IN-PATIENT ANTIBIOTIC EXPOSURE PROMOTES SARS-COV-2 PERSISTENCE IN THE GI TRACT IN COVID-19 ADMITTED PATIENTS

ABSTRACT

Background: SARS-COV-2 shedding in the stool long after clearance from the respiratory tract has been reported in several studies during the COVID-19 pandemic. This suggests a long tail of viral persistence in the GI tract even after a patient has tested negative via oronasal swabs. Most patients admitted to the ICU or wards for COVID-19 at Cedars-Sinai are placed on between 2-13 antimicrobials at admission in order to prevent secondary respiratory infections, leading us to question whether the effect of reducing or eliminating the gut microbiome during SARS-COV-2 infection may result in prolonged GI infection and longterm GI side-effects. Antibiotic pre-treatment in rodent studies has shown that flaviviruses persist longer in the GI tract in the absence of gut microbiota. Studies have also demonstrated that antibiotic pre-treatment attenuates the antibody responses to the flu vaccine in mice and humans. Collectively, this suggests a reduction or elimination of the gut the microbiota by antibiotics before or during viral infection can drive viral persistence in the GI tract. Methods: Longitudinal stool samples were collected from 29 COVID-19 in-patients (wards, n=12;ICU, n=17, n=79 stool samples total) and 9 non-COVID-19 in-patients admitted for other respiratory infections. Ten of 29 COVID-19 in-patients were antibiotic naive. Stool metagenomics, metabolomics, and SARS-COV-2 viral quantification by qPCR, and fecal calprotectin were measured and aligned with antibiotic exposure of each patient. Results: Our findings show that 72% of stool samples from COVID-19 patients that tested negative for SARS-COV-2 in the stool were never exposed to in-patient antibiotics. Fecal calprotectin was significantly higher in ICU-admitted COVID-19 patients compared to those in the wards and non-COVID-19 controls. The highest fecal calprotectin levels corresponded to nine samples from three ICU patients, all of whom were on the heaviest regimen of antibiotics and were positive for SARS-COV-2 in the stool. Expectedly, gut microbiota variance was explained largely by antibiotic status, but also independently by stool SARS-COV-2 status. We recruited an additional 34 patients during the delta variant surge, and these samples are currently being analyzed along with fecal metabolomics. Conclusion: The heavy-dose antibiotic regimen administered to COVID-19 in-patients is associated with viral persistence of SARS-COV-2 in the GI tract, suggesting an important role of the gut microbiome in excluding SARS-COV-2 from the GI tract, perhaps by competitive exclusion or promoting interferon responses. Intestinal inflammation was significantly greater in COVID-19 ICU patients, with the highest levels of fecal calprotectin correlating to the heaviest dose of antibiotics and presence of SARS-COV-2 in the stool.