We developed a mathematical model of colon physiology driven by serotonin signaling in the enteric nervous system. No such models are currently available to assist drug discovery and development for GI motility disorders. Model parameterization was informed by published preclinical and clinical data. Our simulations provide clinically relevant readouts of bowel movement frequency and stool consistency. The model recapitulates healthy and slow transit constipation phenotypes, and the effect of a 5-HT₄ receptor agonist in healthy volunteers. Using the calibrated model, we predicted the agonist dose to normalize defecation frequency in slow transit constipation while avoiding the onset of diarrhea. Model sensitivity analysis predicted that changes in HAPC frequency and liquid secretion have the greatest impact on colonic motility. However, exclusively increasing the liquid secretion can lead to diarrhea. In contrast, increasing HAPC frequency alone can enhance bowel frequency without leading to diarrhea. The quantitative systems pharmacology approach used here demonstrates how mechanistic modeling of disease pathophysiology expands our understanding of biology and supports judicious hypothesis generation for therapeutic intervention.

中文翻译：

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结肠运动的定量系统药理模型及其在药物开发中的应用。

我们开发了由肠神经系统中5-羟色胺信号传导驱动的结肠生理学数学模型。目前尚无此类模型可协助胃肠道运动性疾病的药物发现和开发。通过公开的临床前和临床数据了解模型参数。我们的模拟提供了与临床相关的排便频率和粪便稠度的读数。该模型概括了健康和慢速便秘的表型，以及5-HT ₄的作用。健康志愿者体内的受体激动剂。使用校准的模型，我们预测了激动剂的剂量以使慢速便秘中的排便频率正常化，同时避免腹泻的发作。模型敏感性分析预测，HAPC频率和液体分泌的变化对结肠运动的影响最大。但是，仅增加液体分泌会导致腹泻。相反，仅增加HAPC频率可增强肠频率，而不会导致腹泻。这里使用的定量系统药理学方法证明了疾病病理生理学的机理模型如何扩展了我们对生物学的理解，并支持了明智的假说产生以进行治疗性干预。