such a digestive disease?

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

Coronavirus-Intestine (UnlimPhoto)
Coronavirus-Intestine (UnlimPhoto)

SARS-CoV-2 has been detected for a prolonged period in the digestive tract. The intestinal barrier exerts 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 disrupts the integrity of the biological, mechanical and immunological intestinal barrier. The diversity of the microbiota and the population of beneficial bacteria are reduced, along with 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 tight barrier. If this intestinal barrier is dysfunctional, the passage of bacteria, fungi and endotoxins to the circulation is possible. A pre-existing alteration of the intestinal barrier found in patients with comorbidities (cardiovascular diseases, obesity, diabetes and immunosuppression) promotes this deleterious passage and makes them more vulnerable. [1]. Pr C. Devaux’s team (CNRS – Marseille) has shown that in patients carrying intestinal SARS-CoV-2, the virus can trigger damage to the barrier by disrupting these tight junctions, thus contributing to gastrointestinal symptoms of COVID-19 [2].

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

Without any viral particles in the respiratory tract, 12.7% of patients had SARS-CoV-2 in the stool at 120 days and 3.8% still excreted SARS-CoV-2 at 210 days [3]. In addition, viable virus was found in the appendix of 2 patients with long Covid symptoms at D + 175 and D + 462 days. This is the first study to detect a viable virus for so long in the digestive tract [4]
In addition, out of 31 patients with long COVID, the researchers were able, using ultrasensitive technology (Simoa), to identify in circulation in the blood, either the spike protein, the N nucleocapsid or the S1 subunit in approximately 65% of COVID patients long several months after. The authors suggest the presence of a active persistent viral reservoir of SARS-CoV-2 at the origin of their 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 unite the cells of the wall. Produced in excess, it can cause the passage of undesirable compounds in the body.
As of July 2021, a team identifies zonulin as a marker and potential therapeutic target in the multisystem inflammatory syndrome (MIS-C or PIMS) which affects 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 (DR)
Pierre Sonigo (DR)

Pierre Sonigo, former INSERM research director, specialist in viruses, believes that “there is nothing more pro-inflammatory in the body than the endotoxins (LPS) of the bacterial wall” He notes that “we all have the digestive tract a potential inflammatory bomb. When intestinal permeability increases, a phenomenon called LPS translocation can occur. The permeability increases a lot in case of digestive infection. All this is unfortunately common in the event 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 a hyper inflammation 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 an adjuvant treatment. Thus, 4 young MIS-C patients treated with larazotide saw their Spike protein levels decrease to undetectable levels, a faster improvement in gastrointestinal symptoms as well as a tendency towards a reduction in the length of hospital stay. [8].

And vitamin D?

Vitamin D is known to be involved in inflammatory bowel disease and is involved in tight junction intestinal 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 junction complexes and in the healing capacity of the colon epithelium. [9].
Vitamin D levels are also inversely correlated with symptom score and faecal 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 with vitamin D levels. This finding again suggests a relationship between vitamin D deficiency and alterations early signs of intestinal permeability. Thus, assessment of vitamin D levels and preventive correction of the deficiency may be warranted. [11].
Both in vitro and in vivo, another study shows that vitamin D3 attenuated the increased permeability of the intestinal mucosa. Finally, vitamin D3 treatment significantly decreased zonulin release levels [12].

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

Severe vitamin D and MIS-C deficiency

Finally, out of 31 young patients with MIS-C, 10 had a 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 March 2021 in a 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 virus are determining in the understanding of the disease COVID – the long COVID and the MIS-C. Further studies and clinical trials are necessary to determine the therapeutic impact of larazotid on the prevention of MIS-C, and correction of vitamin D deficiency on severe COVIDs and long COVIDs.

  • Bibliography
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  • 2) Osman IO, Devaux CA: Control of CDH1/E-Cadherin Gene Expression and Release of a Soluble Form of E-Cadherin in SARS-CoV-2 Infected Caco-2 Intestinal Cells: Physiopathological Consequences for the Intestinal Forms of COVID-19 . Front Cell Infect Microbiol. 2022 May 4;12:798767. doi: 10.3389/fcimb.2022.798767.
  • 3) Rubin R.: SARS-CoV-2 RNA Can Persist in Stool Months After Respiratory Tract Clears Virus. JAMA. 2022;327(22):2175–2176. doi:10.1001/jama.2022.7892
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  • 9) Zhao H, et al. : Protective role of 1,25(OH)2 vitamin D3 in the mucosal injury and epithelial barrier disruption in DSS-induced acute colitis in mice. BMC Gastroenterol. 2012 May 30;12:57. doi: 10.1186/1471-230X-12-57. PMID: 22647055; PMCID: PMC3464614.
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