Intestinal Host Response to SARS-CoV-2 Infection and COVID-19 Outcomes in Patients With Gastrointestinal Symptoms

Alexandra E. Livanos, Divya Jha, Francesca Cossarini, Ana S. Gonzalez-Reiche, Minami Tokuyama, Teresa Aydillo, Tommaso L. Parigi, Mark S. Ladinsky, Irene Ramos, Katie Dunleavy, Brian Lee, Rebekah E. Dixon, Steven T. Chen, Gustavo Martinez-Delgado, Satish Nagula, Emily A. Bruce, Huaibin M. Ko, Benjamin S. Glicksberg, Girish Nadkarni, Elisabet PujadasJason Reidy, Steven Naymagon, Ari Grinspan, Jawad Ahmad, Michael Tankelevich, Yaron Bram, Ronald Gordon, Keshav Sharma, Jane Houldsworth, Graham J. Britton, Alice Chen-Liaw, Matthew P. Spindler, Tamar Plitt, Pei Wang, Andrea Cerutti, Jeremiah J. Faith, Jean Frederic Colombel, Ephraim Kenigsberg, Carmen Argmann, Miriam Merad, Sacha Gnjatic, Noam Harpaz, Silvio Danese, Carlos Cordon-Cardo, Adeeb Rahman, Robert E. Schwartz, Nikhil A. Kumta, Alessio Aghemo, Pamela J. Bjorkman, Francesca Petralia, Harm van Bakel, Adolfo Garcia-Sastre, Saurabh Mehandru

Research output: Contribution to journalArticlepeer-review

110 Scopus citations


Background & Aims: Given that gastrointestinal (GI) symptoms are a prominent extrapulmonary manifestation of COVID-19, we investigated intestinal infection with SARS-CoV-2, its effect on pathogenesis, and clinical significance. Methods: Human intestinal biopsy tissues were obtained from patients with COVID-19 (n = 19) and uninfected control individuals (n = 10) for microscopic examination, cytometry by time of flight analyses, and RNA sequencing. Additionally, disease severity and mortality were examined in patients with and without GI symptoms in 2 large, independent cohorts of hospitalized patients in the United States (N = 634) and Europe (N = 287) using multivariate logistic regressions. Results: COVID-19 case patients and control individuals in the biopsy cohort were comparable for age, sex, rates of hospitalization, and relevant comorbid conditions. SARS-CoV-2 was detected in small intestinal epithelial cells by immunofluorescence staining or electron microscopy in 15 of 17 patients studied. High-dimensional analyses of GI tissues showed low levels of inflammation, including down-regulation of key inflammatory genes including IFNG, CXCL8, CXCL2, and IL1B and reduced frequencies of proinflammatory dendritic cells compared with control individuals. Consistent with these findings, we found a significant reduction in disease severity and mortality in patients presenting with GI symptoms that was independent of sex, age, and comorbid illnesses and despite similar nasopharyngeal SARS-CoV-2 viral loads. Furthermore, there was reduced levels of key inflammatory proteins in circulation in patients with GI symptoms. Conclusions: These data highlight the absence of a proinflammatory response in the GI tract despite detection of SARS-CoV-2. In parallel, reduced mortality in patients with COVID-19 presenting with GI symptoms was observed. A potential role of the GI tract in attenuating SARS-CoV-2–associated inflammation needs to be further examined.

Original languageEnglish
Pages (from-to)2435-2450.e34
Issue number7
StatePublished - Jun 2021


  • COVID-19
  • GI infection
  • GI symptoms
  • SARS-CoV-2
  • host immune response
  • outcomes


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