BREAKING! Autopsy Studies By King’s College London Reveal That COVID-19 Is Causing Severe Gastrointestinal Damage Especially On The Ileal Peyers’s Patches

COVID-19 Research: A new study by researchers from King’s College London has revealed that the SARS-CoV-2 coronavirus is causing severe gastrointestinal damage especially on the ileal Peyer’s Patches and is also causing dysbiosis, both of which can also lead to disease severity due to disruptions in immune function.

 
Peyer's patches are an important part of gut associated lymphoid tissue usually found in humans in the lowest portion of the small intestine, mainly in the distal jejunum and the ileum, but also could be detected in the duodenum. They are basically groupings of lymphoid follicles in the mucus membrane that lines the small intestine. Lymphoid follicles are small organs in the lymphatic system that are similar to lymph nodes.

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Because the lumen of the gastrointestinal tract is exposed to the external environment, much of it is populated with potentially pathogenic microorganisms. Peyer's patches thus establish their importance in the immune surveillance of the intestinal lumen and in facilitating production of the immune response within the mucosa.
 
Pathogenic microorganisms and other antigens entering the intestinal tract encounter macrophages, dendritic cells, B-lymphocytes, and T-lymphocytes found in Peyer's patches and other sites of gut-associated lymphoid tissue (GALT). Peyer's patches thus act for the gastrointestinal system much as the tonsils act for the respiratory system, trapping foreign particles, surveilling them, and destroying them.
 
The study team demonstrated that severe coronavirus disease 2019 (COVID-19) is associated with pronounced changes in the ileal Peyer’s Patches, which could be responsible for the suppression of intestinal immune responses and subsequent disruption of microbiota homeostasis in the gastrointestinal (GI) tract.
 
The study findings were published on a preprint server and are currently being peer reviewed. https://www.biorxiv.org/content/10.1101/2021.12.17.473179v1
 
Confirmed SARS-coronavirus-2 infection with gastrointestinal symptoms and changes in microbiota associated with coronavirus disease 2019 (COVID-19) severity have been previously reported, but the disease impact on the architecture and cellularity of ileal Peyers patches (PP) remains unknown.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7290409/
 
https://pubmed.ncbi.nlm.nih.gov/32235945/
 
https://pubmed.ncbi.nlm.nih.gov/33461210/
 
https://pubmed.ncbi.nlm.nih.gov/32877699/
 
The study team analyzed post-mortem tissues from throughout the gastrointestinal (GI) tract of patients who died with COVID-19. When virus was detected by PCR in the GI tract, immunohistochemistry identified virus in epithelium and lamina propria macrophages, but not in lymphoid tissues.
 
Detailed immunohistochemistry and imaging mass cytometry (IMC) analysis of ileal PP revealed depletion of germinal centres (GC), disruption of B cell/T cell zonation and decreased potential B and T cell interaction and lower nuclear density in COVID-19 patients. This occurred independent of the local viral levels. The changes in PP demonstrate that the ability to mount an intestinal immune response is compromised in severe COVID-19, which could contribute to observed dysbiosis.
 
Typically, in viral infections, presence of viruses in the GI tract is known to support long-lived antibody responses that are vital for inhibiting viral propagation.
 
However, an absence of such response has been found to associate with persistent disease. In about 12% of COVID-19 patients, GI symptoms including diarrhea and vomiting have been observed, indicating the propagation of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in the GI tract epithelial cells.
 
It has been known that in the GI tract, immune responses originate in the lymphoid tissues that produce activated B and T cells. The clusters of gut-associated lymphoid tissues in the terminal ileum are called Peyer’s patches, which contain antigen-specific germinal centers. Antibodies secreted in response to germinal centers play vital roles in regulating the gut microbiota and maintaining homeostasis.
 
The COVID-19 Research team analyzed GI tract samples collected from deceased COVID-19 patients to localize SARS-CoV-2 and quantify viral RNA. In addition, they have conducted immunohistochemistry and imaging mass cytometry to analyze structural and functional characteristics of ileal Peyer’s patches.     
   
The detailed localization and quantification of SARS-CoV-2 were conducted using samples from the esophagus, stomach, duodenum, ileum, colon, lungs, and spleen.
 
The study findings revealed that in severe infection, SARS-CoV-2 is localized throughout the GI tract, with the highest localization in the epithelium and subepithelial lamina propria. However, no presence of the virus was observed in the lymphoid tissues.
 
The detailed characterization of ileum Peyer’s patches was conducted by double staining the receptors expressed by B and T cells on the lymphoid tissues. In addition, the germinal center was stained.
 
The study findings revealed that compared to control tissues, the ileum Payer’s patches isolated from COVID-19 patients have significantly reduced germinal centers irrespective of the levels of viral RNA.
 
Subsequent immunohistochemistry and imaging mass cytometry analysis was conducted on cells specifically isolated from the lymphoid tissues in the Peyer’s patches.
 
These findings revealed that in COVID-19 patients, the structure of Peyer’s patches is disrupted, and the zonation of B and T cells is lost. In addition, a reduction in the expression of a germinal center-associated transcription factor BCL6 was observed in B and T cells. This transcription factor is required for the development of germinal center B cells and follicular helper T cells.
 
The detailed analysis of cellular interactions in Peyer’s patches revealed a higher fraction of macrophages in follicles of COVID-19 samples compared to that in control follicles.
 
Furthermore, a significantly reduced cellular density was observed in the lymphoid tissues obtained from COVID-19 patients.
 
Also, a significantly reduced interaction between B cell and T cell was observed in the ileal follicles in Peyer’s patches of COVID-19 patients.
 
The study findings also showed that a significantly lower level of memory B cells was observed in Peyer’s patches of COVID-19 patients.
  
Implications Of Study Findings
 
The research findings demonstrate significantly altered structure and cellularity of Peyer’s patches in deceased COVID-19 patients. The depletion in germinal centers, reduction in B cell - T cell interaction, and lower cellular density observed in ileal Peyer’s patches indicate that the gut immune system is disrupted and cannot induce sufficient immune responses. Collectively, these factors could lead to significant dysbiosis.  
 
However, interestingly, changes in Peyer’s patches are not associated with the levels of viral RNA. This possibly indicates that the changes are due to systemic inflammation and not due to the virus.
 
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