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

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 ¼ 19) and uninfected control individuals (n ¼ 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 ¼ 634) and Europe (N ¼ 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. Highdimensional 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

COVID-19 Gastrointestinal Symptoms and Attenuation of the Immune Response to SARS-CoV-2

“…12 They attribute this finding to increased MUC2þ goblet cell prevalence in distal small intestine, which colocalized with NP immunostaining, and their transmission electron microscopy images showing viral particles present primarily in exit vesicles of goblet cells. 12 This finding may corroborate findings from bronchial air-liquid interface cultures demonstrating tropism for goblet cells, 13 but were nevertheless surprising given relatively low ACE2 expression in intestinal goblet cell clusters, 5 evidence of goblet cell depletion in an infected patient's colonic biopsies, 9 and data from human intestinal organoids demonstrating enterocytes were susceptible to infection whereas goblet cells were not. 6,11 Livanos et al 12 also find evidence of NP staining in a nongoblet crypt base cell population but do not discern this population as Paneth, stem cells, or another population.…”

“…The authors analyzed endoscopic biopsy specimens from COVID-19-afflicted patients, finding no gross abnormalities when compared with matched controls. 12 Although they found angiotensinconverting enzyme 2 (ACE2) diffusely expressed throughout the GI tract, viral NP was found more prominently in the ileum versus duodenum in the limited number of specimens studied. 12 They attribute this finding to increased MUC2þ goblet cell prevalence in distal small intestine, which colocalized with NP immunostaining, and their transmission electron microscopy images showing viral particles present primarily in exit vesicles of goblet cells.…”

“…12 Although they found angiotensinconverting enzyme 2 (ACE2) diffusely expressed throughout the GI tract, viral NP was found more prominently in the ileum versus duodenum in the limited number of specimens studied. 12 They attribute this finding to increased MUC2þ goblet cell prevalence in distal small intestine, which colocalized with NP immunostaining, and their transmission electron microscopy images showing viral particles present primarily in exit vesicles of goblet cells. 12 This finding may corroborate findings from bronchial air-liquid interface cultures demonstrating tropism for goblet cells, 13 but were nevertheless surprising given relatively low ACE2 expression in intestinal goblet cell clusters, 5 evidence of goblet cell depletion in an infected patient's colonic biopsies, 9 and data from human intestinal organoids demonstrating enterocytes were susceptible to infection whereas goblet cells were not.…”

“…In this issue of Gastroenterology, Livanos et al 12 attempt to correlate clinical observations in patients with COVID-19 with immunologic changes within the GI tract on histologic, transcriptomic, and proteomic levels. The authors analyzed endoscopic biopsy specimens from COVID-19-afflicted patients, finding no gross abnormalities when compared with matched controls.…”

The Role of IL-36 in Infectious Diseases: Potential Target for COVID-19?

“…Moreover, human basal lung epithelial cells exposed to poly(I:C) exhibited significant increase in protein concentrations of IL-36g (55). SARS-CoV-2 viral RNA and viral nucleocapsid protein can be detected in gastrointestinal tissues from the patients (93,94). This might be due to the highly expressed ACE2 in human gastrointestinal epithelial cells (95).…”