Integrated Network Pharmacology and DSS-Induced Colitis Model to Determine the Anti-Colitis Effect of Herbal Pair AMK-PLP

Ethnopharmacological relevance: Atractylodes macrocephala Koidz (AMK) and Paeonia lactiflora Pall (PLP), frequently used traditional Chinese medicine (TCM) in treatment of gastrointestinal disease, exerted predominate efficacies in colitis treatment. Meanwhile, AMK and PLP were normally used synergistically due to their similar and strong pharmacological effects clinically, but only certain patients will benefit from this combination.Aim of the study: To systematically explore the pharmacological effect of the combination of AMK and PLP in treating colitis, we used DSS-induced colitis model, either in alone or combined prescriptions.Materials and methods: For the in vivo animal experiment, colitis mice model was established using 2.5% DSS drinking water, AMK-PLP herb pair and corresponding single drugs were administrated daily. Weight changes, disease-activity (DAI) score, colon length and histopathology of colon were the parameters to evaluate colitis model and therapeutic effects. Bioinformatics tools were used to explore the underlying mechanism of combined use of AMK and PLP. After prediction of compounds and targets, we screened core targets of AMK and PLP, molecular docking was conducted. And targets shared by AMK-PLP herb pair and exclusively in AMK or PLP were analyzed separately.Results: Through colitis mice model, we found that when treated with single herb, the significant effects could be observed, while for combination, the strong effects from single herb were attenuate dramatically, either in colon shortening preventing effect or DAI score. As for study of network pharmacology, 16 core targets were overlapped in AMK and PLP, among these targets and 10 of key components, scopoletin from AMK, and sitogluside from PLP simultaneously targeting AKT1 at similar binding pocket, which would attribute to the attenuated effects via exhibiting competitive inhibition. Furthermore, targets exclusively belonged to AMK or PLP targeting MAPK and the toll-like receptor pathways seemed to exert opposite effects, which would alternate clue for the antagonism of AMK and PLP.Conclusions: In summary, our study indicated that AMK and PLP alone could exert strong anti-colitis effects, but that of which was significantly attenuated by their combination, and the competitive binding to AKT1 and opposite effects in MAPK and toll-like receptor pathways would the novel mechanism underlying. Our study not only provide the first evidence for understanding the combined effect of AMK and PLP, but also bring up a new strategy and suggestive thoughts for reconsideration of the rational of herbal pairs used frequently in TCM.