Covid: such a digestive disease?

We know that SARS-COV 2 colonizes the digestive tract, actively replicates there, and even persists for a long time by passing through the bloodstream, which may explain prolonged COVID. Correction of vitamin D deficiency could have an important protective role.

SARS-CoV-2 has been detected for a prolonged period in the digestive tract. The intestinal barrier plays a central role in the events that lead from SARS-CoV-2 infection to serious complications. The most recent studies suggest that SARS-CoV-2 alters the integrity of the biological, mechanical and immunological intestinal barrier. The diversity of the microbiota and the population of beneficial bacteria are reduced, as well as the proliferation of pathogenic bacteria (dysbiosis).

A pre-existing dysfunction amplified by SARS-COV-2

The spaces between the intestinal cells, the tight junctions (TJ) play an essential role as a hermetic barrier. If this intestinal barrier is dysfunctional, the passage of bacteria, fungi and endotoxins into the circulation is possible. A pre-existing alteration of the intestinal barrier found in patients with comorbidities (cardiovascular diseases, obesity, diabetes and immunosuppression) favors this deleterious step and makes them more vulnerable. [1]. The team of Prof. C. Devaux (CNRS – Marseille) has shown that in patients carrying intestinal SARS-CoV-2, the virus can cause barrier damage by disrupting these tight junctions, contributing to the gastrointestinal symptoms of COVID -19 [2].

Long COVID: prolonged digestive presence of SARS-COV2 and circulating spike

With no viral particles in the respiratory tract, 12.7% of patients had SARS-CoV-2 in stool at 120 days and 3.8% were still excreting SARS-CoV-2 at 210 days [3]. In addition, viable virus was found in the appendix of 2 patients with prolonged Covid symptoms on days D+175 and D+462. This is the first study to detect viable virus for such a long time in the digestive tract. [4]
Furthermore, from 31 patients with prolonged COVID, the researchers were able, using ultrasensitive technology (Simoa), to identify in the circulation in the blood, either the spike protein, the nucleocapsid N or the S1 subunit in approximately 65% of COVID patients long months later. The authors suggest the presence of a active persistent viral reservoir of SARS-CoV-2 at the origin of his discovery [5].

Zonulin marker of altered intestinal permeability

Zonulin is a molecule that alters the tightness of the intestine, by opening these tight junctions that join the cells of the wall. Produced in excess, it can cause the passage of undesirable compounds in the body.
In July 2021, a team identifies zonulin as a marker and potential therapeutic target in multisystem inflammatory syndrome (MIS-C or PIMS) affecting children. [6].
A study has shown that in the MIS-C group, compared to a control group, zonulin was significantly higher. However, zonulin opens the tight junctions (TJ), and allows the passage of highly pro-inflammatory viral particles into the circulation, but also of endotoxins or lipopolysaccharides (LPS) of bacterial origin from the digestive tract. These results indicate that increased intestinal permeability may be involved in explaining severe COVID infection and MIS-C disease in children. [7].

An inflammatory bomb in the digestive tract

Pierre Sonigo, former director of research at INSERM, a specialist in viruses, believes that “there is nothing more pro-inflammatory in the body than the endotoxins (LPS) of the bacterial wall”. He points out that “we all have a potential inflammatory bomb in our digestive tract.” . When intestinal permeability increases, a phenomenon called LPS translocation can occur. The permeability is greatly increased in case of digestive infection. Unfortunately, all of this is common in the case of COVID. Digestive manifestations are also known to increase the risk of a severe form of COVID with shock.”

A hope for treatment in children with MIS-C

In children with MIS-C, the prolonged presence of SARS-CoV-2 in the gastrointestinal tract led to the release of zonulin with passage of SARS-CoV-2 antigens into the bloodstream, resulting in hyperinflammation according to a team from Massachusetts. General Hospital. the larazotide, a zonulin inhibitor used in the treatment of Celiac Disease, would prevent the alteration of digestive permeability (tight junctions = TJ), limiting the passage of deleterious antigens: this treatment would be well tolerated and useful as adjuvant treatment. Thus, 4 young patients with MIS-C treated with larazotide saw their Spike protein levels decrease to undetectable levels, a more rapid improvement in gastrointestinal symptoms as well as a trend towards a reduction in hospital stay. [8].

And vitamin D?

Vitamin D is known to be involved in inflammatory bowel disease and mediates intestinal tight junction permeability.
Since 2007, experimental studies have shown that vitamin D3 can play a protective role in the mucosal barrier by maintaining the integrity of the junctional complexes and in the healing capacity of the colonic epithelium. [9].
Vitamin D levels are also inversely correlated with symptom score and fecal zonulin. These data highlight the close relationship between vitamin D and the intestinal barrier [10].

Plasma endotoxin and zonulin decreased with increasing vitamin D levels. Analyzes showed a significant association between plasma zonulin levels and vitamin D levels. This finding again suggests a relationship between Vitamin D deficiency and alterations first signs of intestinal permeability. Therefore, assessment of vitamin D levels and preventive correction of deficiency may be warranted. [11].
Both in vitro and in vivo, another study shows that vitamin D3 attenuates the increased permeability of the intestinal mucosa. Finally, vitamin D3 treatment significantly reduced the levels of zonulin release. [12].

Experimentally in mice on a diet deficient in vitamin D, a team finds a significant decrease in the thickness of the lining of the colon, a marked increase in levels of pro-inflammatory cytokines, elevated levels of zonulin-1. Vitamin D supplementation could be part of a therapeutic strategy for human diseases involving intestinal barrier dysfunction (leaky gut) according to the authors [13].

Severe vitamin D and MIS-C deficiency

Finally, of 31 young patients with MIS-C, 10 had severe vitamin D deficiency with an average level of 7.2 ng/ml (the desirable level is above 30 ng/ml, or even 50 ng/ml). . 90% with severe vitamin D deficiency had severe disease and increased risk of heart damage [14]. The preventive effect of vitamin D is also suggested in a March 2021 mini-review of the scientific literature. [15].

All these data suggest that the alteration of the digestive permeability concomitant with the penetration and the presence of digestive replicative viruses are determinants in the understanding of the COVID disease – the long COVID and MIS-C. Further studies and clinical trials are needed to determine the therapeutic impact of larazotide on the prevention of MIS-C, and correction of vitamin D deficiency in severe COVID and prolonged COVID.

• Bibliography
  1) Assimakopoulos: SARS CoV-2-induced viral sepsis: the role of intestinal barrier dysfunction. Microorganisms 2022, 10, 1050. https://doi.org/10.3390/microorganisms10051050
• 2) Osman IO, Devaux CA: Control of CDH1/E-cadherin gene expression and release of a soluble form of E-cadherin in intestinal Caco-2 cells infected with SARS-CoV-2: pathophysiological consequences for intestinal forms of COVID-19. Front Cell Infect Microbiol. May 4, 2022; 12:798767. doi:10.3389/fcimb.2022.798767.
• 3) Rubin R.: SARS-CoV-2 RNA can persist in feces for months after the virus is cleared from the respiratory tract. JAMA. 2022;327(22):2175–2176. doi:10.1001/jama.2022.7892
• 4) Goh, D. et al. Persistence of residual SARS-CoV-2 viral RNA and antigen in tissues of patients with prolonged COVID-19 (June 2022) Researchgate DOI: 10.21203/rs.3.rs-1379777/v2
• 5) Zoe Swank et al.: Spike in persistent circulating SARS-CoV-2 is associated with post-acute sequelae of COVID-19 medRxiv 2022.06.14.22276401;
• 6) Hensley-McBain T et al. Zonulin as a biomarker and potential therapeutic target in multisystem inflammatory syndrome in children. J Clin Invest. July 15, 2021; 131(14):e151467. doi: 10.1172/JCI151467. PMID: 34160366; PMCID: PMC8279574.
• 7) Kılıç AO et al. Zonulin and claudin-5 levels in multisystem inflammatory syndrome and SARS-CoV-2 infection in children. J Pediatr Child Health. May 30, 2022. doi: 10.1111/jpc.16033. Epub before printing. PMID: 35638118.
• 8) Yonker LM, Swank Z, Gilboa T, Senussi Y, Kenyon V, Papadakis L, Boribong BP, Carroll RW, Walt DR, Fasano A. Zonulin Antagonist, Larazotide (AT1001), as Adjunctive Treatment for Multisystem Inflammatory Syndrome in Children : a series of cases. Critical care scan. February 18, 2022; 10(2):e0641. doi: 10.1097/CCE.0000000000000641. PMID: 35211683; PMCID: PMC8860335.
• 9) Zhao H, et al. : Protective role of 1,25(OH)2 vitamin D3 in mucosal injury and epithelial barrier disruption in DSS-induced acute colitis in mice. BMC Gastroenterol. May 30, 2012; 12:57. doi: 10.1186/1471-230X-12-57. PMID: 22647055; PMCID: PMC3464614.
• 10) Linsalata M, et al The relationship between low serum vitamin D levels and impaired intestinal barrier function in patients with IBS diarrhea undergoing a long-term low-FODMAP diet: Novel observations from a clinical trial. Nutrients. 2021 March 21; 13 (3): 1011. doi: 10.3390/nu13031011.
• 11) Islamian G, et al. Association of intestinal permeability with vitamin D deficiency at admission in critically ill patients. J Investig Med. 2020 Feb;68(2):397-402. doi: 10.1136/jim-2019-001132. Epub 2019 October 30
• 12) Dong Seal. : Protective effect of 1,25-dihydroxy vitamin D3 on tight junction lesions induced by trypsin- and pepsin-resistant gliadin. Dig Dis Sci. 2018 Jan;63(1):92-104. doi: 10.1007/s10620-017-4738-0. Epub 2017 September 4. PMID: 28871457
• 13) Yeung CY, et al:. Effects of vitamin D deficient diet on intestinal epithelial integrity and zonulin expression in a C57BL/6 mouse model. Front Med (Lausanne). August 3, 2021; 8:649818. doi:10.3389/fmed.2021.649818.
• 14) Torpoco-Rivera D: Vitamin D and morbidity in children with multisystem inflammatory syndrome related to Covid-19. Pediatric Cardiol Program. 2022 March 1:101507. doi: 10.1016/j.ppedcard.2022.101507.
• 15) Feketea G, et al. : Vitamin D in Corona Virus Disease 2019 (COVID-19) Related Multisystem Inflammatory Syndrome in Children (MIS-C). frontal immunol. March 8, 2021; 12:648546. doi: 10.3389/fimmu.2021.648546.