Sustained Delivery of Microbes to Treat Ulcerative Colitis

持续输送微生物来治疗溃疡性结肠炎

• 批准号: 10219242
• 负责人: Aaron C Anselmo
• 金额: $ 3.35万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-13 至 2021-10-02
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10219242
• 关键词: Address; Adhesions; Affect; Anaerobic Bacteria; Anti-Inflammatory Agents; Binding; Biological Response Modifier Therapy; Chronic; Clinical; Clinical Trials; Colitis; Colon; Crohn' s disease; Development; Disease; Dose; Dysplasia; Encapsulated; Engineering; Ensure; Etiology; Failure; Family suidae; Film; Formulation; Gastrointestinal tract structure; Gnotobiotic; Growth; Immune; Immune response; Immune system; In Vitro; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Inflammatory Response; Intestines; Large Intestine; Lead; Life; Living Standards; Location; Mediating; Microbe; Modality; Modeling; Mus; Oral; Patients; Pharmaceutical Preparations; Polymers; Polyvinyl Alcohol; Prevention; Regimen; Reporting; Reproduction spores; Research Personnel; Role; Site; Stomach; Surface; System; Technology; Testing; Therapeutic; Therapeutic Trials; Therapeutic Uses; Time; Ulcerative Colitis; United States; Upper digestive tract structure; Work; base; capsule; clinically relevant; design; dysbiosis; fecal transplantation; gut colonization; gut microbiota; human microbiota; improved; in vivo; inflammatory disease of the intestine; member; microbiome; microbiota; novel; novel strategies; prevent; reduce symptoms; residence; small molecule; spatiotemporal; therapy development; treatment group

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.

摘要 肠道炎症包括一系列令人衰弱的疾病，包括克罗恩病和溃疡性 结肠炎，可由对驻留微生物区系的免疫反应失调引起。这些疾病影响着超过 美国有150万人，目前批准的治疗方案包括抗炎药物 和免疫系统抑制因子。不幸的是，这些药物并不能解决高血压的机制。 发炎，专注于减轻症状。先前的工作已经表明，调制 微生物群的保护性成分可以是预防结肠炎诱导的有效策略。 然而，通过运送活微生物来调节微生物群仍然是一个挑战。因此，我们将 开发一种新的方法来控制将微生物输送到 胃肠道改善微生物群调控，从而在预防和治疗胃肠道疾病中的疗效 结肠炎。有两个独立的目标。在目标1中，我们将开发和优化一种能够 控制结肠表面的微生物浓度和接触时间，以调节微生物的黏附、生长 和殖民主义。在这个目标中，我们将确定交付的微生物的时空相互作用 影响了他们的殖民。在目标2中，我们将确定时空相互作用在 释放的微生物对实验性结肠炎的保护和治疗。在这个目标中，我们将首先测试 23个成员的沙棘科联盟的交付影响了对实验性溃疡性结肠炎的保护。 我们将对这两种情况进行评估：(I)使用标准口服通过不同剂量方案输送的非配方微生物 灌胃，以及(Ii)在聚合物膜中配制的能够实现不同递送轮廓的微生物， 停留时间和当地浓度。总的来说，我们的目标是开发新的方法来控制 微生物治疗药物的输送、黏附、定植和疗效。