ABSTRACT
Introduction: Since 2020 COVID-19 pandemic has spread throughout the world and became an ongoing global health crisis due to SARS-CoV-2 virus. Elderly and pre-existing disorders including hypertension, heart problems, diabetes, cancer, autoimmune diseases and IBD are found associated with an increased risk of COVID-19. Although COVID-19 leads to mild flu-like symptoms in the majority of patients, the disease may cause severe complications and death. To date, a few clinical studies suggested that IBD and/or immunomodulation may reduce the susceptibility to COVID-19;however, the mechanisms through which this is happening is largely unknown. Aims & Methods: Aim of this study is to investigate the effects of IBD and different therapies on the risk of SARS-CoV-2 infection and COVID-19 severity through serum proteomics and metabolomics. Between April 2020 and April 2022, 238 IBD patients (N=145 Crohn disease, N=93 Ulcerative colitis) and 45 healthy controls (HC) of the North Italy area were enrolled and serum samples were collected. To evaluate the exposure to SARSCoV- 2, both clinical data were collected and seroprevalence of anti-SARSCoV- 2 Ab were analyzed by means of multiplex technology, the BioPlex 2200 Sars-Cov-2 IgG Panel (biorad, Italy). Serum samples underwent untargeted metabolomics analysis and the frequency of a serum metabolomics signature associated with protection were evaluated in IBD compared to HC and also between anti-TNF and Vedolizumab biological therapies for IBD patients. Result(s): The seroprevalence of anti-SARS-CoV-2 Ab in IBD cohort (22/238) indicates an overall lower incidence of COVID-19 in comparison with the general population of Lombardy. Our data indicated that IBD patients in treated with biologic drugs as anti-TNF (10,5%) and Vedolizumab (7,5%) have a lower incidence than IBD patients treated with conventional therapies (28,0%). Accordingly, we observed that serum metabolomics signature associated with protection was more frequent in IBD patients treated with anti-TNF (N=50, 70%), and with Vedolizumab (N=57, 85%) than healthy controls (N=45, 50%). The metabolomic protective profile is characterized by the presence of fat-soluble Tocopherols family members and Cholecalciferol and also of omega-3 and omega-6 polyunsaturated fatty acid. Conclusion(s): Our study indicates that IBD population treated with biologics has an overall lower risk to contract SARS-CoV-2 infection and a serum proteomic/metabolomic protection profile. The increased presence in IBD patients of radical scavengers such as tocopherols which are incorporated into cell membranes and protect against oxidative damage and anti-inflammatory and immunomodulating fatty acids suggest a better response to SARS-CoV-2 infection. Also increased levels of omega;-3 interfere with the entry of the virus by modulating the Lipid Rafts where ACE2 and TMPRSS2 are mainly expressed and PUFAs inhibit the attachment of SARS-CoV-2 virions to the human ACE2 receptor by interacting directly with the RBD sequence. Mechanistically understanding how this protection profile exerts its effects on COVID-19 severity might shed light on potential targets to increase resistance in higher risk subgroups of patients.
ABSTRACT
Introduction: The current pandemia is due to the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) that was originally identified in China in 2019, when numerous cases of atypical pneumonia were reported. Elderly and pre-existing disorders including hypertension, heart problems, diabetes, cancer, autoimmune diseases and IBD are found associated with an increased risk of COVID-19. A few clinical studies suggested that IBD and immunomodulation may reduce the susceptibility to COVID-19;however, the molecular mechanisms are not fully revealed. Aims & Methods: In this study, we attempted to identify a transcriptomic signature as candidate of the effects of IBD and different therapies on the risk of SARS-CoV-2 infection and COVID-19 severity through colonic tissue gene expression. In 2020-2022, 192 IBD patients, 115 Crohn disease (CD), 77 Ulcerative colitis (UC) and 36 Healthy Controls (HC) of the North Italy area were enrolled. Colon biopsies from inflamed and non-inflamed mucosa were collected from IBD patients and healthy mucosa samples were collected from HC. To evaluate the exposure to SARS-CoV-2, clinical data were collected and seroprevalence of anti-SARS-CoV-2 Ab were analyzed by means of multiplex technology with BioPlex 2200 Sars-Cov-2 IgG Panel (biorad, Italy). Gene expression analysis of ACE2, TMPRSS2, TMPRSS4, ADAM17 were performed by qPCR in biopsies of the three experimental groups. Result(s): In IBD patients cohort the seroprevalence of anti-SARS-CoV-2 antibodies indicates an overall lower incidence of COVID-19 in comparison with the general population of Lombardy, and also a lower incidence in IBD patients in biological therapies vs. conventional ones. Gene expression analysis of the proteins involved in SARS-CoV-2 entry indicated that IBD patients treated with anti-TNF (N=72) had a lower mucosal level of SARS-CoV-2 receptor ACE2 and its sheddase ADAM17 than non-IBD subjects along with higher expression of the proteases TMPRSS2 and TMPRSS4. Moreover, vedolizumab-treated patients (N=40) showed a significant lower expression of ACE2, TMPRSS2 and TMPRSS4 than controls, whereas ADAM17 levels were similar. Conclusion(s): Data presented in our study suggest that the biologic-treated IBD population has an overall lower risk of contracting SARS-CoV-2 infection. Colonic expression of proteins involved in SARS-CoV-2 virus entry suggested an additional protective mechanism. Understanding the association of this protection profile with COVID-19 severity and the mechanisms of virus entry into the colon could reveal resistance pathways in higher-risk patient subgroups.
ABSTRACT
Background: The current novel coronavirus (SARS-CoV-2) pandemic is an ongoing global health crisis, which represents an important challenge for the whole society and mankind. Patients with inflammatory bowel disease (IBD) are treated with immunosuppressive drugs that are usually associated with more severe viral infections. However, the effects of the different therapies on the risk of SARS-CoV-2 infection and Covid-19 severity in IBD patients are still under investigation. Methods: Between April 2020 and April 2021, 238 IBD patients (N=145 with Crohn disease and N=93 with Ulcerative colitis) of the North Italy area have been enrolled. Both serum samples (N=238 IBD patients and N=45 healthy donors) and colon biopsies from inflamed and non-inflamed mucosa (N=88 IBD patients N=20 non-IBD control) have been collected. To evaluate the exposure to SARS-CoV-2, both clinical data and seroprevalence of anti-SARS-CoV-2 Ab have been analyzed. Serum samples were analyzed by untargeted metabolomics analysis and the frequency of a serum metabolomics signature associated with protection were evaluated in IBD versus healthy donors. Moreover, gene expression analysis of key proteins for virus entry (ACE2, TMPRSS2, TMPRSS4, ADAM17) were analyzed by qPCR in the gut mucosa biopsies of IBD patients. Results: The seroprevalence of anti-SARS-CoV-2 Ab in our cohort of IBD patients (10/238) indicates an overall lower incidence of COVID-19 in comparison with the general population of Lombardy. Accordingly, we observed that the serum metabolomics signature associated with protection was more frequent in IBD patients treated with anti-TNF (N=50, 70%), than healthy controls (N=45, 50%). Gene expression analysis of the proteins involved in SARS-CoV-2 entry also indicated that IBD patients treated with anti-TNF (N=14) had a lower mucosal level of SARS-CoV-2 receptor ACE2 and its sheddase ADAM17 than non-IBD subjects along with higher expression of the proteases TMPRSS2 and TMPRSS4. Moreover, vedolizumab-treated patients (N=7) showed a significant lower expression of ACE2, TMPRSS2 and TMPRSS4 than controls, whereas ADAM17 levels were similar. Conclusion: Our study indicates that IBD population treated with biologics has an overall lower risk to contract SARS-CoV-2 infection. Future studies to gather the mechanisms underpinning the effects of biologics on the expression of the proteins involved in SARS-CoV-2 viral entry in association with the specific metabolomics signature of viral susceptibility might shed light on potential targets to increase resistance in higher risk subgroups of patients.