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

治疗性珍珠奶茶：利用水凝胶固定微生物预防尿毒症毒素的形成

基本信息

批准号：
10332134
负责人：
Mari-Karoliina Winkler
金额：
$ 47.58万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-01-01 至 2026-12-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10332134
关键词：
Aerobic Aftercare Alkanesulfonates American Amino Acids Anaerobic Bacteria Bacteria Binding Binding Proteins Biological Biological Assay Biomedical Engineering Bioreactors Blood Blood Circulation Cardiovascular system Chemistry Chronic Kidney Failure Clinical Colon Communities Cresol Data Dialysis procedure Diffuse Diffusion Dose Drug Delivery Systems End stage renal failure Engineering Environment Environmental Engineering technology Excision Fermentation Formulation Gastrointestinal tract structure Gel Goals Human Microbiome Hydrogels Immobilization Impaired cognition In Vitro Indican Indoles Ingestion Intestines Kidney Kidney Failure Kinetics Large Intestine Liver Mathematics Measures Membrane Metabolism Microbe Microbiology Morbidity - disease rate Needles Nutrient Oxygen Patient-Focused Outcomes Patients Performance Personal Satisfaction Plasma Plasma Albumin Polymer Chemistry Polymers Probiotics Research Residual state Running Science Side Site Small Intestines Source Stomach Sulfate Symptoms Tea Technology Testing Therapeutic Time Toxic effect Toxin absorption base conventional therapy design experience experimental study gastrointestinal system gut microbiome high reward high risk improved improved outcome innovation mathematical model microbial microbiome microorganism microorganism culture mortality novel pH gradient particle preservation prevent protein degradation response scale up solute success symptomatology tool

项目摘要

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.

项目概要每年有超过 100,000 名美国人在肾脏失去排泄能力时开始透析血液中的毒素，其中一半在五年内死亡。这些高死亡率的部分原因是由于透析无法有效去除蛋白质结合的尿毒症毒素 (PBUT)，例如硫酸吲哚酚和硫酸对甲酚，否则它们会被健康的肾脏清除。在此，我们提出了一种非侵入性可食用珍珠奶茶，以降低血液中的浓度 PBUT 并改善终末期肾病 (ESKD) 患者的预后。与试图通过透析去除血液中毒素的传统治疗相反，这项研究提供了一种完全不同的方法，可以防止毒素的形成起源。 PBUT 是肠道微生物代谢的副产品；吲哚和对甲酚起源于来自氨基酸发酵的肠道，两种溶质在肝脏中磺化形成 PBUT 硫酸吲哚酚和硫酸对甲酚。我们提出了一种新型的富含微生物的珍珠奶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为有毒形式。气泡成分将被设计成在胃中保持紧密，从而保护被截留的水凝胶微生物从低 pH 值开始，然后在小肠和结肠中在中性 pH 值下膨胀，从而允许 UT 扩散到水凝胶中，UT 降解微生物将使它们失活。最后，珍珠奶茶将完整地排出体外，而不会改变天然肠道微生物群。这这一概念建立在富含微生物的水凝胶在生物工程中的成功应用之上以及药物输送和废水处理的环境工程。我们将首先富集新型吲哚和对甲酚降解微生物来开发珍珠奶茶从环境中，第二次设计用于微生物的专用水凝胶载体，以及最终在控制良好的生物反应器装置中复制了它们穿过肠道的旅程。基材曲线、pH 梯度和去除率将通过实验测量和数学计算进行模拟以可视化细菌的空间定位并确定 UT 随着时间的推移的降解情况。将这些水凝胶放入配制的珍珠奶茶饮料中可以改善慢性病患者的生活通过减轻尿毒症症状的负担和并发症。