Long-Term Effects of COVID-19 on the Gastrointestinal System

Written by Rahul Panchal, Scientist II at Proteintech Group in Chicago, IL.

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Gastrointestinal issues following COVID-19 have long been known as a side effect of infection. In this blog, we detail some of the mechanisms causing long-term intestinal side effects due to increased inflammation, and the highlight some reagents needed to help research these effects.

COVID-19 increases gut inflammation

Due to high levels of ACE2 receptor expression in intestinal tissue, the gastrointestinal system is often targeted by SARS-COV-2 infections. The virus occupies the ACE2 receptor, thereby preventing it from converting angiotensin II into Ang 1-7. Under normal circumstances, the routine conversion of angiotensin II to Ang 1-7 is important as it promotes an anti-inflammatory state. However, when ACE2 receptors are occupied by SARS-COV-2, the level of angiotensin II accumulates resulting in a pro-inflammatory state due to increased NAPDH activity, thrombogenic factors, vasoconstriction, and pro-inflammatory cytokines.

COVID-19 infection in the intestine typically results in increased immune cell recruitment and activation. The high expression of CCL25 on intestinal cells results in the recruitment of CCR9-CD4+ T cells. The persistence of the SARS-CoV-2 virus several months after the acute phase of the infection has been linked to increased serum levels of interferons and chemokines as well as an expansion of activated immune cell types such as PD1+ CD8+/TIM3+CD8+ memory T cells and CD86+CD38+ dendritic cells. Elevated levels of these cell have been found as late as 8 months post-infection. As these immune cells circulate, they continue to produce and release high-levels of pro-inflammatory cytokines such as IL-1 beta, IL-6, and TNF alpha.

Mechanisms of SARS-CoV-2 inflammatory effects on the gastrointestinal tract. Figure adapted from Ye et al., 2020.

COVID-19 and the microbiome

There is also evidence to suggest that COVID-19 infection disrupts the microbial balance in the intestine, which results in further downstream consequences. Healthy microbiomes typically work to inhibit the action of pro-inflammatory cytokines and promote gut barrier integrity through upregulation of tight junction proteins and increased mucus production. Disruption of the intestinal microbiome can be triggered by the increased recruitment of CCR9-CD4+ T cells. Additionally, through occupying the ACE2 receptor, SARS-CoV-2, blocks the action of the B0AT1 transporter protein, whose activity is co-dependent upon ACE2. B0AT1 aids in the transport of helpful amino acids, such as tryptophan across the cell membrane. Tryptophan absorption by intestinal cells promotes signaling pathways that increase the production of anti-microbial peptides, which in turn help to regulate microbial homeostasis in the gut. When tryptophan cannot be absorbed due to blocked access to B0AT1, this leads to reduced anti-microbial peptide secretion and microbiome dysbiosis. This condition has been linked to increased pro-inflammatory cytokines and decreased barrier tightness. The loss of barrier integrity has been shown to be a major cause of post-acute phase symptoms such as abdominal pain and diarrhea.

Associated Products: Immune Cell Markers

Target	SKU	Applications
CD14	17000-1-AP/60253-1-Ig	WB, IHC, IF, FC, ELISA
CCR9/ACKR2	60046-1-Ig/11386-1-AP	IHC, IF, ELISA
CD86	13395-1-AP	WB, IF, FC, ELISA
CD38	60006-1-Ig/25284-1-AP	WB, IHC, IF, FC, ELISA
CD4	67786-1-Ig	IHC, IF, ELISA
CD8	66868-1-Ig	WB, IHC, IF, FC, ELISA
CD16	66779-2-Ig/16559-1-AP	WB, IHC, IF, FC, ELISA
PD1	18106-1-AP	IHC, IF, FC, CoIP, ELISA
TIM3	60355-1-Ig/11872-1-AP	WB, IHC, FC, ELISA

ELISA Kits for Cytokine Secretion

Target	SKU	Range
IL-1 beta	KE00021	3.9-250 pg/mL
IL-6	KE00139	7.8-500 pg/mL
TNF alpha	KE00154	15.6-500 pg/mL
IFN beta	KE00195	7.8-500 pg/mL
IFN lambda 1/IL-29	KE00241	62.5-4000 pg/mL

Gap Junction Proteins

Target	SKU	Applications
Claudin 2	26912-1-AP	WB, IF, ELISA
Claudin 7	10118-1-AP	IHC, IF, ELISA
Occludin	13409-1-AP	WB, IP, IHC, FC, ELISA
ZO-1	66542-1-Ig	WB, IHC, IF, ELISA

Intestinal Cell Markers

Target	SKU	Applications
Angiopoietin 1	23302-1-AP	WB, IHC, IF, ELISA
CCL25	25285-1-AP	IHC, IF, ELISA
B0AT1/SLC6A19	29372-1-AP	WB, IHC, ELISA

References:

1. Meringer, H., & Mehandru, S. (2022). Gastrointestinal post-acute COVID-19 syndrome. Nature Reviews Gastroenterology &Amp; Hepatology, 19(6), 345–346. https://doi.org/10.1038/s41575-022-00611-z

2. Phetsouphanh, C., Darley, D. R., Wilson, D. B., Howe, A., Munier, C. M. L., Patel, S. K., Juno, J. A., Burrell, L. M., Kent, S. J., Dore, G. J., Kelleher, A. D., & Matthews, G. V. (2022). Immunological dysfunction persists for 8 months following initial mild-to-moderate SARS-CoV-2 infection. Nature Immunology, 23(2), 210–216. https://doi.org/10.1038/s41590-021-01113-x

3. Wu, X., Jing, H., Wang, C., Wang, Y., Zuo, N., Jiang, T., Novakovic, V. A., & Shi, J. (2022). Intestinal Damage in COVID-19: SARS-CoV-2 Infection and Intestinal Thrombosis. Frontiers in Microbiology, 13. https://doi.org/10.3389/fmicb.2022.860931

4. Ye Q, Wang B, Zhang T, Xu J, Shang S. The mechanism and treatment of gastrointestinal symptoms in patients with COVID-19. Am J Physiol Gastrointest Liver Physiol. 2020 Aug 1;319(2):G245-G252. doi: 10.1152/ajpgi.00148.2020. Epub 2020 Jul 8. PMID: 32639848; PMCID: PMC7414235.

5. Yusuf, F., Fahriani, M., Mamada, S. S., Frediansyah, A., Abubakar, A., Maghfirah, D., Fajar, J. K., Maliga, H. A., Ilmawan, M., Emran, T. B., Ophinni, Y., Innayah, M. R., Masyeni, S., Ghouth, A. S. B., Yusuf, H., Dhama, K., Nainu, F., & Harapan, H. (2021). Global prevalence of prolonged gastrointestinal symptoms in COVID-19 survivors and potential pathogenesis: A systematic review and meta-analysis. F1000Research, 10, 301. https://doi.org/10.12688/f1000research.52216.1