Development of a therapeutic bacterial consortium for constipation

便秘治疗细菌联盟的开发

• 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
• 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

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.

拟议项目的目标是开发一种用于治疗便秘的益生菌，由2-3个抗- 增强宿主血清素（5-羟色胺，5-HT）的人肠道衍生细菌的炎性菌株 生产和信号。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），我们期望该项目的结果具有广泛的实用性。 便秘影响了高达20%的普通人群，老年人的患病率甚至更高， 多种形式，严重程度不等。最严重的形式，慢传输型便秘（STC），影响约15至30%的 便秘患者不太严重，但仍然代表着一个重大的社会负担，是肠易激惹 便秘综合征（IBS-C）和年龄相关性便秘。便秘也是一个主要的副作用 阿片类药物，并与神经系统疾病包括帕金森综合征共病。病因 是多种多样的，通常涉及肠神经系统功能障碍，饮食不良和炎症，但在许多 在某些情况下，人们仍然知之甚少。目前的治疗选择通常很差，包括饮食调整， 药物干预，和严重的形式，如STC-手术。因此，新的治疗选择是 需要的，最好是那些可以参与多个治疗目标。新疗法的一个来源是 肠道微生物组：驻留在胃肠道中的细菌。这些共生有机体参与了 健康和疾病的许多组成部分，包括免疫系统的发育和维持， 肠神经系统最近，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剂：无菌小鼠血清5-HT减少50%， 有便秘，这两种情况都可以通过与正常微生物组或人类的代谢来纠正- 衍生财团还表明，人类的便秘可以通过粪便转移到动物身上。 微生物组移植;通过破坏肠道5-HT信号传导和炎症驱动的表型。这 提出了一个明确的干预策略：将抗炎的5-HT调节细菌输送到肠道。在我们 初步研究中，我们筛选了一组专有的100多种非致病性人类肠道细菌 在细胞培养模型中调节5-HT的能力。我们鉴定了17种细菌菌株， 通过四种机制调节5-HT信号传导。在第一阶段的申请中，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物。要做到这一点，菌株将首先进行分析， 体外和计算机模拟的安全性和可制造性。将符合这些标准的菌株组装成候选菌株 在一个实施方案中，将2-3个菌株的聚生体（consortia）进行重组，其将进一步优化以影响5-HT释放和炎症。这些将是 在小鼠便秘模型中进行测试，以评估疗效、安全性和植入。最 将在II期项目支持的PK/PD和给药研究中进一步测试有前途的联合体。