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Intestinal adverse outcomes in COVID-19: Current evidence and uncertainties using the adverse outcome pathway framework.
Citation:
Clerbaux, L., J. Fillipovska, A. Munoz, M. Petrillo, H. Soares, S. Mayasich, M. Amorim, AND L. Grenga. Intestinal adverse outcomes in COVID-19: Current evidence and uncertainties using the adverse outcome pathway framework. European Society of Toxicology in Vitro (ESTIV), Barcelona, N/A, SPAIN, November 21 - 25, 2022. https://doi.org/10.23645/epacomptox.21685295
Impact/Purpose:
Poster presented to the European Society of Toxicology in Vitro (ESTIV) November 2022. The Modelling the Pathogenesis of COVID-19 Using the Adverse Outcome Pathway (AOP) Framework (CIAO) working group has been developing AOPs to better understand and organize the information needed to treat COVID-19, support new research to defeat the disease, and prevent future pandemics. This will be a presentation to a toxicology-focused group familiar with AOPs but with the novel use to show the versatility of the framework and enlighten the audience on the latest COVID-19 science. The European Society of Toxicology In Vitro (ESTIV) congress is organizing special sessions jointly with the European Union-Joint Research Council on bridging across methods in the biosciences (BeAMS), which provides the opportunity to present COVID-19 AOP work. The idea is to highlight how COVID-19 and gut research can benefit from developing AOPs.
Description:
- Background and objectives. COVID-19 patients could experience gastrointestinal disorders and alteration of gut microbiota. Besides, the SARS-CoV-2 receptor angiotensin converting enzyme 2 (ACE2) is highly expressed in enterocytes. Thus, it has been proposed that SARS-CoV-2 enteric infection leads to intestinal barrier disruption, inflammation, and dysbiosis. However, the underlying mechanisms are still poorly understood. - Methods. Here, we applied the Adverse Outcome Pathway (AOP) framework to explore existing evidence supporting the sequence of events of proposed pathways depicting the mechanisms behind SARS-CoV-2 mediated gut pathophysiology. - Results. One AOP outlines SARS-CoV-2 enteric infection leading to intestinal barrier dysfunction via cytopathic effects. Studies with human enterocytes in vitro demonstrate SARS-CoV-2 infection. However, evidence for the viral replication in vivo in animals and in (healthy) human gut is unclear, either due to timely interferon response limiting viral replication or the multiple layered barrier. While the biological plausibility is high, currently, there is not enough evidence to support enterocyte massive cell death due to SARS-CoV-2 infection. Besides, ACE2 plays a key role in intestinal homeostasis, notably in dietary amino acids uptake, such as tryptophan. Evidence supports high plausibility for intestinal ACE2 dysregulation due to spike (S) protein binding, but further examination is needed to distinguish between the direct effect of the spike protein ACE2 binding and subsequent replication. In addition, more evidence is required to understand the role of observed tryptophan alteration which regulates the secretion of antimicrobial peptides, altering the gut microbiota. Lastly, another putative AOP proposes a new mechanism for COVID-19 transmission mediated by gut bacteria that may be transducing infective SARS-CoV-2 components. Current inconsistencies regarding detection of replicating SARS-CoV-2 in feces calls for additional research. - Conclusion. This AOP-aligned approach highlights current significant inconsistencies in the evidence and knowledge gaps that can guide future research. In addition, it facilitates synergy from different disciplines to address health issues.
URLs/Downloads:
DOI: Intestinal adverse outcomes in COVID-19: Current evidence and uncertainties using the adverse outcome pathway framework.
ESTIV GUT POSTER CLERBAUX _ NOV 2022.PDF (PDF, NA pp, 744.877 KB, about PDF)