Rear Window—What Can the Gut Tell Us About Long-COVID?

Abstract

See “Postacute COVID-19 is characterized by gut viral antigen persistence in inflammatory bowel diseases,” by Zollner A, Koch R, Jukic A, et al, on page 495; and “Reduced replication efficacy of severe acute respiratory syndrome coronavirus 2 omicron variant in “mini-gut” organoids” by Miyakawa K, Machida M, Kawasaki T, et al, on page 514.While life-threatening acute coronavirus disease 2019 (COVID-19) is mostly linked to respiratory insufficiency or exacerbation of underlying comorbidity, up to 50% of patients with acute COVID-19 may experience mild to moderate gastrointestinal symptoms,1Lin L. Jiang X. Zhang Z. et al.Gastrointestinal symptoms of 95 cases with SARS-CoV-2 infection.Gut. 2020; 69: 997-1001Crossref PubMed Scopus (503) Google Scholar because intestinal cells are also prone to infection by severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) and widely express the viral entry receptor angiotensin-converting enzyme 2 (ACE2).2Xiao F. Tang M. Zheng X. et al.Evidence for gastrointestinal infection of SARS-CoV-2.Gastroenterology. 2020; 158: 1831-1833.e3Abstract Full Text Full Text PDF PubMed Scopus (1623) Google Scholar In this issue of Gastroenterology, two articles focus on the intestine and pressing issues in dealing with the COVID-19 pandemic.3Miyakawa K. Machida M. Kawasaki T. et al.Reduced replication efficacy of severe acute respiratory syndrome coronavirus 2 omicron variant in “mini-gut” organoids.Gastroenterology. 2022; 163: 514-516Abstract Full Text Full Text PDF Scopus (2) Google Scholar,4Zollner A. Koch R. Jukic A. et al.Post-acute COVID-19 is characterized by gut viral antigen persistence in inflammatory bowel diseases.Gastroenterology. 2022; 163: 495-506Abstract Full Text Full Text PDF Scopus (18) Google Scholar The article by Miyakawa et al3Miyakawa K. Machida M. Kawasaki T. et al.Reduced replication efficacy of severe acute respiratory syndrome coronavirus 2 omicron variant in “mini-gut” organoids.Gastroenterology. 2022; 163: 514-516Abstract Full Text Full Text PDF Scopus (2) Google Scholar addresses the direct infection of intestinal cells by SARS-CoV2. Gastrointestinal symptoms, including diarrhea, abdominal cramping, and pain, are frequently observed in patients with COVID-19,5Redd W.D. Zhou J.C. Hathorn K.E. et al.Prevalence and characteristics of gastrointestinal symptoms in patients with severe acute respiratory syndrome coronavirus 2 infection in the United States: a multicenter cohort study.Gastroenterology. 2020; 159: 765-767.e2Abstract Full Text Full Text PDF PubMed Scopus (179) Google Scholar, 6Pan L. Mu M. Yang P. et al.Clinical characteristics of COVID-19 patients with digestive symptoms in Hubei, China: a descriptive, cross-sectional, multicenter study.Am J Gastroenterol. 2020; 115: 766-773Crossref PubMed Scopus (955) Google Scholar, 7Dong Z.Y. Xiang B.J. Jiang M. et al.The prevalence of gastrointestinal symptoms, abnormal liver function, digestive system disease and liver disease in COVID-19 infection: a systematic review and meta-analysis.J Clin Gastroenterol. 2021; 55: 67-76Crossref PubMed Scopus (25) Google Scholar, 8Neurath M.F. COVID-19 and immunomodulation in IBD.Gut. 2020; 69: 1335-1342Crossref PubMed Scopus (162) Google Scholar possibly due to direct infection of the intestinal cells. In fact, stomach cells and epithelial cells of the small and large intestine have been shown to express ACE2 and the coreceptor transmembrane protease, serine 2 (TMPRSS2),2Xiao F. Tang M. Zheng X. et al.Evidence for gastrointestinal infection of SARS-CoV-2.Gastroenterology. 2020; 158: 1831-1833.e3Abstract Full Text Full Text PDF PubMed Scopus (1623) Google Scholar,9Patankar J.V. Chiriac M.T. Lehmann M. et al.Severe acute respiratory syndrome coronavirus 2 attachment receptor angiotensin-converting enzyme 2 is decreased in Crohn’s disease and regulated by microbial and inflammatory signaling.Gastroenterology. 2021; 160: 925-928.e4Abstract Full Text Full Text PDF PubMed Scopus (7) Google Scholar,10Hoffmann M. Kleine-Weber H. Schroeder S. et al.SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor.Cell. 2020; 181: 271-280Abstract Full Text Full Text PDF PubMed Scopus (10278) Google Scholar underlining the possibility that these cells are directly targeted by SARS–CoV2.The possibility that gastrointestinal cells are infected by SARS–CoV2 was previously demonstrated by studies in intestinal organoids. These studies showed that SARS-CoV2 infection may cause direct infection of epithelial cells, followed by production of infectious viral particles.11Lamers M.M. Beumer J. van der Vaart J. et al.SARS-CoV-2 productively infects human gut enterocytes.Science. 2020; 369: 50-54Crossref PubMed Scopus (887) Google Scholar However, the question about potential differences in gastrointestinal infection due to variants of the virus remained to be investigated. In this issue, Miyakawa et al3Miyakawa K. Machida M. Kawasaki T. et al.Reduced replication efficacy of severe acute respiratory syndrome coronavirus 2 omicron variant in “mini-gut” organoids.Gastroenterology. 2022; 163: 514-516Abstract Full Text Full Text PDF Scopus (2) Google Scholar now make use of mini-guts as tools to study cell-type specific replication behavior of novel variants of potential concern. Other studies had previously observed altered cell-type specific viral replication efficacies of B.1.529/ Omicron BA.1 compared with B.1.617.2/Delta in lower airway organoids, while upper airway replication was increased.12Hui K.P.Y. Ho J.C.W. Cheung M.C. et al.SARS-CoV-2 Omicron variant replication in human bronchus and lung ex vivo.Nature. 2022; 603: 715-720Crossref PubMed Scopus (144) Google Scholar,13Meng B. Abdullahi A. Ferreira I. et al.Altered TMPRSS2 usage by SARS-CoV-2 Omicron impacts infectivity and fusogenicity.Nature. 2022; 603: 706-714Crossref PubMed Scopus (157) Google ScholarExtending these findings, Miyakawa et al3Miyakawa K. Machida M. Kawasaki T. et al.Reduced replication efficacy of severe acute respiratory syndrome coronavirus 2 omicron variant in “mini-gut” organoids.Gastroenterology. 2022; 163: 514-516Abstract Full Text Full Text PDF Scopus (2) Google Scholar now show reduced viral replication efficacy of Omicron BA.1 and BA.2 compared with the B.1.617.2/Delta variant. This interesting observation correlated to less cell damage as well as to reduced lactose dehydrogenase and high mobility group box 1 protein (HMGB1) release, induced by BA.1 and BA.2. It will be important to follow epidemiology and gastrointestinal symptomatology of the current Omicron wave to assess whether this translates to clinically observed reductions in gastrointestinal symptoms associated to Omicron infection.For many patients, COVID-19 has been a transient acute illness. However, persistence of symptoms and newly occurring signs of disease not attributable to other causes have emerged in others and lead to an ongoing need to characterize epidemiology, natural history, pathophysiology, diagnosis, and treatment of the phenomenon of post-COVID-19 syndrome, also called post-COVID conditions, long-COVID, postacute COVID-19, or chronic COVID.14Nalbandian A. Sehgal K. Gupta A. et al.Post-acute COVID-19 syndrome.Nat Med. 2021; 27: 601-615Crossref PubMed Scopus (1186) Google Scholar In addition, it has been observed that the burden of cardiovascular comorbidities is increased in COVID-19 survivors and remains elevated up to 1 year compared with historical control populations,15Xie Y. Xu E. Bowe B. et al.Long-term cardiovascular outcomes of COVID-19.Nat Med. 2022; 28: 583-590Crossref PubMed Scopus (166) Google Scholar even in patients not hospitalized during acute disease.There remains an incomplete understanding of the pathophysiology of post-COVID-19 syndrome. Different hypotheses can be formulated to explain ongoing symptoms in the postacute phase:1.Tissue damage that occurred during acute COVID-19 as a result of direct viral toxicity, vessel injury, microthrombosis or macrothrombosis, and ongoing or incomplete healing processes might cause persistent symptoms.16Ackermann M. Verleden S.E. Kuehnel M. et al.Pulmonary vascular endothelialitis, thrombosis, and angiogenesis in Covid-19.N Engl J Med. 2020; 383: 120-128Crossref PubMed Scopus (2910) Google Scholar,17Leppkes M. Knopf J. Naschberger E. et al.Vascular occlusion by neutrophil extracellular traps in COVID-19.EBioMedicine. 2020; 58102925Abstract Full Text Full Text PDF PubMed Scopus (220) Google Scholar2.Incomplete viral clearance and persistent low-level viral replication or continued presence of viral antigens in specialized niches of the body might affect recovery.3.Autoimmune attacks instigated by the immune response to SARS-CoV2 might cause ongoing damage to specific tissues.4.Increased body awareness and the perceived association of diffuse symptoms to COVID might spike reporting of symptoms that usually would remain unnoted by health care providers.5.Consequences of aggressive therapy—especially in the setting of postcritical illness—might contribute to prolonged or incomplete recovery.Fecal shedding of viral RNA has been observed to persist longer than oropharyngeal shedding of SARS-CoV2,18Du W. Yu J. Liu X. et al.Persistence of SARS-CoV-2 virus RNA in feces: a case series of children.J Infect Public Health. 2020; 13: 926-931Crossref PubMed Scopus (27) Google Scholar,19Natarajan A. Zlitni S. Brooks E.F. et al.Gastrointestinal symptoms and fecal shedding of SARS-CoV-2 RNA suggest prolonged gastrointestinal infection.Med (N Y). 2022; 3: 371-387.e9Scopus (23) Google Scholar putting the gastrointestinal tract into the focus of the study of postacute sequelae of COVID-19. In this issue, Zollner et al4Zollner A. Koch R. Jukic A. et al.Post-acute COVID-19 is characterized by gut viral antigen persistence in inflammatory bowel diseases.Gastroenterology. 2022; 163: 495-506Abstract Full Text Full Text PDF Scopus (18) Google Scholar describe substantial novel scientific arguments to this debate by demonstrating persistence of viral antigens in the colon as long as 257 days after initial virus detection, even in the absence of persistent fecal shedding. They made use of various detection methods, including detection of viral RNA by quantitative polymerase chain reaction (RNA-dependent RNA polymerase, nucleocapsid, spike, and envelope proteins) as well as immunofluorescence of colonic biopsy specimens (nucleocapsid protein). They included 46 patients in Austria with inflammatory bowel disease (IBD) who had also experienced a SARS-CoV2 infection from October 2020 to February 2021.During scheduled routine colonoscopy for control of IBD activity, the study team took tissue samples, and patients who were experiencing ongoing COVID-related symptoms were compared with those with a complete symptom resolution. Interestingly, the authors found persistence of viral antigens in many intestinal tissue samples. Persistence of viral antigen was strongly associated to ongoing symptoms in this study cohort. Owing to the selection of the study cohort, whether these findings are limited to patients with IBD currently remains unclear.9Patankar J.V. Chiriac M.T. Lehmann M. et al.Severe acute respiratory syndrome coronavirus 2 attachment receptor angiotensin-converting enzyme 2 is decreased in Crohn’s disease and regulated by microbial and inflammatory signaling.Gastroenterology. 2021; 160: 925-928.e4Abstract Full Text Full Text PDF PubMed Scopus (7) Google Scholar However, Natarajan et al19Natarajan A. Zlitni S. Brooks E.F. et al.Gastrointestinal symptoms and fecal shedding of SARS-CoV-2 RNA suggest prolonged gastrointestinal infection.Med (N Y). 2022; 3: 371-387.e9Scopus (23) Google Scholar reported the association of persistent viral shedding to persistent gastrointestinal symptoms in a general population.On the basis of the current evidence, an IBD-related effect thus seems rather unlikely, although one cannot exclude the possibility that effects on viral persistence in patients with IBD are more pronounced due to IBD-related changes of intestinal epithelial cells or accompanying medication (eg, corticosteroid use). Furthermore, whether prolonged persistence of viral components is gut-specific remains unclear. Prolonged detection of viral RNA in feces compared with oropharyngeal swabs does not at all prove an organ-restricted effect. Fecal RNA can be seen as the integral of the entire gastrointestinal tract rather than the direct shedding of the oropharyngeal swab content, and gastrointestinal tissue samples as in the current study are far more easily accessible than lower airway samples.Taken together, the reported findings by Zollner et al4Zollner A. Koch R. Jukic A. et al.Post-acute COVID-19 is characterized by gut viral antigen persistence in inflammatory bowel diseases.Gastroenterology. 2022; 163: 495-506Abstract Full Text Full Text PDF Scopus (18) Google Scholar do not directly prove the functional role of persisting viral antigens as causative for persistent symptoms or the specificity of the gut as a reservoir of viral antigens. However, this report makes an important contribution to the field by showing that persistent viral antigens in the intestine are present in patients with long-COVID and may play a key role the pathogenesis of post-COVID symptoms.Further studies are clearly needed to further define the molecular mechanisms of post-COVID conditions. However, the ease of tissue sampling in the gut could potentially guide further studies of immunologic mechanisms of prolonged persistence in the context of postacute COVID-19. Colonoscopy thus provides an unexpected “rear window" to the mystery of post-COVID syndrome and provides an easily accessible way to detect viral persistence. See “Postacute COVID-19 is characterized by gut viral antigen persistence in inflammatory bowel diseases,” by Zollner A, Koch R, Jukic A, et al, on page 495; and “Reduced replication efficacy of severe acute respiratory syndrome coronavirus 2 omicron variant in “mini-gut” organoids” by Miyakawa K, Machida M, Kawasaki T, et al, on page 514. See “Postacute COVID-19 is characterized by gut viral antigen persistence in inflammatory bowel diseases,” by Zollner A, Koch R, Jukic A, et al, on page 495; and “Reduced replication efficacy of severe acute respiratory syndrome coronavirus 2 omicron variant in “mini-gut” organoids” by Miyakawa K, Machida M, Kawasaki T, et al, on page 514. See “Postacute COVID-19 is characterized by gut viral antigen persistence in inflammatory bowel diseases,” by Zollner A, Koch R, Jukic A, et al, on page 495; and “Reduced replication efficacy of severe acute respiratory syndrome coronavirus 2 omicron variant in “mini-gut” organoids” by Miyakawa K, Machida M, Kawasaki T, et al, on page 514. While life-threatening acute coronavirus disease 2019 (COVID-19) is mostly linked to respiratory insufficiency or exacerbation of underlying comorbidity, up to 50% of patients with acute COVID-19 may experience mild to moderate gastrointestinal symptoms,1Lin L. Jiang X. Zhang Z. et al.Gastrointestinal symptoms of 95 cases with SARS-CoV-2 infection.Gut. 2020; 69: 997-1001Crossref PubMed Scopus (503) Google Scholar because intestinal cells are also prone to infection by severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) and widely express the viral entry receptor angiotensin-converting enzyme 2 (ACE2).2Xiao F. Tang M. Zheng X. et al.Evidence for gastrointestinal infection of SARS-CoV-2.Gastroenterology. 2020; 158: 1831-1833.e3Abstract Full Text Full Text PDF PubMed Scopus (1623) Google Scholar In this issue of Gastroenterology, two articles focus on the intestine and pressing issues in dealing with the COVID-19 pandemic.3Miyakawa K. Machida M. Kawasaki T. et al.Reduced replication efficacy of severe acute respiratory syndrome coronavirus 2 omicron variant in “mini-gut” organoids.Gastroenterology. 2022; 163: 514-516Abstract Full Text Full Text PDF Scopus (2) Google Scholar,4Zollner A. Koch R. Jukic A. et al.Post-acute COVID-19 is characterized by gut viral antigen persistence in inflammatory bowel diseases.Gastroenterology. 2022; 163: 495-506Abstract Full Text Full Text PDF Scopus (18) Google Scholar The article by Miyakawa et al3Miyakawa K. Machida M. Kawasaki T. et al.Reduced replication efficacy of severe acute respiratory syndrome coronavirus 2 omicron variant in “mini-gut” organoids.Gastroenterology. 2022; 163: 514-516Abstract Full Text Full Text PDF Scopus (2) Google Scholar addresses the direct infection of intestinal cells by SARS-CoV2. Gastrointestinal symptoms, including diarrhea, abdominal cramping, and pain, are frequently observed in patients with COVID-19,5Redd W.D. Zhou J.C. Hathorn K.E. et al.Prevalence and characteristics of gastrointestinal symptoms in patients with severe acute respiratory syndrome coronavirus 2 infection in the United States: a multicenter cohort study.Gastroenterology. 2020; 159: 765-767.e2Abstract Full Text Full Text PDF PubMed Scopus (179) Google Scholar, 6Pan L. Mu M. Yang P. et al.Clinical characteristics of COVID-19 patients with digestive symptoms in Hubei, China: a descriptive, cross-sectional, multicenter study.Am J Gastroenterol. 2020; 115: 766-773Crossref PubMed Scopus (955) Google Scholar, 7Dong Z.Y. Xiang B.J. Jiang M. et al.The prevalence of gastrointestinal symptoms, abnormal liver function, digestive system disease and liver disease in COVID-19 infection: a systematic review and meta-analysis.J Clin Gastroenterol. 2021; 55: 67-76Crossref PubMed Scopus (25) Google Scholar, 8Neurath M.F. COVID-19 and immunomodulation in IBD.Gut. 2020; 69: 1335-1342Crossref PubMed Scopus (162) Google Scholar possibly due to direct infection of the intestinal cells. In fact, stomach cells and epithelial cells of the small and large intestine have been shown to express ACE2 and the coreceptor transmembrane protease, serine 2 (TMPRSS2),2Xiao F. Tang M. Zheng X. et al.Evidence for gastrointestinal infection of SARS-CoV-2.Gastroenterology. 2020; 158: 1831-1833.e3Abstract Full Text Full Text PDF PubMed Scopus (1623) Google Scholar,9Patankar J.V. Chiriac M.T. Lehmann M. et al.Severe acute respiratory syndrome coronavirus 2 attachment receptor angiotensin-converting enzyme 2 is decreased in Crohn’s disease and regulated by microbial and inflammatory signaling.Gastroenterology. 2021; 160: 925-928.e4Abstract Full Text Full Text PDF PubMed Scopus (7) Google Scholar,10Hoffmann M. Kleine-Weber H. Schroeder S. et al.SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor.Cell. 2020; 181: 271-280Abstract Full Text Full Text PDF PubMed Scopus (10278) Google Scholar underlining the possibility that these cells are directly targeted by SARS–CoV2. The possibility that gastrointestinal cells are infected by SARS–CoV2 was previously demonstrated by studies in intestinal organoids. These studies showed that SARS-CoV2 infection may cause direct infection of epithelial cells, followed by production of infectious viral particles.11Lamers M.M. Beumer J. van der Vaart J. et al.SARS-CoV-2 productively infects human gut enterocytes.Science. 2020; 369: 50-54Crossref PubMed Scopus (887) Google Scholar However, the question about potential differences in gastrointestinal infection due to variants of the virus remained to be investigated. In this issue, Miyakawa et al3Miyakawa K. Machida M. Kawasaki T. et al.Reduced replication efficacy of severe acute respiratory syndrome coronavirus 2 omicron variant in “mini-gut” organoids.Gastroenterology. 2022; 163: 514-516Abstract Full Text Full Text PDF Scopus (2) Google Scholar now make use of mini-guts as tools to study cell-type specific replication behavior of novel variants of potential concern. Other studies had previously observed altered cell-type specific viral replication efficacies of B.1.529/ Omicron BA.1 compared with B.1.617.2/Delta in lower airway organoids, while upper airway replication was increased.12Hui K.P.Y. Ho J.C.W. Cheung M.C. et al.SARS-CoV-2 Omicron variant replication in human bronchus and lung ex vivo.Nature. 2022; 603: 715-720Crossref PubMed Scopus (144) Google Scholar,13Meng B. Abdullahi A. Ferreira I. et al.Altered TMPRSS2 usage by SARS-CoV-2 Omicron impacts infectivity and fusogenicity.Nature. 2022; 603: 706-714Crossref PubMed Scopus (157) Google Scholar Extending these findings, Miyakawa et al3Miyakawa K. Machida M. Kawasaki T. et al.Reduced replication efficacy of severe acute respiratory syndrome coronavirus 2 omicron variant in “mini-gut” organoids.Gastroenterology. 2022; 163: 514-516Abstract Full Text Full Text PDF Scopus (2) Google Scholar now show reduced viral replication efficacy of Omicron BA.1 and BA.2 compared with the B.1.617.2/Delta variant. This interesting observation correlated to less cell damage as well as to reduced lactose dehydrogenase and high mobility group box 1 protein (HMGB1) release, induced by BA.1 and BA.2. It will be important to follow epidemiology and gastrointestinal symptomatology of the current Omicron wave to assess whether this translates to clinically observed reductions in gastrointestinal symptoms associated to Omicron infection. For many patients, COVID-19 has been a transient acute illness. However, persistence of symptoms and newly occurring signs of disease not attributable to other causes have emerged in others and lead to an ongoing need to characterize epidemiology, natural history, pathophysiology, diagnosis, and treatment of the phenomenon of post-COVID-19 syndrome, also called post-COVID conditions, long-COVID, postacute COVID-19, or chronic COVID.14Nalbandian A. Sehgal K. Gupta A. et al.Post-acute COVID-19 syndrome.Nat Med. 2021; 27: 601-615Crossref PubMed Scopus (1186) Google Scholar In addition, it has been observed that the burden of cardiovascular comorbidities is increased in COVID-19 survivors and remains elevated up to 1 year compared with historical control populations,15Xie Y. Xu E. Bowe B. et al.Long-term cardiovascular outcomes of COVID-19.Nat Med. 2022; 28: 583-590Crossref PubMed Scopus (166) Google Scholar even in patients not hospitalized during acute disease. There remains an incomplete understanding of the pathophysiology of post-COVID-19 syndrome. Different hypotheses can be formulated to explain ongoing symptoms in the postacute phase:1.Tissue damage that occurred during acute COVID-19 as a result of direct viral toxicity, vessel injury, microthrombosis or macrothrombosis, and ongoing or incomplete healing processes might cause persistent symptoms.16Ackermann M. Verleden S.E. Kuehnel M. et al.Pulmonary vascular endothelialitis, thrombosis, and angiogenesis in Covid-19.N Engl J Med. 2020; 383: 120-128Crossref PubMed Scopus (2910) Google Scholar,17Leppkes M. Knopf J. Naschberger E. et al.Vascular occlusion by neutrophil extracellular traps in COVID-19.EBioMedicine. 2020; 58102925Abstract Full Text Full Text PDF PubMed Scopus (220) Google Scholar2.Incomplete viral clearance and persistent low-level viral replication or continued presence of viral antigens in specialized niches of the body might affect recovery.3.Autoimmune attacks instigated by the immune response to SARS-CoV2 might cause ongoing damage to specific tissues.4.Increased body awareness and the perceived association of diffuse symptoms to COVID might spike reporting of symptoms that usually would remain unnoted by health care providers.5.Consequences of aggressive therapy—especially in the setting of postcritical illness—might contribute to prolonged or incomplete recovery. Fecal shedding of viral RNA has been observed to persist longer than oropharyngeal shedding of SARS-CoV2,18Du W. Yu J. Liu X. et al.Persistence of SARS-CoV-2 virus RNA in feces: a case series of children.J Infect Public Health. 2020; 13: 926-931Crossref PubMed Scopus (27) Google Scholar,19Natarajan A. Zlitni S. Brooks E.F. et al.Gastrointestinal symptoms and fecal shedding of SARS-CoV-2 RNA suggest prolonged gastrointestinal infection.Med (N Y). 2022; 3: 371-387.e9Scopus (23) Google Scholar putting the gastrointestinal tract into the focus of the study of postacute sequelae of COVID-19. In this issue, Zollner et al4Zollner A. Koch R. Jukic A. et al.Post-acute COVID-19 is characterized by gut viral antigen persistence in inflammatory bowel diseases.Gastroenterology. 2022; 163: 495-506Abstract Full Text Full Text PDF Scopus (18) Google Scholar describe substantial novel scientific arguments to this debate by demonstrating persistence of viral antigens in the colon as long as 257 days after initial virus detection, even in the absence of persistent fecal shedding. They made use of various detection methods, including detection of viral RNA by quantitative polymerase chain reaction (RNA-dependent RNA polymerase, nucleocapsid, spike, and envelope proteins) as well as immunofluorescence of colonic biopsy specimens (nucleocapsid protein). They included 46 patients in Austria with inflammatory bowel disease (IBD) who had also experienced a SARS-CoV2 infection from October 2020 to February 2021. During scheduled routine colonoscopy for control of IBD activity, the study team took tissue samples, and patients who were experiencing ongoing COVID-related symptoms were compared with those with a complete symptom resolution. Interestingly, the authors found persistence of viral antigens in many intestinal tissue samples. Persistence of viral antigen was strongly associated to ongoing symptoms in this study cohort. Owing to the selection of the study cohort, whether these findings are limited to patients with IBD currently remains unclear.9Patankar J.V. Chiriac M.T. Lehmann M. et al.Severe acute respiratory syndrome coronavirus 2 attachment receptor angiotensin-converting enzyme 2 is decreased in Crohn’s disease and regulated by microbial and inflammatory signaling.Gastroenterology. 2021; 160: 925-928.e4Abstract Full Text Full Text PDF PubMed Scopus (7) Google Scholar However, Natarajan et al19Natarajan A. Zlitni S. Brooks E.F. et al.Gastrointestinal symptoms and fecal shedding of SARS-CoV-2 RNA suggest prolonged gastrointestinal infection.Med (N Y). 2022; 3: 371-387.e9Scopus (23) Google Scholar reported the association of persistent viral shedding to persistent gastrointestinal symptoms in a general population. On the basis of the current evidence, an IBD-related effect thus seems rather unlikely, although one cannot exclude the possibility that effects on viral persistence in patients with IBD are more pronounced due to IBD-related changes of intestinal epithelial cells or accompanying medication (eg, corticosteroid use). Furthermore, whether prolonged persistence of viral components is gut-specific remains unclear. Prolonged detection of viral RNA in feces compared with oropharyngeal swabs does not at all prove an organ-restricted effect. Fecal RNA can be seen as the integral of the entire gastrointestinal tract rather than the direct shedding of the oropharyngeal swab content, and gastrointestinal tissue samples as in the current study are far more easily accessible than lower airway samples. Taken together, the reported findings by Zollner et al4Zollner A. Koch R. Jukic A. et al.Post-acute COVID-19 is characterized by gut viral antigen persistence in inflammatory bowel diseases.Gastroenterology. 2022; 163: 495-506Abstract Full Text Full Text PDF Scopus (18) Google Scholar do not directly prove the functional role of persisting viral antigens as causative for persistent symptoms or the specificity of the gut as a reservoir of viral antigens. However, this report makes an important contribution to the field by showing that persistent viral antigens in the intestine are present in patients with long-COVID and may play a key role the pathogenesis of post-COVID symptoms. Further studies are clearly needed to further define the molecular mechanisms of post-COVID conditions. However, the ease of tissue sampling in the gut could potentially guide further studies of immunologic mechanisms of prolonged persistence in the context of postacute COVID-19. Colonoscopy thus provides an unexpected “rear window" to the mystery of post-COVID syndrome and provides an easily accessible way to detect viral persistence. Reduced Replication Efficacy of Severe Acute Respiratory Syndrome Coronavirus 2 Omicron Variant in “Mini-gut” OrganoidsGastroenterologyVol. 163Issue 2PreviewOver 480 million infections and 6 million deaths have been recorded since the novel coronavirus disease 2019 pandemic began over 2 years ago. Coronavirus disease 2019 is principally a respiratory illness caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which infects the cells of the airway and can also replicate in the gastrointestinal tract. Notably, over half of those with SARS-CoV-2 infections shed SARS-CoV-2 genomes in their stool,1 and infectious viruses can be isolated from their fecal samples,2 suggesting that the virus also infects and replicates in the intestinal tract. Full-Text PDF Open AccessPostacute COVID-19 is Characterized by Gut Viral Antigen Persistence in Inflammatory Bowel DiseasesGastroenterologyVol. 163Issue 2PreviewPost-acute COVID-19 is a rapidly growing health-care challenge across the globe. This study identifies that postacute COVID-19 is accompanied by viral antigen persistence in the gut from patients with inflammatory bowel diseases. Full-Text PDF