janus kinase (JAK)/signal transducer and activator of transcription 3 (STAT3) phosphorylation. In summary, ETP attenuated CTX‐induced immunotoxicity through integrated mechanisms involving antioxidant, anti‐inflammatory, microbiota‐regulating, and JAK/STAT3‐inhibitory activities. The enzymatic hydrolysis process was associated with an increased release of bioactive constituents, underscoring the value of whole‐plant extraction approaches. Collectively, these findings provide mechanistic support for the development of ETP as a chemoprotective functional food.