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

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.

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References

Ke Z, Oton J, Qu K, Cortese M, Zila V, McKeane L . Structures and distributions of SARS-CoV-2 spike proteins on intact virions. Nature. 2020; 588(7838):498-502. PMC: 7116492. DOI: 10.1038/s41586-020-2665-2. View

Aghemo A, Piovani D, Parigi T, Brunetta E, Pugliese N, Vespa E . COVID-19 Digestive System Involvement and Clinical Outcomes in a Large Academic Hospital in Milan, Italy. Clin Gastroenterol Hepatol. 2020; 18(10):2366-2368.e3. PMC: 7211605. DOI: 10.1016/j.cgh.2020.05.011. View

He W, Ladinsky M, Huey-Tubman K, Jensen G, McIntosh J, Bjorkman P . FcRn-mediated antibody transport across epithelial cells revealed by electron tomography. Nature. 2008; 455(7212):542-6. PMC: 2773227. DOI: 10.1038/nature07255. View

Gupta A, Madhavan M, Sehgal K, Nair N, Mahajan S, Sehrawat T . Extrapulmonary manifestations of COVID-19. Nat Med. 2020; 26(7):1017-1032. DOI: 10.1038/s41591-020-0968-3. View

Rao X, Wu C, Wang S, Tong S, Wang G, Wu G . The importance of overweight in COVID-19: A retrospective analysis in a single center of Wuhan, China. Medicine (Baltimore). 2020; 99(43):e22766. PMC: 7581045. DOI: 10.1097/MD.0000000000022766. View

Xiao F, Tang M, Zheng X, Liu Y, Li X, Shan H . Evidence for Gastrointestinal Infection of SARS-CoV-2. Gastroenterology. 2020; 158(6):1831-1833.e3. PMC: 7130181. DOI: 10.1053/j.gastro.2020.02.055. View

Liao M, Liu Y, Yuan J, Wen Y, Xu G, Zhao J . Single-cell landscape of bronchoalveolar immune cells in patients with COVID-19. Nat Med. 2020; 26(6):842-844. DOI: 10.1038/s41591-020-0901-9. View

Kotarsky K, Sitnik K, Stenstad H, Kotarsky H, Schmidtchen A, Koslowski M . A novel role for constitutively expressed epithelial-derived chemokines as antibacterial peptides in the intestinal mucosa. Mucosal Immunol. 2009; 3(1):40-8. DOI: 10.1038/mi.2009.115. View

Klein S, Cortese M, Winter S, Wachsmuth-Melm M, Neufeldt C, Cerikan B . SARS-CoV-2 structure and replication characterized by in situ cryo-electron tomography. Nat Commun. 2020; 11(1):5885. PMC: 7676268. DOI: 10.1038/s41467-020-19619-7. View

10.

Wilkerson M, Hayes D . ConsensusClusterPlus: a class discovery tool with confidence assessments and item tracking. Bioinformatics. 2010; 26(12):1572-3. PMC: 2881355. DOI: 10.1093/bioinformatics/btq170. View

11.

Pujadas E, Chaudhry F, McBride R, Richter F, Zhao S, Wajnberg A . SARS-CoV-2 viral load predicts COVID-19 mortality. Lancet Respir Med. 2020; 8(9):e70. PMC: 7836878. DOI: 10.1016/S2213-2600(20)30354-4. View

12.

Cohen A, Gnanapragasam P, Lee Y, Hoffman P, Ou S, Kakutani L . Mosaic nanoparticles elicit cross-reactive immune responses to zoonotic coronaviruses in mice. Science. 2021; 371(6530):735-741. PMC: 7928838. DOI: 10.1126/science.abf6840. View

13.

Mastronarde D, Held S . Automated tilt series alignment and tomographic reconstruction in IMOD. J Struct Biol. 2016; 197(2):102-113. PMC: 5247408. DOI: 10.1016/j.jsb.2016.07.011. View

14.

Reimand J, Kull M, Peterson H, Hansen J, Vilo J . g:Profiler--a web-based toolset for functional profiling of gene lists from large-scale experiments. Nucleic Acids Res. 2007; 35(Web Server issue):W193-200. PMC: 1933153. DOI: 10.1093/nar/gkm226. View

15.

Falschlehner C, Schaefer U, Walczak H . Following TRAIL's path in the immune system. Immunology. 2009; 127(2):145-54. PMC: 2691779. DOI: 10.1111/j.1365-2567.2009.03058.x. View

16.

Zang R, Gomez Castro M, McCune B, Zeng Q, Rothlauf P, Sonnek N . TMPRSS2 and TMPRSS4 promote SARS-CoV-2 infection of human small intestinal enterocytes. Sci Immunol. 2020; 5(47). PMC: 7285829. DOI: 10.1126/sciimmunol.abc3582. View

17.

Mackall C, Fry T, Gress R . Harnessing the biology of IL-7 for therapeutic application. Nat Rev Immunol. 2011; 11(5):330-42. PMC: 7351348. DOI: 10.1038/nri2970. View

18.

Barker N, van de Wetering M, Clevers H . The intestinal stem cell. Genes Dev. 2008; 22(14):1856-64. PMC: 2735277. DOI: 10.1101/gad.1674008. View

19.

Ladinsky M, Huey-Tubman K, Bjorkman P . Electron tomography of late stages of FcRn-mediated antibody transcytosis in neonatal rat small intestine. Mol Biol Cell. 2012; 23(13):2537-45. PMC: 3386217. DOI: 10.1091/mbc.E12-02-0093. View

20.

Turonova B, Sikora M, Schurmann C, Hagen W, Welsch S, Blanc F . In situ structural analysis of SARS-CoV-2 spike reveals flexibility mediated by three hinges. Science. 2020; 370(6513):203-208. PMC: 7665311. DOI: 10.1126/science.abd5223. View