DOI: 10.37349/ent.2026.1004159 ISSN: 2769-6510

Redefining post-stress depression as a spatiotemporal five-disease multimorbidity trajectory: ghrelin-driven anchoring by Shugan absorbed compounds

Xi Huang, Runze Zhou, Chendong Xu, Haotian Qian, Yunke Huang, Zhan Gao, Qiulong Zhao, Min Xu, Shaoqi Shi, Ailing Yu, Jialing Zhou, Yaling Liu, Chenxiao Shan, Ping Ren
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Aim: This study aimed to redefine post-stress depressive pathogenesis through a novel five-disease multimorbidity trajectory model (brain1-coronary-brain2-gastro-enteric; B1CB2GE) and to evaluate the multifunctional anchoring effects of Bupleurum chinense Shugan-San (BSS) and its absorbed compounds (ACs), including meranzin hydrate (MH), in AFS (acute forced swimming) male Sprague-Dawley rats. Methods: Temporal multimorbidity trajectories of B1CB2GE clusters were established in AFS rats and compared with single-disease models using 10 integrative analytic methods, including dynamic cluster trajectory modeling, biochemical profiling, and pharmacokinetic-pharmacodynamic (PK-PD) correlation analyses. A multi-cell experiment was used as a proxy for the in vivo system, whereas H-ECs (H2O2-treated endothelial cells) were used as a proxy for the multicellular system. Circulatory biomarkers related to oxidative, endothelial, and inflammatory (OEI) impairment, brain-derived neurotrophic factor (BDNF) levels, and cecal butyrate contents were measured. The role of the ghrelin (Ghr) receptor was examined using the antagonist D-Lys3-GHRP-6 (D-Lys). Forced-swim test, gastric emptying, enteric transit, and coronary flow were used to characterize post-AFS multimorbidity trajectory phenotypes in animals. Results: Fifteen minutes after AFS, distinct temporal B1CB2GE multimorbidity clusters emerged with normalized ranking values: G 15.31 > B2 1.17 > B1 0.85 > C 0.49 > E 0.32. These clusters were accurately anchored by BSS and its five tailored sets of 1–10 ACs, demonstrating multifunctional modulation ranging from 53.23% to 156.32%, with optimal anchoring efficiency of 96.37–104.14%. MH, a representative multifunctional compound, exhibited the strongest prokinetic and OEI-restorative effects, elevating BDNF and cecal butyrate levels. These therapeutic effects were abolished by D-Lys, confirming a Ghr-dependent mechanism. Conclusions: This study introduces a multimorbidity trajectory framework (B1CB2GE) for modeling post-stress depression and demonstrates that Shugan-like herbal formulas such as BSS effectively anchor dynamic multimorbidity progression via multifunctional compounds like MH. These findings provide a systems-pharmacology basis for understanding and treating complex comorbid depressive disorders through multifunctional anchoring herbal therapeutics.

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