According to data from the World Health Organization (WHO) as of November 2023, the 2019 coronavirus disease (COVID-19) has resulted in over 770 million Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-COV-2) infections and more than 6.9 million deaths (Available online: https://covid19.who.int/). Unlike Middle East respiratory syndrome coronavirus (MERS-CoV) and seven other human coronaviruses (HCoVs), SARS-COV-2 exhibits genetic alterations, including the D614G mutation in the S1 subunit of the surface spiking protein and a modification in the Flynn protease cleavage site. These genetic changes notably contribute to the increased transmissibility of SARS-COV-2 and are associated with a spectrum of respiratory, gastrointestinal, and neurological manifestations, encompassing symptoms such as fever, cough, abdominal pain, diarrhea, as well as anosmia and ageusia. Clinical observations reveal that a significant proportion of SARS-COV-2 patients (80–90%) either remain asymptomatic or experience mild symptoms, thereby directing the treatment approach towards antiviral interventions such as antiviral drugs, neutralizing antibody therapy, Janus kinase inhibitors, and steroids (1–4), however, according to a retrospective study covering a 2- to 6-month recovery period from SARS-COV-2 infection, some patients were found to experience persistent disturbances in smell and taste, increased fatigue, chest pains, muscle pains, cognitive symptoms, and abdominal symptoms. Additionally, these individuals were observed to be at a higher risk of developing anxiety disorders, dementia, and Parkinson’s syndrome (5–7). Therefore, it is important to investigate whether COVID-19 has an effect on other systems in the body and to provide guidance for prevention and the development of effective therapeutic strategies.

In modern times, with the continuous improvement of living standards, the prevalence of smoking, alcohol consumption, and excessive nitrosamine intake among the population has increased. As a result, there has been a rise in the proportion of individuals affected by various esophageal diseases, including Barrett’s esophagus, esophagitis, esophageal ulcers, gastro-esophageal reflux disease, esophageal cancer, and other related disorders. This upward trend has been observed to occur annually (8–13). Additionally, in the context of the global SARS-COV-2 pandemic, there have been reports indicating that SARS-COV-2 can cause dysphagia, pancreatic achalasia, and esophagitis. Pertinently, it has been observed that SARS-COV-2 is capable of infecting esophageal cells through the expression of ACE2 and TMPRSS2, potentially contributing to the development of esophageal carcinogenesis (14–17). However, due to the current decrease in the number of diagnosed SARS-COV-2 patients (18), the definitive impact of SARS-COV-2 on various facets of esophageal disease remains elusive, and there is a lack of unequivocal studies establishing a causal link between COVID-19 and esophageal disease. Thus, it is valuable to investigate the potential causal relationship between SARS-COV-2 and various esophageal conditions, such as esophageal varices, esophagitis, Barrett’s esophagus, esophageal obstruction, esophageal ulcers, esophageal perforation, gastroesophageal reflux disease, congenital esophageal malformations, esophageal adenocarcinomas, and benign esophageal tumors. These investigations are of utmost importance for protecting the esophageal safety of individuals infected with SARS-COV-2.

In contrast to the causal conclusions drawn in retrospective studies, Mendelian randomization using single nucleotide polymorphisms (SNPs) as an instrumental variable can accurately reflect the causal relationship between exposures and outcomes. This is achieved through Mendelian randomization analyses that satisfy the criteria of independence, association, and exclusivity, effectively reducing the effects brought about by genetic variants and other confounding factors (19). In summary, the purpose of this paper is to investigate the potential causal relationship among critically ill COVID-19 patients, COVID-19 hospitalized and COVID-19 ambulatory patients, COVID-19 hospitalized patients and diagnosed COVID-19 patients, and ten distinct types of esophageal diseases. These diseases include esophageal varices, esophagitis, Barrett’s esophagus, esophageal obstruction, esophageal ulcers, esophageal perforation, gastroesophageal reflux disease, congenital esophageal malformations, esophageal adenocarcinomas, and benign esophageal tumors. This investigation will be conducted through the use of MR analysis. The ultimate objective is to provide valuable insights that can guide the prevention and treatment of esophageal diseases following infection with SARS-COV-2.

With the onset of the global COVID-19 pandemic, an increasing number of patients are clinically diagnosed with symptoms extending beyond the respiratory system. This can be attributed to the structural composition of the spike (S) protein of the SARS-CoV-2 virus, which comprises a lengthy N-terminal S1 subunit and a shorter C-terminal S2 subunit. These subunits serve as the primary functional components of the protein, with the S1 subunit predominantly engaging with the angiotensin-converting enzyme 2 (ACE2) receptor, which exhibits widespread expression across various tissues and organs of the human body. The interaction between the S1 subunit and the ACE2 receptor necessitates the activation of a serine protease known as TMPRSS2. This protease plays a crucial role in cleaving the S1 and S2 subunits of the S protein, thereby facilitating the binding of the separated S2 subunit to the host cells. Consequently, this binding allows for the entry of the SARS-CoV-2 virus into the host cells, subsequently triggering the release of replication-related substances within these cells. As a result, the virus further propagates and inflicts damage upon adjacent cells, perpetuating the cycle of infection and cellular injury (26–30). However, As the number of newly detected cases gradually decreases, it becomes increasingly challenging to ascertain the long-term effects of COVID-19 on a wide spectrum of diseases. Research has indicated that SARS-COV-2 can invade esophageal epithelial cells via the ACE2 receptor (31). Therefore, for the first time, we have used MR to explore the potential causal relationship between COVID-19 and esophageal diseases. This investigation aims to facilitate subsequent rehabilitation efforts for COVID-19-induced esophageal disorders.

Our research findings indicate potential causal links between COVID-19 and four esophageal diseases: esophagitis, esophageal obstruction, benign esophageal tumor, and congenital esophageal malformation. We found no evidence of genetic pleiotropy at the gene level of COVID-19 as an exposure to these esophageal diseases. Furthermore, there was no causal effect resulting from the presence of a single SNP driver, and no heterogeneity factors were found to influence the results. Our sensitivity analyses confirmed the robustness of these findings. We observed that genetic liability was associated with an increased risk of esophagitis in hospitalized COVID-19 patients compared to non-hospitalized COVID-19 patients (odds ratio [OR] [95% confidence interval]: 1.443859 [1.0890568–1.914252]; p-value = 0.01068201). Conversely, genetic liability was associated with a six-fold increased risk of congenital esophageal malformations in COVID-19 patients with SARS-CoV-2 infection (OR [95% CI]: 6.959561 [1.1955828–40.51204]; p-value = 0.03086835). Surprisingly, SARS-CoV-2 infection reduced the risk of esophageal obstruction by almost 50% (OR [95% CI]: 0.5275458 [0.2822400–0.9860563]; p-value = 0.0450699), and by as much as 72% for benign esophageal tumors (OR [95% CI]: 0.2715453 [0.09368493–0.7870724]; p-value = 0.0163510). However, there was a trend towards a significantly lower risk of congenital esophageal malformations for severe COVID-19 compared to mild COVID-19 (OR [95% CI]: 1.4425145 [0.9545951–2.179823]; p-value = 0.08196500). While these results did not reach statistical significance for the characteristics of the four types of COVID-19, they provide suggestive evidence. Hospitalization appears to be a risk factor for increased risk of esophagitis in COVID-19 patients, while it acts as a protective factor against esophageal obstruction and benign esophageal tumors. However, it may increase the risk of congenital esophageal malformations in offspring. Overall, our findings suggest that COVID-19 may cause varying degrees of damage to the esophagus through different invasive modes and the production of different cytokines. Additionally, it may unexpectedly have a protective effect on esophageal cells, indicating that the effects of COVID-19 on the esophagus are heterogeneous. For hospitalized patients, the severity of their COVID-19 is generally greater than that of COVID-19 patients who do not need to be hospitalized. Therefore, a larger amount of SARS-COV-2 is likely to invade esophageal mucosal cells via ACE2 receptors, leading to an escalating increase in the release of pro-inflammatory cytokines such as IL-1β, IL-1RA, IL-7, IL-8, IL-10, and IFN-γ, as well as the recruitment of macrophages and granulocytes from Th1 lymphocytes induced by SARS-COV-2. The levels of IL-10, IFN-γ, and the recruited macrophages and granulocytes will continue to rise, resulting in an imbalance in the ratio of Th1 to Th2 responses, which in turn triggers the release of anti-inflammatory factors such as IL-4, IL-10, and IL-13. Ultimately, this process leads to the production of a cytokine storm that exacerbates esophageal inflammation (32–34).

In COVID-19 patients, the effects of cytokines and macrophage recruitment induced by SARS-COV-2 lead to an increase in the number of macrophages in the esophageal smooth muscle. Additionally, prostaglandin E2 released from the receptor potential protein V4 (TRPV4) channel and CX3C chemokine receptor 1 (CX3CR1), expressed by macrophages, promote gastrointestinal (GI) smooth muscle peristalsis. Therefore, the substantial macrophage recruitment induced by SARS-COV-2 infection results in an increase in peristalsis of the esophageal smooth muscle, which is part of the GI smooth muscle, consequently enhancing esophageal motility and reducing the likelihood of esophageal obstruction (35), Additionally, acute inflammation of the esophagus caused by SARS-COV-2 infection of esophageal cells via the ACE2 receptor in the esophageal mucosa also accelerates the maturation of dendritic cells (DCs) and the cross-presentation of tumor antigens, initiating the activation of tumor-specific CD8+ T cells. This immune response polarizes various immune cells, including tumor-associated macrophages (TAMs), towards tumor suppression, thereby resisting the process of tumorigenesis and its progression. Consequently, this mechanism may be one of the reasons for the reduced risk of benign esophageal tumors. Thus, it provides a potential explanation for the observed decrease in the incidence of such tumors (36). Unlike esophageal obstruction and benign esophageal tumors, the risk of preeclampsia, preterm labor, and stillbirth is further elevated when the COVID-19 patient is a pregnant woman (37, 38), While esophageal atresia is among the most prominent defects observed in preterm infants with malformations, it is important to note that esophageal peristalsis is reliant on both central and peripheral vagal nerve pathways. Furthermore, the neurons located in the motor and sensory vagal nuclei of the brainstem are still in an immature state in preterm infants. This immaturity may be one of the factors contributing to the increased risk of congenital esophageal malformations (39, 40). The current treatments for COVID-19 encompass various therapeutic approaches, including nucleoside and nucleotide reverse transcriptase inhibitors, JAK1/JAK2 inhibitors, neutralizing monoclonal and polyclonal antibody therapies, as well as the administration of glucocorticosteroids such as dexamethasone and prednisone. These interventions are primarily targeted at reducing the cytokine storm induced by SARS-COV-2, thereby inhibiting the immune activation and inflammatory signaling it triggers. All of these therapeutic methods have demonstrated their ability to alleviate the clinical symptoms of COVID-19 in the respiratory system. However, further validation is needed to determine their efficacy in treating esophageal diseases (4).

Given that patients with COVID-19 present clinical symptoms of dysphagia and pancreatic achalasia, indicating a suggestive causal relationship between COVID-19 and the risk of esophageal disease that is not coincidental, we used univariate MR analysis for the first time to investigate this relationship. We fully adhered to the three assumptions required in MR analysis for instrumental variables (IVs), Considering that the IVW method is widely employed in two-sample Mendelian randomization (MR) studies and that its asymptotic standard error estimation of the causal ratio of the SNP excludes the intercept effect, enabling the exposure to offer a consistent estimate of its effect on the outcome, IVW demonstrates superior precision over MR-Egger and better accommodates between-study heterogeneity (20, 22, 41). Therefore, our MR analyses relied on IVW calculations. Notably, we found no evidence of heterogeneity for esophagitis, esophageal obstruction, benign esophageal tumors, and congenital esophageal malformations. Our study on the causality between COVID-19 and esophageal diseases was virtually unaffected by confounding and reverse causality when compared with traditional retrospective cohort studies. However, due to limitations in the available data sources, most of our studies were based on individuals of European ancestry, which may restrict the applicability of our findings to those of African and Asian ancestry. Furthermore, despite excluding confounders such as smoking, alcohol consumption, polyunsaturated fats, and inositol hexaphosphate, and employing supplementary methods like MR-Egger, Weighted, Simple mode, and Weighted mode to complement the IVW results, we cannot guarantee the complete elimination of pleiotropy. Therefore, a more extensive investigation using larger data resources is needed to delve deeper into the relationship between COVID-19 and esophageal diseases.

In conclusion, while the current clinical treatments for COVID-19 are primarily focused on its respiratory aspects, the potential long-term risks of esophagitis and congenital esophageal malformations should not be overlooked. Therefore, in the future, efforts should be directed towards developing a comprehensive health test for COVID-19 that encompasses multiple organs and systems. Additionally, there is a need for a more convenient viral load analysis method for SARS-CoV-2 to prevent the more serious consequences of COVID-19. These measures could help mitigate the severe outcomes of COVID-19.

Publicly available datasets were analyzed in this study. This data can be found here: summary‐level data of COVID‐19 GWAS are available at the COVID‐19 Host Genetics Initiative website (https://www.covid19hg.org/results/r7/). Data of esophageal diseases are available at the FinnGen databases (r8.finngen.fi) and GWAS Catalog (https://www.ebi.ac.uk/gwas/home).

Ethical approval was not required for the studies involving humans because summary‐level data of COVID‐19 GWAS are available at the COVID‐19 Host Genetics Initiative website (https://www.covid19hg.org/results/r7/). Data of esophageal diseases are available at the FinnGen databases (r8.finngen.fi) and GWAS Catalog. The studies were conducted in accordance with the local legislation and institutional requirements. The human samples used in this study were acquired from gifted from another research group. Written informed consent to participate in this study was not required from the participants or the participants’ legal guardians/next of kin in accordance with the national legislation and the institutional requirements.

XH: Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Resources, Software, Validation, Visualization, Writing – original draft. YL: Investigation, Visualization, Writing – original draft. JuL: Investigation, Visualization, Writing – original draft. GY: Writing – review & editing. XG: Writing – review & editing. GL: Formal analysis, Writing – original draft. LW: Visualization, Writing – original draft. GF: Visualization, Writing – original draft. JiL: Visualization, Writing – original draft. HZ: Funding acquisition, Project administration, Supervision, Writing – review & editing.