Sustained Delivery of Microbes to Treat Ulcerative Colitis

摘要 肠道炎症包括一组使人衰弱的疾病，包括克罗恩病和溃疡性结肠炎。 结肠炎，其可由对驻留微生物群的免疫应答失调引起。这些疾病影响超过 1.5在美国有100万人，目前批准的治疗方案包括抗炎药物 和免疫系统抑制剂不幸的是，这些药物并不能解决 炎症，并专注于减轻症状。以前的工作表明， 因此，将微生物组中的微生物转化为保护性组合物可以是预防结肠炎诱导的有效策略。 然而，通过递送活微生物来调节微生物组仍然是一个挑战。因此，我们将 开发一种新的方法来控制微生物的位置、持续时间和浓度， 改善微生物群系调节，从而改善预防和治疗胃肠道疾病的功效。 结肠炎有两个独立的目标。在目标1中，我们将开发和优化能够 控制结肠表面的微生物浓度和接触时间以调节微生物粘附、生长， 和殖民化。在这个目标中，我们将确定如何时空相互作用的交付微生物 影响他们的殖民。在目标2中，我们将确定时空相互作用在 在实验性结肠炎的保护和治疗中递送微生物。为此，我们将首先测试 23个成员的毛螺菌科聚生体的递送影响对实验性溃疡性结肠炎的保护。 我们将评估以下两种：（i）使用标准口服给药方案通过各种给药方案递送的非配制微生物， 管饲法，和（ii）配制在聚合物膜中的微生物，所述聚合物膜能够实现不同的递送特性， 停留时间和局部浓度。总的来说，我们的目标是开发新的方法，可以控制 递送、粘附、定殖和微生物治疗剂的功效。

Abstract Intestinal inflammation encompasses a debilitating set of diseases, including Crohn's disease and ulcerative colitis which can result from dysregulated immune responses to resident microbiota. These diseases affect over 1.5 million people in the Unites States and currently approved treatment options include anti-inflammatory drugs and immune system suppressors. Unfortunately, these drugs do not address the mechanistic cause of inflammation and are focused on reducing symptoms. Previous work has shown that modulation of the microbiome towards a protective composition can be an effective strategy to prevent the induction of colitis. However, microbiome modulation via the delivery of living microbes remains a challenge. Accordingly, we will develop a new approach to control the location, duration, and concentration of delivered microbes to the gastrointestinal tract to improve microbiome modulation and thus efficacy in both prevention and treatment of colitis. There are two independent aims. In Aim 1, we will develop and optimize a formulation capable of controlling microbe concentration and contact time at the colon surface to modulate microbe adhesion, growth, and colonization. In this aim, we will determine how the spatiotemporal interactions of delivered microbes influences their colonization. In Aim 2, we will determine the role of spatiotemporal interactions between delivered microbes in the protection and treatment of experimental colitis. In this aim, we will first test how the delivery of a 23-member Lachnospiraceae consortium impacts protection against experimental ulcerative colitis. We will evaluate both: (i) non-formulated microbes delivered via various dosing regiments using standard oral gavage, and (ii) microbes formulated in polymer films that are capable achieving distinct delivery profiles, residence times, and local concentrations. Overall, we aim to develop new approaches that can control the delivery, adhesion, colonization, and efficacy of microbe therapeutics.