The presence of viral antigens, but not infectious virions, in the intestinal mucosa of patients with inflammatory bowel disease and long COVID

The Austrian authors conducted an endoscopy study in patients with inflammatory bowel disease (IBD) and a history of mild acute COVID-19, approximately 7.3 months after the first positive polymerase chain reaction (PCR) test. The findings revealed that viral antigens, but not infectious virions, were found in the intestinal mucosa of 70% of patients diagnosed with inflammatory bowel disease and symptoms of long COVID.

After more than two years since the global COVID-19 outbreak, it is clear that SARS-CoV-2 infection can lead to a new disease called postacute COVID syndrome or long COVID. The prevalence of postacute COVID is subject of considerable disagreement, ranging from 10% to 87%. The syndrome is now recognized as involving multiple organs, but there has been no significant advancement in understanding the underlying mechanism.

About the study

The researchers performed gastrointestinal endoscopy in a cohort of 46 patients with IBD and a history of PCR-confirmed SARS-CoV-2 infection. The procedure was done 94–257 days (on average, 7.3 months) following the SARS-CoV-2 infection, which was confirmed by PCR. All patients had a negative COVID-19 nasal or pharyngeal PCR test on the day of endoscopic examination. Postacute COVID was assessed using a standardized questionnaire.

The specimens were taken from the duodenum, terminal ileum, and colon, and the biopsy-derived tissue was phenotyped for SARS-CoV-2 antigen persistence and inflammatory bowel disease activity. The persistence of viral antigens in biopsy specimens from the small and large intestine was assessed using quantitative PCR (qPCR), immunofluorescence, and viral culture from gut tissue. The authors also evaluated gut inflammation by fecal calprotectin.


91% (42/46) of patients had mild acute COVID-19, and 45% (21/46) of them reported at least one postacute COVID symptom. The results showed that 70% (32/46) of patients with IBD and symptoms of long COVID had viral antigens in at least one segment of the gut (i.e., duodenum, ileum, or colon) approximately 7 months after acute COVID-19. 31% of patients (10/32) with positive SARS-CoV-2 RNA in the gut mucosa were not vaccinated.

Out of 32 patients, viral RNA was detected in one biopsy from 19 patients, two biopsies from 9 patients, and all three biopsies from 4 patients. 15/46 duodenal, 10/46 ileal, and 13/46 colonic samples had viral RNA.

The image from original text of Zollner et al.

The RNA-dependent RNA polymerase was detected in 13.6% of biopsy specimens, the spike glycoprotein in 11.4%, the nucleocapsid in 10.6%, and the envelope protein in 6.1% of specimens. There was a specific localization of nucleocapsid immunoreactivity to epithelial cells and, to a lesser extent, to CD8+ T cells within the epithelium and lamina propria. The stool of patients in this cohort did not contain SARS-CoV-2 antigens.

The presence of viral antigens was not related to the intestinal location or IBD activity, as indicated by fecal calprotectin. In addition, patients with and without immunosuppressive therapy (azathioprine, anti-TNF therapy, or vedolizumab) had persistent viral antigens.

The scientists then explored whether the persistence of viral antigens in the gut mucosa could be explained by SARS-CoV-2 replication. They homogenized biopsy-derived mucosal tissue from each of the 46 patients and then cocultured the lysate with ACE2 and TMPRSS2 overexpressing Vero cells. This system demonstrated a robust replication of SARS-CoV-2 in lysates obtained from nasal swabs of patients with symptomatic acute COVID-19. However, intestinal biopsy lysates from this cohort did not show evidence of replication. These findings suggest the presence of viral antigens, but not infectious virions, in the intestinal mucosa. Because the researchers couldn’t replicate the virus from biopsy-derived tissue, they concluded that viral antigen persistence reflects incomplete clearance of SARS-CoV-2 rather than subclinical (latent or persistent) infection.

Moreover, symptoms of postacute COVID were reported only by patients with gut antigen persistence (determined by qPCR). Patients without evidence of viral antigen persistence (n= 14) did not have symptoms of postacute COVID.

In summary, viral antigens, but not infectious virions, were detected in the intestinal mucosa of 70% of patients diagnosed with IBD and symptoms of long COVID in this study. According to the authors, the assumption that viral antigen persistence (in and outside the intestine) underlies the pathophysiology of postacute COVID warrants further clinical studies.

This article was published in Gastroenterology.

Journal Reference

Zollner A. et al. Postacute COVID-19 is Characterized by Gut Viral Antigen Persistence in Inflammatory Bowel Diseases. Gastroenterology 2022; 163: 495506.