The mechanism by why COVID-19 affects the digestive organs is not yet fully understood. However, several hypotheses have been proposed to explain the various gastrointestinal and hepatobiliary manifestations of COVID-19. SARS-CoV-2 has a spike protein on its surface. The enzyme protease cleaves the spike protein to bind to the angiotensin-converting enzyme 2 (ACE2) receptor on the surface of the infected cell, thereby causing infection [3,4]. Li et al. demonstrated that the liver and colon, as well as lung, exhibited a medium ACE2 expression level, while the small intestine displayed the highest ACE2 expression [5]. It remains unclear whether the differences in ACE2 expression between organs are associated with the corresponding symptoms of COVID-19. However, the interaction of the virus with ACE2 may lead to the production of inflammatory cytokines and disruption of the mucous membrane barrier [6]. The other hypothesis is that of an intestinal microbiome dysbiosis. Yeoh et al. investigated the significant alteration of gut microbiome composition in patients with COVID-19 [7]. They demonstrated a reduction in the number of Bifido-bacterium adolescentis, Faecalibacterium prausnitzii, and Eubacterium rectale, gut bacteria known to influence immune response. The dysbiotic gut microbiota that persists after disease resolution may be a factor in developing persistent symptoms and/or systemic inflammatory syndromes in some patients.

The World Health Organization defines long COVID as post-COVID-19 condition that occurs in indivisuals with a history or probable or confirmed SARS-CoV-2 infection, usually 3 months from the onset of COVID-19 with symptoms that last for at least 2 months and cannot be explained by an alternative diagnosis [8]. These post-COVID-19 condition could impact quality of life, psychological health and ability to work. A recent meta-analysis showed a statistical result of approximately 22% for gastrointestinal manifestations in individuals with long-COVID, based on data from 50 studies [9]. However, meta-analysis has been limited by several factors, including the lack of representative data sources, the absence of a comparable control group without COVID-19, and significant heterogeneity. The previous study by Xu et al. analyzed approximately 14 million de-identified medical records in a database maintained by the U.S. Department of Veterans Affairs, the nation’s largest integrated healthcare system. A controlled data set of 154,068 individuals who had tested positive for COVID-19 was used to compare gastrointestinal outcomes through statistical modelling. A total of 12 diagnostic codes and laboratory abnormalities in the data set of COVID-19 individuals were compared with two other groups of people not infected with the virus [10].

In this issue of Clinical and Molecular Hepatology, Lee et al. demonstrated that the incidence of gastrointestinal disease, hepatobiliary disease, and other digestive abnormalities increased in patients with SARS-CoV-2 infection during the post-acute phase [11]. It has a strength of showing the long-term gastrointestinal and hepatobiliary outcomes of COVID-19 by analyzing the effect across a time span to reduce the risk of reverse causation and including external validation. Validation in national cohorts from Japan and the UK was conducted to enhance reliability and offset potential issues with diagnosis codes. This study attempted to analyze the impact of post-COVID-19 on the digestive organ using a more diverse disease code (ICD code for 17 gastrointestinal disease, 8 hepatobiliary disease, and 9 other digestive abnormalities) to overcome the limitations of population-based cohorts. However, the data from the three nation cohorts exhibited disparate hazard ratios, particularly those from the Japanese cohort, which demonstrated an elevated risk for all disease codes in patients with COVID-19. The data from the Korean cohort indicated that functional intestinal disorders, abdominal pain, and heartburn, which have been previously identified as gastrointestinal diseases, were relatively uncommon. Moreover, the risk profile was not sustained after a three-month period compared with that in validation cohorts, suggesting the potential for misclassification or loss, whereby individuals with a disease were not assigned a disease code [9,10,12]. This is a limitation of a research based on population-based cohorts that is difficult to overcome even when robust methodology and extensive analysis are employed. Consequently, further studies, including prospective studies, are necessary to address these limitations.

Lee and colleagues presented that the SARS-CoV-2 vaccination was associated with a reduced risk of gastrointestinal disease. However, no impact on hepatobiliary disease or other digestive disorders was observed in the South Korean cohort, and the vaccination status was not available in the validation cohort, so it may be lacking in evidence to conclude from this study that vaccination can lower the risk of gastrointestinal disease as well as prevent SARS-CoV-2 infection. A number of recent studies have reported a favourable impact of SARS-CoV-2 vaccination on gastrointestinal symptoms following COVID-19, despite the existence of case reports and small-scale studies indicating that vaccination might cause gastrointestinal complications [13-15]. Fischer et al. investigated the effect of SARSCoV-2 vaccination for gastrointestinal symptoms associated with the post-COVID-19 condition [13]. This study employed a comparative approach to examine the immune responses to COVID-19 vaccination in two distinct groups: a group of 20 SARS-CoV-2 native healthcare workers and the other group of 540 individuals with varying infection histories and known post-COVID condition. The analysis demonstrated that those with ongoing post-COVID symptoms who had received the vaccination exhibited diminished IL-1β and IL-18 levels, along with a reduction in gastrointestinal symptoms.

Immunocompromised patients were more concerned about the management and the safety of SARS-CoV-2 vaccination during the ongoing COVID-19 pandemic. Bidirectional interactions between the immune system and the gut microbiota are key contributors to various physiological functions. It has been demonstrated that COVID-19 has been shown to cause microbial dysbiosis [7]. It is therefore important to ascertain whether the inflammatory response associated with SARS-CoV-2 vaccination impacts the microbiota. A recent study has showed that the gut microbiome is resilience to host immune changes triggered by vaccination. This suggests that there is minimal, if any, impact on microbiome-mediated processes [14]. A meta-analysis showed that COVID-19 vaccination in patients with inflammatory bowel disease (IBD) appears to be safe [15]. Furthermore, the position statement endorsed by the British Society of Gastroenterology IBD section and IBD clinical Research Group strongly supports SARS-CoV-2 vaccination for patients with IBD [16]. A multicenter cross-sectional study in China investigated the protective efficacy of SARS-CoV-2 vaccination against the new onset gastrointestinal symptoms. A study following 537 patients with IBD after receiving the vaccine showed that the group had received three vaccination doses was associated with a 44% reduction in gastrointestinal symptoms after injection compared with the unvaccinated [17]. These results support the conclusion that SARS-CoV-2 vaccination, even for immunocompromised individuals, is relatively safe and can relieve gastrointestinal manifestations during post-COVID. Therefore, vaccination should not be hindered.

Post-COVID-19 conditions remain a global public health problem. The principle conclusion of this study is that physicians, including gastroenterologists, should be aware that COVID-19 can result in prolonged gastrointestinal and hepatobiliary complications. In the situation of persistent symptoms for which the underlying cause remains undetermined, the patient may feel anxiety. Physicians can understand the patient’s symptoms and avoid unnecessary testing when they are aware of the potential for post-COVID-19 condition and have access to a comprehensive medical history.

Despite the numerous studies related to COVID-19 that have been conducted over the years, the complexity of symptoms and numerous other variables require further investigation into post-COVID -19 condition. The implementation of effective management strategies for post-COVID-19 can facilitate an improvement in patients’ work performance, psychological well-being, and quality of life.