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

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 clearthat SARS-CoV-2 can enter the gastrointestinal (GI) tract, that it can bind to the ACE2 receptor abundantlyexpressed on intestinal epithelial cells, that it can be isolated live from stool, and that it sheds in the stool forseveral weeks after COVID-19 symptom onset. This information combined with the observations that GImanifestations of the disease, such as nausea and diarrhea, appear to be on the rise, place an urgent need formore clearly understanding the intestinal microenvironment in patients with COVID-19. This broad objective willnot 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 GIpathology. Perhaps most importantly, this objective will help understand the factors that influence degree ofSARS-CoV-2 GI persistence and shedding in stool, which directly relate to the potential of fecal-oraltransmission. This proposal specifically addresses these objectives by examining whether the extensiveantibiotics administered to COVID-19 patients are creating unintended effects on the GI tract that result in afavorable environment for SARS-CoV-2 infection and persistence in the gut. The principle of competitiveexclusion has been demonstrated in the human GI tract in multiple publications using both oral and intravenousantibiotics, whereby the suppression of the total bacterial community and/or specific members, can result inincreased colonization by fungi, viruses, and antibiotic-resistant bacteria. Among the many roles of the gutmicrobiota, one fundamental role is to provide colonization resistance against foreign invaders. We do not yetknow how this microbial ecology plays out in the context of SARS-CoV-2. We hypothesize that antibioticperturbation of the gut microbiota and its metabolome in COVID-19 patients results in increased load andpersistence of SARS-CoV-2 in the intestines, and intestinal inflammation. We believe this may reflect diseasestage/severity. As a result, we anticipate findings will be rapidly translated to govern clinical managementof 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 haveprospectively collected, we will test our hypotheses in the following specific aims: Aim 1. Determine therelationship between bacterial and fungal intestinal communities and SARS-CoV-2 viral load longitudinally inSARS-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 inflammatoryprofile.