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：
10733487
负责人：
Mari-Karoliina Winkler
金额：
$ 1.03万
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/10733487
关键词：
Aerobic Aftercare Alkanesulfonates American Amino Acids 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 Excretory function Fermentation Formulation Gastrointestinal tract structure Gel Goals Human Microbiome Hydrogels Immobilization Impaired cognition In Vitro Indican Indoles Ingestion Intestines Kidney Kidney Diseases 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 Swelling Symptoms Tea Technology Testing Therapeutic Time Toxic effect Toxin Uremia Visualization absorption 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.

项目摘要每年有超过100,000名美国人肾脏失去去除的能力时开始透析血液中的毒素和一半的毒素在五年内死亡。这些高死亡率是部分由于透析在去除蛋白质结合的尿毒症毒素（PBUT）时的效果无效硫酸吲哚基和硫酸盐酸盐，否则将通过健康的肾脏去除。本文中，我们提出了一种非侵入性的可食用气泡茶，以降低血液浓度 PBUTS并改善终阶段肾脏疾病（ESKD）患者的结局。与常规治疗相反，这些治疗试图通过透析从血液中清除毒素，这项研究提供了一种根本不同的方法，可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P-Cresol起源于将氨基酸发酵和两种溶质发酵的肠道均在肝脏中磺化以形成 PBUTS硫酸盐和硫酸盐酸中心。我们提出了一种新颖的微生物富含气泡茶这将扩大肠道降解尿毒症毒素（UT）前体的能力（吲哚和 p-cresol），从而防止其硫成肝脏中的有毒形式。气泡组件将设计为保持胃部紧绷，因此保护被夹住的水凝胶来自低pH的微生物，然后在小肠和结肠中以中性pH膨胀，允许 UTS扩散到水凝胶中，在该水凝胶中，UT降解的微生物将停用它们。最后，泡泡茶将被完整地排出，而不会改变天然的肠道微生物组。这概念以富含微生物的水凝胶在生物工程中的成功应用为基础以及用于药物输送和废水处理的环境工程。我们将首先富集新颖的吲哚和p-Cresol降解微生物来发展泡泡茶从环境中，微生物的第二工程专业水凝胶载体，以及最终以良好的生物反应器单位复制他们穿越肠道的行程。基板轮廓，pH梯度和去除率将进行实验测量和数学测量模拟以可视化细菌的空间定位，并随着时间的推移确定UT降解。在配制的泡泡茶饮料中输送这些水凝胶可以改善慢性的生活通过减轻尿毒症症状和ESKD患者的肾脏疾病和ESKD患者并发症。