Microbial and metabolomic profiling of the intestinal microenvironment distinguishing patients with mild and severe COVID-19 symptoms.

肠道微环境的微生物和代谢组学分析可区分轻度和重度 COVID-19 症状的患者。

• 批准号: 10177673
• 负责人: Suzanne Devkota
• 金额: $ 37.19万
• 依托单位: CEDARS-SINAI MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-01-20 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10177673
• 关键词: 2019-nCoV; Address; Antibiotics; Bacterial Antibiotic Resistance; Binding; Biological Markers; COVID-19; COVID-19 pandemic; Cessation of life; Clinical Management; Communities; Development; Diagnosis; Diarrhea; Disease; Ecology; Environment; Epithelial Cells; Exclusion; Exposure to; Feces; Gastrointestinal tract structure; Human; Infection; Inflammatory; Intestines; Intravenous; Lead; Nausea; Oral; Pathology; Pathway interactions; Patients; Play; Publications; Resolution; Role; Severities; Site; Specimen; Symptoms; Testing; Translating; Viral; Viral Load result; Virus; antimicrobial; bacterial community; biobank; colonization resistance; falls; fungus; gastrointestinal; gut microbiome; gut microbiota; individualized medicine; inflammatory disease of the intestine; insight; intestinal epithelium; member; metabolome; metabolomics; microbial; prospective; public health emergency; receptor; transmission process

Project Summary The COVID-19 pandemic currently has infected over 4 million people worldwide and led to over 300,000 deaths. These numbers continue to grow and with an anticipated resurgence in the fall and winter months. It is now clear that SARS-CoV-2 can enter the gastrointestinal (GI) tract, that it can bind to the ACE2 receptor abundantly expressed on intestinal epithelial cells, that it can be isolated live from stool, and that it sheds in the stool for several weeks after COVID-19 symptom onset. This information combined with the observations that GI manifestations of the disease, such as nausea and diarrhea, appear to be on the rise, place an urgent need for more clearly understanding the intestinal microenvironment in patients with COVID-19. This broad objective will not only allow for more tailored treatment for patients with GI manifestations currently diagnosed with COVID- 19, it will also help to understand whether a perturbed GI tract as a result of COVID-19 may lead to later GI pathology. Perhaps most importantly, this objective will help understand the factors that influence degree of SARS-CoV-2 GI persistence and shedding in stool, which directly relate to the potential of fecal-oral transmission. This proposal specifically addresses these objectives by examining whether the extensive antibiotics administered to COVID-19 patients are creating unintended effects on the GI tract that result in a favorable environment for SARS-CoV-2 infection and persistence in the gut. The principle of competitive exclusion has been demonstrated in the human GI tract in multiple publications using both oral and intravenous antibiotics, whereby the suppression of the total bacterial community and/or specific members, can result in increased colonization by fungi, viruses, and antibiotic-resistant bacteria. Among the many roles of the gut microbiota, one fundamental role is to provide colonization resistance against foreign invaders. We do not yet know how this microbial ecology plays out in the context of SARS-CoV-2. We hypothesize that antibiotic perturbation of the gut microbiota and its metabolome in COVID-19 patients results in increased load and persistence of SARS-CoV-2 in the intestines, and intestinal inflammation. We believe this may reflect disease stage/severity. As a result, we anticipate findings will be rapidly translated to govern clinical management of antimicrobials in patients as well as provide insight into pathways that influence transmission, development and resolution of COVID-19. Using biobanked specimens from COVID-19 patients that we have prospectively collected, we will test our hypotheses in the following specific aims: Aim 1. Determine the relationship between bacterial and fungal intestinal communities and SARS-CoV-2 viral load longitudinally in SARS-CoV-2 positive and negative patients, with and without exposure to different antibiotics, and Aim 2. Determine whether alterations to the gut microbiome is reflected in an altered metabolite and inflammatory profile.

项目摘要 目前，Covid-19-19的大流行已感染了全球超过400万人，并导致30万人死亡。 这些数字继续增长，并在秋季和冬季预计复兴。现在很清楚 SARS-COV-2可以进入胃肠道（GI），它可以大量结合到ACE2受体 在肠上皮细胞上表达，可以将其与粪便分离出来，并在粪便中脱落 COVID-19症状发作后几周。这些信息与GI的观察结果相结合 这种疾病的表现，例如恶心和腹泻，似乎正在上升，迫切需要 更清楚地了解Covid-19患者的肠道微环境。这个广泛的目标将 不仅允许对目前诊断为COVID的胃肠道表现的患者进行更量身定制的治疗 19，这也将有助于了解covid-19的扰动的胃肠道是否可能导致GI以后 病理。也许最重要的是，这个目标将有助于了解影响程度的因素 SARS-COV-2 GI的持久性和粪便中的脱落，这与粪便的潜力直接相关 传播。该提案通过检查是否广泛来解决这些目标 对COVID-19患者施​​用的抗生素正在对胃肠道产生意想不到的影响，从而导致 SARS-COV-2感染和肠道持久性的有利环境。竞争原则 使用口腔和静脉注射的多个出版物中的人类胃肠道已经证明了排除 抗生素抑制了总细菌群落和/或特定成员的抗生素，可能会导致 真菌，病毒和抗生素抗性细菌的定殖增加。在肠道的众多角色中 微生物群，一个基本作用是对外国入侵者提供抗性抗性。我们还没有 知道这种微生物生态学在SARS-COV-2的背景下如何发挥作用。我们假设该抗生素 肠道菌群的扰动及其代谢组在Covid-19患者中的扰动导致负载增加和 SARS-COV-2在肠道和肠炎中的持久性。我们认为这可能反映出疾病 阶段/严重性。结果，我们预计发现将迅速转化为管理临床管理 患者的抗菌剂，以及对影响传播的途径的见解， Covid-19的开发和解决。使用来自COVID-19患者的生物群标本，我们 前瞻性收集，我们将在以下具体目的中检验我们的假设：目标1。确定 细菌和真菌肠道群落与SARS-COV-2病毒载荷之间的关系纵向 SARS-COV-2阳性和阴性患者，有或没有暴露于不同抗生素的情况下，AIM 2。 确定肠道微生物组的改变是否反映在改变的代谢物和炎症中 轮廓。