Background & Aims

Disturbances of the enterohepatic circulation of bile acids (BAs) are seen in a number of clinically important conditions, including metabolic disorders, hepatic impairment, diarrhea, and gallstone disease. To facilitate the exploration of underlying pathogenic mechanisms, we developed a mathematical model built on quantitative physiological observations across different organs.

Methods

The model consists of a set of kinetic equations describing the syntheses of cholic, chenodeoxycholic, and deoxycholic acids, as well as time-related changes of their respective free and conjugated forms in the systemic circulation, the hepatoportal region, and the gastrointestinal tract. The core structure of the model was adapted from previous modeling research and updated based on recent mechanistic insights, including farnesoid X receptor–mediated autoregulation of BA synthesis and selective transport mechanisms. The model was calibrated against existing data on BA distribution and feedback regulation.

Results

According to model-based predictions, changes in intestinal motility, BA absorption, and biotransformation rates affected BA composition and distribution differently, as follows: (1) inhibition of transintestinal BA flux (eg, in patients with BA malabsorption) or acceleration of intestinal motility, followed by farnesoid X receptor down-regulation, was associated with colonic BA accumulation; (2) in contrast, modulation of the colonic absorption process was predicted to not affect the BA pool significantly; and (3) activation of ileal deconjugation (eg, in patents with small intestinal bacterial overgrowth) was associated with an increase in the BA pool, owing to higher ileal permeability of unconjugated BA species.

Conclusions

This model will be useful in further studying how BA enterohepatic circulation modulation may be exploited for therapeutic benefits.

中文翻译：

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在人体健康和病理条件下基于生理学的胆汁酸分布和代谢模型。

背景与目标

在许多临床上重要的疾病中，包括代谢紊乱，肝功能不全，腹泻和胆结石疾病，都可以看到胆汁酸（BAs）肝肠循环的紊乱。为了促进对潜在致病机制的探索，我们开发了一个基于跨不同器官的定量生理观察建立的数学模型。

方法

该模型由一组动力学方程式组成，描述了胆酸，鹅去氧胆酸和脱氧胆酸的合成，以及它们各自的游离和结合形式在体循环，肝门区和胃肠道中随时间的变化。该模型的核心结构改编自先前的模型研究，并根据最近的机械学见识进行了更新，包括法呢素X受体介导的BA合成的自动调节和选择性转运机制。该模型已根据BA分布和反馈调节的现有数据进行了校准。

结果

根据基于模型的预测，肠蠕动，BA吸收和生物转化率的变化对BA组成和分布的影响不同，如下所示：（1）抑制跨肠BA通量（例如，BA吸收不良的患者）或肠蠕动加快继之于法呢素X受体的下调，与结肠BA积累有关；（2）相反，预计结肠吸收过程的调节不会显着影响BA池；（3）回肠解偶联的激活（例如，在小肠细菌过度生长的专利中）与BA库增加有关，这是由于未结合的BA种类的回肠通透性较高。

结论

该模型将有助于进一步研究如何利用BA肠肝循环调节来获得治疗益处。