Development of a therapeutic bacterial consortium for constipation

便秘治疗细菌联盟的开发

基本信息

批准号：
10254559
负责人：
Philip Peter Strandwitz
金额：
$ 29.96万
依托单位：
HOLOBIOME, INC.
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-07-06 至 2022-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10254559
关键词：
Address Affect Age Agonist Animals Anti-Inflammatory Agents Antibiotic susceptibility Antibiotics Bacteria Biological Assay Blood specimen Body Weight Cecum Cell Culture Techniques Cells Clinical Constipation Development Diet Diet Modification Disease Dose Dyes Eating Effectiveness Elderly Engraftment Enteral Enteric Nervous System Etiology Exhibits Exposure to Feces Fiber Freeze Drying Freezing Future Gastrointestinal tract structure Gene Expression General Population Germ-Free Goals Growth Health Human Immune Immunologics In Vitro Individual Inflammation Inflammatory Intervention Intestinal Mucosa Intestines Inulin Irritable Bowel Syndrome Lactobacillus casei rhamnosus Liquid substance Maintenance Measures Modality Modeling Morphine Morphology Mus Neurobiology Operative Surgical Procedures Opioid Oral Organism Organoids Output Parkinsonian Disorders Patients Peripheral Blood Mononuclear Cell Pharmacology Phase Phenotype Population Predisposition Probiotics Production Recovery Safety Serotonin Serotonin Agonists Serotonin Receptors 5-HT4 Serum Severities Signal Transduction Source Symptoms Technology Testing Therapeutic Tissues Toxin Tryptamines Unhealthy Diet arm associated symptom base cell motility comorbidity cytokine effective therapy experience fecal transplantation feeding food surveillance genome sequencing gut bacteria gut microbiome in silico in vivo Model liquid chromatography mass spectrometry manufacturability meetings member metagenomic sequencing microbiome microbiome sequencing microorganism mouse model nervous system disorder novel novel therapeutics pharmacokinetics and pharmacodynamics prebiotics prescription opioid programs screening side effect stem subcutaneous synergism therapeutic candidate therapeutic target treatment arm

项目摘要

The goal of the proposed project is to develop a probiotic for the treatment of constipation, comprised of 2-3 anti- inflammatory strains of human gut-derived bacteria that enhance host serotonin (5-hydroxytryptamine, 5-HT) production and signaling. By addressing multiple targets associated with the etiology and symptoms of constipation (5-HT signaling and inflammation), we expect the result of this project to have broad utility. Constipation affects up to 20% of the general population, with rates even higher in the elderly, and comes in many forms ranging in severity. The most severe form, slow transit constipation (STC), affects ~15 to 30% of constipated patients. Less severe, but still representing a significant societal burden, are irritable bowel syndrome with constipation (IBS-C) and age-associated constipation. Constipation is also a major side effect of opioid medications, and is comorbid with neurological diseases including Parkinsonian syndromes. The etiology is multifarious, often involving a dysfunctional enteric nervous system, poor diet, and inflammation, but in many cases it is still poorly understood. Current treatment options are generally poor and include dietary modifications, pharmacological interventions, and—for severe forms like STC—surgery. As such, novel treatment options are needed, preferably those that can engage multiple therapeutic targets. One source of new therapeutics is the gut microbiome: the bacteria that reside in the gastrointestinal tract. These symbiotic organisms are involved in numerous components of health and disease, including development and maintenance of the immune and enteric nervous systems. Recently, it has been shown by a member of Holobiome’s team that the gut microbiome is a major regulator of host enteric 5-HT signaling: Germ free mice have a 50% reduction in serum 5-HT and have constipation, both of which can be corrected via recolonization with a normal microbiome or a human- derived consortium. It has also been shown that constipation in humans can be transferred into animals via fecal microbiome transplant; a phenotype that is driven via disrupted enteric 5-HT signaling and inflammation. This suggests a clear intervention strategy: deliver anti-inflammatory, 5-HT-modulating bacteria to the gut. In our preliminary studies we screened a proprietary panel of over 100 non-pathogenic species of human gut bacteria for the ability to modulate 5-HT in a cell culture model. We identified 17 bacterial strains with the capability to modulate 5-HT signaling via four mechanisms. In this Phase 1 application we seek to further test these strains as candidates for a 5-HT modulating and anti-inflammatory consortium. To do this, strains will first be profiled for safety and manufacturability in vitro and in silico. Strains meeting these criteria will be assembled into candidate consortia of 2-3 strains, which will be further optimized to impact 5-HT release and inflammation. These will be advanced for testing in mouse models of constipation to assess efficacy, safety, and engraftment. The most promising consortium will be further tested in PK/PD and dosing studies supported in a Phase 2 program.

该项目的目标是开发一种用于治疗便秘的益生菌，其中包含 2-3 种抗- 人类肠道来源的细菌炎症菌株，可增强宿主血清素（5-羟色胺，5-HT）通过解决与病因和症状相关的多个目标。便秘（5-HT 信号传导和炎症），我们预计该项目的结果具有广泛的用途。高达 20% 的总人口患有便秘，其中老年人的比例更高，并且便秘的严重程度有多种，其中最严重的是慢传输型便秘 (STC)，影响约 15% 至 30% 的人。便秘患者病情较轻，但仍造成重大社会负担，即肠易激。便秘综合征（IBS-C）和年龄相关性便秘也是便秘的主要副作用。阿片类药物，并与包括帕金森综合症在内的神经系统疾病共存。病因多种多样，通常涉及肠神经系统功能失调、不良饮食和炎症，但在许多情况下目前的治疗选择普遍较差，包括饮食调整，药物干预，以及针对 STC 等严重形式的手术因此，新的治疗选择是存在的。需要的，最好是那些可以参与多个治疗靶点的新疗法的来源之一。肠道微生物群：存在于胃肠道中的细菌，这些共生生物参与其中。健康和疾病的许多组成部分，包括免疫和免疫系统的发育和维持最近，Holobiome 团队的一名成员表明，肠道微生物组。是宿主肠道 5-HT 信号传导的主要调节因子：无菌小鼠的血清 5-HT 水平降低 50%，并且有便秘，这两种情况都可以通过正常微生物组或人类微生物的重新定植来纠正研究还表明，人类的便秘可以通过粪便转移到动物身上。微生物组移植；由肠道 5-HT 信号传导破坏和炎症驱动的表型。提出了一个明确的干预策略：将抗炎、调节 5-HT 的细菌输送到我们的肠道中。初步研究中，我们筛选了超过 100 种非致病性人类肠道细菌的专有组合我们鉴定了 17 种能够在细胞培养模型中调节 5-HT 的细菌菌株。通过四种机制调节 5-HT 信号传导在这一阶段的应用中，我们寻求进一步测试这些菌株。作为 5-HT 调节和抗炎联合体的候选者，首先要对菌株进行分析。符合这些标准的菌株将被组装成候选菌株。 2-3 个菌株组成的联合体，将进一步优化以影响 5-HT 释放和炎症。用于在小鼠便秘模型中进行测试以评估功效、安全性和植入。该联盟将承诺在 PK/PD 和第二阶段计划支持的剂量研究中进行进一步测试。