Therapeutic bubble tea: Preventing the formation of uremic toxins with hydrogel immobilized microbes

项目总结 每年有超过10万美国人在肾脏失去排出能力时开始透析 血液中的毒素，其中一半在五年内死亡。这些高死亡率在一定程度上 由于透析在清除蛋白结合的尿毒症毒素(PBUT)方面无效，例如 吲哚硫酸盐和对甲酚硫酸盐，否则会被健康的肾脏清除。 在此，我们提出了一种非侵入性的可食用泡泡茶来降低血药浓度 PBUT和改善终末期肾病(ESKD)患者的预后。 与传统疗法不同的是，传统疗法试图通过透析去除血液中的毒素， 这项研究提供了一种截然不同的方法，它可以防止人体内毒素的形成 起源。多溴联苯并呋喃是肠道微生物代谢的副产品；吲哚和对甲酚起源于 氨基酸和两种溶质的发酵产生的肠道在肝脏中磺化，形成 硫代吲哚硫酸盐和对甲酚硫酸盐。我们提出了一种新型的富含微生物的泡泡茶 这将扩大肠道降解尿毒症毒素(UT)前体(吲哚和 对甲酚)，从而防止它们在肝脏中磺化成有毒形式。气泡组件 会在胃里保持紧致，从而保护被困住的水凝胶 微生物来自低pH，然后在中性pH下在小肠和结肠中膨胀，允许 UTS扩散到水凝胶中，在那里UT降解微生物将使它们失活。 最后，泡茶将被原封不动地排泄出来，而不会改变自然的肠道微生物群。这 概念建立在富微生物水凝胶在生物工程中的成功应用 以及药物输送和废水处理的环境工程。 我们将首先通过丰富新的吲哚和对甲酚降解菌来开发泡茶 从环境方面来说，二次工程专门为微生物设计了水凝胶载体，以及 最后，在控制良好的生物反应器单元中，复制它们的肠道之旅。该衬底 将对剖面、pH梯度和去除速率进行实验测量和数学计算 模拟以可视化细菌的空间定位并确定UT随时间的降解。 将这些水凝胶制成配方泡泡茶饮料可以改善慢性阻塞性肺病患者的生活 肾脏疾病和ESKD患者通过减少尿毒症症状和 并发症。

Project summary Each year over 100,000 Americans begin dialysis when their kidneys lose the capacity to remove toxins from the blood and half of them die within five years. These high mortality rates are in part due to the ineffectiveness of dialysis at removing protein-bound uremic toxins (PBUTs) such as indoxyl sulfate and p-cresol sulfate, which would otherwise be removed by healthy kidneys. Herein, we propose a non-invasive ingestible bubble tea to reduce the blood concentration of PBUTs and improve the outcomes of patients with end stage kidney disease (ESKD). In contrast to conventional treatments, which attempt to remove toxins from the blood by dialysis, this research offers a radically different approach, which prevents the formation of toxins at their origin. PBUTs are byproducts of gut microbial metabolism; indole and p-cresol originate in the gut from fermentation of amino acids and both solutes are sulfonated in the liver to form the PBUTs indoxyl sulfate and p-cresol sulfate. We propose a novel microbe enriched bubble tea which will expand the capacity of the gut to degrade the uremic toxin (UT) precursors (indole and p-cresol) and thereby prevent their sulfonation to toxic forms in the liver. The bubble components will be engineered to remain tight in the stomach, hence protecting the hydrogel entrapped microbes from low pH, and then swell at neutral pH in the small intestine and colon, allowing UTs to diffuse into the hydrogel where the UT degrading microorganisms will deactivate them. Finally, the bubble tea will be excreted intact without altering the natural gut microbiome. This concept builds on the successful applications of microbe enriched hydrogels in bioengineering and environmental engineering for drug delivery and wastewater treatment. We will develop the bubble tea by first enriching novel indole and p-cresol degrading microbes from the environment, second engineering specialized hydrogel carriers for the microbes, and finally replicating their trip through the gut in well controlled bioreactor units. The substrate profiles, pH gradients, and removal rates will be experimentally measured and mathematically simulated to visualize spatial localization of bacteria and to determine UT degradation over time. Delivering these hydrogels in a formulated bubble tea drink could improve the lives of chronic kidney disease and ESKD patients by reducing the burden from uremic symptoms and complications.