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 Pujadas; Jason 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

doi:10.1053/j.gastro.2021.02.056

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

Gastroenterology. 2021 Jun;160(7):2435-2450.e34. doi: 10.1053/j.gastro.2021.02.056. Epub 2021 Mar 4.

Authors

Alexandra E Livanos¹, Divya Jha¹, Francesca Cossarini², Ana S Gonzalez-Reiche³, Minami Tokuyama¹, Teresa Aydillo⁴, Tommaso L Parigi⁵, Mark S Ladinsky⁶, Irene Ramos⁷, Katie Dunleavy⁸, Brian Lee⁹, Rebekah E Dixon¹⁰, Steven T Chen¹¹, Gustavo Martinez-Delgado¹, Satish Nagula¹⁰, Emily A Bruce¹², Huaibin M Ko¹³, Benjamin S Glicksberg¹⁴, Girish Nadkarni¹⁵, Elisabet Pujadas¹⁶, Jason Reidy¹⁶, Steven Naymagon¹⁰, Ari Grinspan¹⁰, Jawad Ahmad¹⁰, Michael Tankelevich¹, Yaron Bram¹⁷, Ronald Gordon¹⁶, Keshav Sharma¹, Jane Houldsworth¹⁶, Graham J Britton¹⁸, Alice Chen-Liaw¹⁸, Matthew P Spindler¹⁸, Tamar Plitt¹⁸, Pei Wang³, Andrea Cerutti¹⁹, Jeremiah J Faith¹⁸, Jean-Frederic Colombel¹, Ephraim Kenigsberg¹⁸, Carmen Argmann³, Miriam Merad²⁰, Sacha Gnjatic²¹, Noam Harpaz¹⁶, Silvio Danese⁵, Carlos Cordon-Cardo²², Adeeb Rahman²³, Robert E Schwartz¹⁷, Nikhil A Kumta¹⁰, Alessio Aghemo⁵, Pamela J Bjorkman⁶, Francesca Petralia²⁴, Harm van Bakel²⁵, Adolfo Garcia-Sastre²⁶, Saurabh Mehandru²⁷

Affiliations

¹ Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, New York; The Dr. Henry D. Janowitz Division of Gastroenterology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York.
² Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, New York; Division of Infectious Disease, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York.
³ Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York.
⁴ Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, New York; Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, New York.
⁵ Department of Biomedical Sciences, Humanitas University, Milan, Italy.
⁶ Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, California.
⁷ Department of Neurology and Center for Advanced Research on Diagnostic Assays, Icahn School of Medicine at Mount Sinai, New York, New York.
⁸ Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York.
⁹ Human Immune Monitoring Center (HIMC) Icahn School of Medicine at Mount Sinai New York, New York, New York.
¹⁰ The Dr. Henry D. Janowitz Division of Gastroenterology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York.
¹¹ Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, New York; Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, New York.
¹² Division of Immunobiology, Department of Medicine, University of Vermont, Larner College of Medicine, Burlington, Vermont.
¹³ The Dr. Henry D. Janowitz Division of Gastroenterology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York; Department of Pathology, Molecular and Cell Based Medicine Icahn School of Medicine at Mount Sinai, New York, New York.
¹⁴ Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York; The Hasso Plattner Institute for Digital Health at Mount Sinai, Icahn School of Medicine at Mount Sinai, New York, New York.
¹⁵ Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York; The Hasso Plattner Institute for Digital Health at Mount Sinai, Icahn School of Medicine at Mount Sinai, New York, New York; The Charles Bronfman Institute of Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, New York; The Mount Sinai Clinical Intelligence Center, Icahn School of Medicine at Mount Sinai, New York, New York.
¹⁶ Department of Pathology, Molecular and Cell Based Medicine Icahn School of Medicine at Mount Sinai, New York, New York.
¹⁷ Division of Gastroenterology and Hepatology, Department of Medicine, Weill Cornell Medicine, New York, New York.
¹⁸ Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, New York; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York.
¹⁹ Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, New York; Catalan Institute for Research and Advanced Studies, Barcelona, Spain; Program for Inflammatory and Cardiovascular Disorders, Institut Hospital del Mar d'Investigacions Mèdiques, Barcelona, Spain.
²⁰ Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, New York; Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York; Human Immune Monitoring Center (HIMC) Icahn School of Medicine at Mount Sinai New York, New York, New York; Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, New York.
²¹ Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, New York; Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York; Human Immune Monitoring Center (HIMC) Icahn School of Medicine at Mount Sinai New York, New York, New York; Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, New York; Department of Pathology, Molecular and Cell Based Medicine Icahn School of Medicine at Mount Sinai, New York, New York.
²² Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York; Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, New York; Department of Pathology, Molecular and Cell Based Medicine Icahn School of Medicine at Mount Sinai, New York, New York.
²³ Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, New York; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York; Human Immune Monitoring Center (HIMC) Icahn School of Medicine at Mount Sinai New York, New York, New York; Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, New York.
²⁴ Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York. Electronic address: francesca.Petralia@mssm.edu.
²⁵ Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York; Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, New York, New York. Electronic address: harm.vanbakel@mssm.edu.
²⁶ Division of Infectious Disease, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York; Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, New York; Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, New York. Electronic address: adolfo.Garcia-Sastre@mssm.edu.
²⁷ Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, New York; The Dr. Henry D. Janowitz Division of Gastroenterology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York. Electronic address: saurabh.mehandru@mssm.edu.

Abstract

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.

Keywords: COVID-19; GI infection; GI symptoms; SARS-CoV-2; host immune response; outcomes.

Publication types

Multicenter Study
Research Support, N.I.H., Extramural

MeSH terms

Aged
Aged, 80 and over
COVID-19 / diagnosis
COVID-19 / immunology
COVID-19 / mortality
COVID-19 / virology*
Case-Control Studies
Cells, Cultured
Cytokines / blood
Female
Gastrointestinal Diseases / diagnosis
Gastrointestinal Diseases / immunology
Gastrointestinal Diseases / mortality
Gastrointestinal Diseases / virology*
Host-Pathogen Interactions
Humans
Immunity, Mucosal*
Inflammation Mediators / blood
Intestinal Mucosa / immunology
Intestinal Mucosa / virology*
Italy
Male
Middle Aged
New York City
Prognosis
Risk Assessment
Risk Factors
SARS-CoV-2 / immunology
SARS-CoV-2 / pathogenicity*
Viral Load

Substances

Cytokines
Inflammation Mediators

Abstract

Publication types

MeSH terms

Substances

Grants and funding