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.
| Original language | English |
|---|---|
| Pages (from-to) | 2435-2450.e34 |
| Journal | Gastroenterology |
| Volume | 160 |
| Issue number | 7 |
| DOIs | |
| State | Published - Jun 2021 |
Keywords
- COVID-19
- GI infection
- GI symptoms
- SARS-CoV-2
- host immune response
- outcomes
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In: Gastroenterology, Vol. 160, No. 7, 06.2021, p. 2435-2450.e34.
Research output: Contribution to journal › Article › peer-review
TY - JOUR
T1 - Intestinal Host Response to SARS-CoV-2 Infection and COVID-19 Outcomes in Patients With Gastrointestinal Symptoms
AU - Livanos, Alexandra E.
AU - Jha, Divya
AU - Cossarini, Francesca
AU - Gonzalez-Reiche, Ana S.
AU - Tokuyama, Minami
AU - Aydillo, Teresa
AU - Parigi, Tommaso L.
AU - Ladinsky, Mark S.
AU - Ramos, Irene
AU - Dunleavy, Katie
AU - Lee, Brian
AU - Dixon, Rebekah E.
AU - Chen, Steven T.
AU - Martinez-Delgado, Gustavo
AU - Nagula, Satish
AU - Bruce, Emily A.
AU - Ko, Huaibin M.
AU - Glicksberg, Benjamin S.
AU - Nadkarni, Girish
AU - Pujadas, Elisabet
AU - Reidy, Jason
AU - Naymagon, Steven
AU - Grinspan, Ari
AU - Ahmad, Jawad
AU - Tankelevich, Michael
AU - Bram, Yaron
AU - Gordon, Ronald
AU - Sharma, Keshav
AU - Houldsworth, Jane
AU - Britton, Graham J.
AU - Chen-Liaw, Alice
AU - Spindler, Matthew P.
AU - Plitt, Tamar
AU - Wang, Pei
AU - Cerutti, Andrea
AU - Faith, Jeremiah J.
AU - Colombel, Jean Frederic
AU - Kenigsberg, Ephraim
AU - Argmann, Carmen
AU - Merad, Miriam
AU - Gnjatic, Sacha
AU - Harpaz, Noam
AU - Danese, Silvio
AU - Cordon-Cardo, Carlos
AU - Rahman, Adeeb
AU - Schwartz, Robert E.
AU - Kumta, Nikhil A.
AU - Aghemo, Alessio
AU - Bjorkman, Pamela J.
AU - Petralia, Francesca
AU - van Bakel, Harm
AU - Garcia-Sastre, Adolfo
AU - Mehandru, Saurabh
N1 - Funding Information: Funding This research was partly funded by National Institutes of Health (NIH)/National Institute of Diabetes and Digestive and Kidney Diseases 123749 0S1 (to Saurabh Mehandru). Additional support was provided by the Center for Research for Influenza Pathogenesis, a National Institute of Allergy and Infectious Diseases (NIAID)–supported Center of Excellence for Influenza Research and Surveillance (contract no. HHSN272201400008C), and NIAID R01AI113186 (to Harm van Bakel). Additionally, the work was supported by the generous support of the JPB Foundation, the Open Philanthropy Project (research grant 2020-215611 [5384]), the Defense Advanced Research Projects Agency, and anonymous donors to Adolfo Garcia-Sastre. Minami Tokuyama was funded by the Digestive Disease Research Foundation. Ana S. Gonzalez-Reiche is supported in part by a Robin Chemers Neustein Postdoctoral Fellowship Award. The research carried out by Harm van Bakel and Ana S. Gonzalez-Reiche was supported by the Office of Research Infrastructure of the NIH under awards S10OD018522 and S10OD026880. Robert E. Schwartz is funded by NCI R01CA234614, NIAID 2R01AI107301, and NIDDK R01DK121072 and is supported as an Irma Hirschl Trust Research Award Scholar. Emily A. Bruce is supported by NIH grant P20GM125498 (awarded to University of Vermont Translational Global Infectious Disease Research Center). Pamela J. Bjorkman and Mark S. Ladinsky are supported by George Mason University Fast Grants. Steven T. Chen is supported by grant F30CA243210. Graham J. Britton is supported by a Research Fellowship Award from the Crohn's and Colitis Foundation of America. Matthew P. Spindler is supported by NIH T32 5T32AI007605. Sacha Gnjatic is supported by grants U24 CA224319, U01 DK124165, and P01 CA190174.The authors would like to thank the clinical staff, physicians, and patients who participated in this study. The authors also thank Dr Randy Albrecht for support with the BSL 3 facility and procedures at the Icahn School of Medicine at Mount Sinai. Alexandra E. Livanos, MD (Investigation: Equal); Divya Jha, PhD (Investigation: Equal); Francesca Cossarini, MD (Investigation: Equal); Ana S. Gonzalez-Reiche, PhD (Investigation: Equal); Minami Tokuyama, BS (Investigation: Equal); Teresa Aydillo, PhD (Investigation: Equal); Tommaso L. Parigi, MD (Investigation: Equal); Mark S. Ladinsky, PhD (Formal analysis: Supporting); Irene Ramos, PhD (Investigation: Supporting); Katie Dunleavy, MD (Investigation: Supporting); Brian Lee, BS (Investigation: Supporting); Rebekah Dixon, BS (Investigation: Supporting); Steven T. Chen, BS (Investigation: Supporting); Gustavo Martinez-Delgado, PhD (Investigation: Supporting); Satish Nagula, MD (Investigation: Supporting); Emily A. Bruce, PhD (Data curation: Supporting); Huaibin M. Ko, MD (Investigation: Supporting); Benjamin S. Glicksberg, PhD (Investigation: Supporting); Girish Nadkarni, MD (Investigation: Supporting); Elisabet Pujadas, MD (Investigation: Supporting); Jason Reidy, MS (Investigation: Supporting); Steven Naymagon, MD (Investigation: Supporting); Ari Grinspan, MD (Investigation: Supporting); Jawad Ahmad, MD (Investigation: Supporting); Michael Tankelevich, BS (Investigation: Supporting); Yaron Bram, PhD (Data curation: Supporting); Ronald Gordon, MD (Investigation: Supporting); Keshav Sharma, MS (Investigation: Supporting); Jane Houldsworth, BS (Investigation: Supporting); Graham J. Britton, PhD (Investigation: Supporting); Alice Chen-Liaw, BS (Investigation: Supporting); Matthew P. Spindler, BS (Investigation: Supporting); Tamar Plitt, BS (Investigation: Supporting); Pei Wang, PhD (Supporting: Supporting); Andrea Cerutti, MD, PhD (Supporting: Supporting); Jeremiah J. Faith, PhD (Supporting: Supporting); Jean-Frederic Colombel, MD (Supporting: Supporting); Ephraim Kenigsberg, PhD (Supporting: Supporting); Carmen Argmann, PhD (Supporting: Supporting); Miriam Merad, MD, PhD (Supporting: Supporting); Sacha Gnjatic, PhD (Supporting: Supporting); Noam Harpaz, MD (Supporting: Supporting); Silvio Danese, MD, PhD (Supporting: Supporting); Carlos Cordon-Cardo, MD, PhD (Supporting: Supporting); Adeeb Rahman, PhD (Supporting: Supporting); Robert E. Schwartz, MD, PhD (Data curation: Supporting; Formal analysis: Supporting; Investigation: Supporting); Nikhil A. Kumta, MD (Supporting: Supporting); Alessio Aghemo, MD, PhD (Supporting: Supporting); Pamela J. Bjorkman, PhD (Formal analysis: Supporting; Investigation: Supporting); Francesca Petralia, PhD (Supporting: Supporting); Harm van Bakel, PhD (Supporting: Supporting); Adolfo Garcia-Sastre, PhD (Supervision: Supporting); Saurabh Mehandru, MD (Investigation: Lead; Writing – original draft: Lead; Writing – review & editing: Lead). Funding Information: Conflicts of interest These authors disclose the following: Girish Nadkarni reports employment with, consultancy agreements with, and ownership interest in Pensieve Health and Renalytix AI; has received consulting fees from AstraZeneca, BioVie, GLG Consulting, and Reata; and has served as a scientific advisor or member of Pensieve Health and Renalytix AI. Jeremiah J. Faith has served on the scientific advisor board of Vedanta Biosciences and has received grants from Janssen (unrelated to this work). Jean-Frederic Colombel has served as a consultant for AbbVie, Amgen, Arena Pharmaceuticals, Boehringer Ingelheim, Celgene Corporations, Celltrion, Eli Lilly, and Enterome (all unrelated to this work). Sacha Gnjatic has received research grants from Bristol Myers Squibb, Genentech, Immune Design, Agenus, and Janssen and has served as a consultant for Merck, OncoMed, and Neon Therapeutics. Noam Harpaz has served as a consultant for Lilly USA and has received a pathology service contract with AbbVie and Celgene. Silvio Danese has served as a consultant for Ely Lilly, Enthera, Ferring Pharmaceuticals, Gilead, Hospira, Inotrem, Janssen, Johnson & Johnson, Merck Sharp & Dohme Mundipharma, Mylan, Pfizer, Roche, Sandoz, Sublimity Therapeutics, Takeda, TiGenix, UCB, and Vifor. Robert E. Schwartz has served on the scientific advisory board of Miromatrix Inc and is a consultant and speaker for Alnylam Inc. Nikhil A. Kumta has served as a consultant for Apollo Endosurgery, Boston Scientific, Gyrus AMCI, and Olympus. The remaining authors disclose no conflicts. Funding Information: Funding This research was partly funded by National Institutes of Health (NIH)/ National Institute of Diabetes and Digestive and Kidney Diseases 123749 0S1 (to Saurabh Mehandru). Additional support was provided by the Center for Research for Influenza Pathogenesis, a National Institute of Allergy and Infectious Diseases (NIAID)–supported Center of Excellence for Influenza Research and Surveillance (contract no. HHSN272201400008C), and NIAID R01AI113186 (to Harm van Bakel). Additionally, the work was supported by the generous support of the JPB Foundation , the Open Philanthropy Project (research grant 2020-215611 [5384]), the Defense Advanced Research Projects Agency , and anonymous donors to Adolfo Garcia-Sastre. Minami Tokuyama was funded by the Digestive Disease Research Foundation . Ana S. Gonzalez-Reiche is supported in part by a Robin Chemers Neustein Postdoctoral Fellowship Award. The research carried out by Harm van Bakel and Ana S. Gonzalez-Reiche was supported by the Office of Research Infrastructure of the NIH under awards S10OD018522 and S10OD026880. Robert E. Schwartz is funded by NCI R01CA234614, NIAID 2R01AI107301, and NIDDK R01DK121072 and is supported as an Irma Hirschl Trust Research Award Scholar. Emily A. Bruce is supported by NIH grant P20GM125498 (awarded to University of Vermont Translational Global Infectious Disease Research Center). Pamela J. Bjorkman and Mark S. Ladinsky are supported by George Mason University Fast Grants. Steven T. Chen is supported by grant F30CA243210. Graham J. Britton is supported by a Research Fellowship Award from the Crohn’s and Colitis Foundation of America. Matthew P. Spindler is supported by NIH T32 5T32AI007605. Sacha Gnjatic is supported by grants U24 CA224319, U01 DK124165, and P01 CA190174. Publisher Copyright: © 2021 AGA Institute
PY - 2021/6
Y1 - 2021/6
N2 - 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.
AB - 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.
KW - COVID-19
KW - GI infection
KW - GI symptoms
KW - SARS-CoV-2
KW - host immune response
KW - outcomes
UR - http://www.scopus.com/inward/record.url?scp=85104884557&partnerID=8YFLogxK
U2 - 10.1053/j.gastro.2021.02.056
DO - 10.1053/j.gastro.2021.02.056
M3 - Article
C2 - 33676971
AN - SCOPUS:85104884557
SN - 0016-5085
VL - 160
SP - 2435-2450.e34
JO - Gastroenterology
JF - Gastroenterology
IS - 7
ER -