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

项目摘要 COVID-19大流行目前已感染全球超过400万人，并导致超过30万人死亡。 这些数字继续增长，预计在秋季和冬季会有所回升。现在很清楚 SARS-CoV-2可以进入胃肠道，它可以大量结合ACE 2受体 在肠上皮细胞上表达，它可以从粪便中分离出活的，并且它在粪便中脱落， 在COVID-19症状出现几周后。这些信息与GI的观察结果相结合， 这种疾病的表现，如恶心和腹泻，似乎在上升，迫切需要 更清楚地了解COVID-19患者的肠道微环境。这一广泛目标将 不仅可以为目前诊断为COVID的胃肠道表现患者提供更有针对性的治疗， 19，这也将有助于了解COVID-19导致的胃肠道紊乱是否可能导致晚期GI 病理也许最重要的是，这一目标将有助于了解影响程度的因素， SARS-CoV-2胃肠道持久性和粪便中的脱落，这直接关系到粪便-口腔的潜力 传输这项建议具体针对这些目标，审查广泛的 给COVID-19患者使用的抗生素对胃肠道产生了意想不到的影响， SARS-CoV-2感染的有利环境和在肠道中的持久性。竞争性原则 在多篇出版物中，使用口服和静脉给药， 抗生素，从而抑制总细菌群落和/或特定成员，可导致 真菌、病毒和抗真菌细菌的定植增加。在肠道的众多作用中 在微生物群落中，一个基本作用是提供对外来入侵者的定殖抗性。我们还不 了解这种微生物生态在SARS-CoV-2的背景下是如何发挥作用的。我们假设抗生素 COVID-19患者肠道微生物群及其代谢组的扰动导致负荷增加， SARS-CoV-2在肠道中的持续存在以及肠道炎症。我们认为这可能反映了疾病 阶段/严重程度。因此，我们预计研究结果将迅速转化为管理临床管理 以及提供对影响传播的途径的深入了解， COVID-19的发展和解决。使用我们从COVID-19患者那里获得的生物样本库样本， 前瞻性收集，我们将测试我们的假设在以下具体目标：目标1。确定 肠道细菌和真菌群落与SARS病毒载量的关系 SARS-CoV-2阳性和阴性患者，暴露于和未暴露于不同抗生素，以及目标2。 确定肠道微生物组的改变是否反映在代谢物和炎症的改变中。 profile.

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.