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Long Covid, the Gut, and Autoimmune Skin Diseases: A Novel Therapeutic Approach

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Preprints on COVID-19 and SARS-CoV-2

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27 December 2023

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28 December 2023

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Abstract
The dermatological manifestations of Long Covid (LC) have languished in the shadows of chronic fatigue and brain fog. Yet they are all linked by gut dysbiosis and the cytokine triad of TNF-α, IL-1β, and IL-6. The gut microbiome common not only to LC, psoriasis, AA, and vitiligo but also to neurodegenerative disease has been recently described. This gut microbiome induces an altered tryptophan metabolism linked to autoimmune disease. SARS CoV2 invades enterochromaffin cells rich in ACE2 receptors and curtails absorption of the essential amino acid tryptophan and subsequent synthesis of serotonin and melatonin. This review suggests that an etiologic prebiotic (d-mannose)/probiotic (lactobacilli, bifidobacteria)/postbiotic (butyrate) approach to autoimmune skin disease that improves intestinal barrier integrity and that suppresses the triad of TNF-α, IL-6, and IL-1β may enhance or even eliminate the traditional immunotherapy of targeted monoclonal antibodies, Janus kinase inhibitors, and steroids. Health benefits of this approach extend well beyond suppression of autoimmune skin disease.
Keywords: 
Subject: Biology and Life Sciences  -   Biochemistry and Molecular Biology

Introduction

LC is considered by many to be primarily an autoimmune disease1. A German study that followed over half a million patients post Covid-19 reported new onset autoimmune disease in almost 50%2. According to the NIH, there are more than 80 different autoimmune diseases. Three of the top ten involve skin disorders - psoriasis (3%), AA (2%), and vitiligo (1%). Two others, pemphigus vulgaris and bullous pemphigoid, have also been reported in those with LC3,4,5,6.
Autoimmune disease risk has traditionally been ascribed to genetic and environmental factors. However, the contributory role of the gut microbiome is rapidly establishing a legitimate challenge to this paradigm. The realm of therapeutic approaches to preventing and treating autoimmune disease has expanded with this recognition. Yet many practicing dermatologists are either unaware of recent therapeutic breakthroughs or fearful of deviating from the designated menu of tailored immunotherapies, e.g., steroids, cytokine monoclonal antibodies, Janus kinase inhibitors. These are not without significant side effects. A gut microbiome approach not only skirts this downside issue but is also much more comprehensive, offering benefits well beyond the integumentary system, e.g., improves diabetes, obesity, lung disease, and some tumors7, not to mention Alzheimer’s disease(AD)8,9. Furthermore, this approach to healthcare puts control back into the hands of the highly motivated patient at less expense and greater convenience.
1. LC, Gut Dysbiosis, and Autoimmune Disease
A decreased CD4+/CD8+ T cell ratio, as seen in AIDS, indicates impaired immune function. An increased ratio, as seen in Covid-19, indicates an overactive immune system. Although impaired CD4+ T cell function in autoimmune disease has been known for decades, CD8+ T cells have recently been identified as key epigenetic contributors, e.g., DNA methylation, in maintaining self recognition10. The loss of CD8+ T cells in LC appears integral to its autoimmune categorization. Autoimmune risk is directly proportional to both Covid 19 severity and age11. Leaky gut syndrome aka dysbiosis is associated with autoimmune disease12,13,14 and is linked to LC15,16. Gut dysbiosis has been associated with other viral infections linked to subsequent autoimmune disease, e.g., EBV17. Leaky gut syndrome stimulates autoimmune pathogenesis. Probiotics containing lactobacilli and bifidobacteria suppress autoimmune risk18.
2. Gut Microbiome of LC, AA, Psoriasis, Vitiligo
Firmicutes and Bacteroidetes are two dominant phyla that together comprise 90% of the total gut microbiota. The F/B ratio is recognized as an important index of gut microbiota health19 and is widely accepted as having an important influence in maintaining normal intestinal homeostasis. Increased or decreased F/B ratio is regarded as dysbiotic. The former is usually observed with obesity and the latter with inflammatory bowel disease (IBD)20. But the real measure of a healthy gut microbiome is an abundance of butyrate producing bacteria21.
The gut microbiome in LC features increased F/B, decreased butyrate producing bacteria, and low biodiversity22,23. In AA the F/B ratio is increased24 and butyrate decreased25. The F/B in the gut microbiome of psoriasis is also increased26 with less biodiversity27 and decreased butyrate producing bacteria28. The gut microbiome of vitiligo also features an increased F/B ratio (twice that of healthy controls)29 and decreased butyrate30.
Decreased butyrate producing bacteria have also been reported in pemphigus vulgaris31 and bullous pemphigoid32.
The increased F/B ratio in the gut microbiome of these three autoimmune skin disorders may be due in part to obesity, which is a risk factor for AA33, psoriasis34, and vitiligo35.
Obesity is also a risk factor for LC36. The adipokines associated with obesity reflect the same cytokine triad signature (TNF-α, IL-6, IL-1β) seen in autoimmune skin disease37. This links the high F/B ratio, low butyrate, low biodiversity in the gut microbiomes that characterize these autoimmune skin disorders and obesity with the cytokine triad they frequently exhibit38,39.
3. The triad of TNF-α, IL-6, and IL-1β in Covid-19, LC, AA, psoriasis, vitiligo, autoimmune disease, cancer, and dementia.
TNF-α, IL-1β, and IL-6 are premiere cytokines linked to autoimmune disease40. TNF-α upregulates IL-1β41 and IL-642. Two other cytokines frequently accompany the triad - IL-17 and IFN-γ. IL-17 can induce the triad (TNFα, IL-6, and IL-1β)43 and in turn can be induced by the triad44. Viruses and fungi, especially Candida, are potent inducers of IFN-γ45,46,47. IFN-γ is especially effective against fungi48 and viruses49. Intermediate levels of IFN-γ(20-150 pg/mL) appear to be beneficial50 and may reflect a healthy gut microbiome51,52, while exhausted levels (<20 pg/mL)49 (LC) and elevated levels (>150 pg/mL) (hospitalization) appear to be unfavorable53.
Females exhibit more robust T cell activation than males54
and produce higher levels of interferon55. Furthermore, estrogen promotes Candida overgrowth56, which fosters gut dysbiosis57. This may explain why 80% of autoimmune disease is seen in females and why LC is encountered more frequently in females. The triad of TNFα, IL-1β, and IL-6 is central to Covid-1958 and LC59,60. This triad of TNF-α, IL-6, and IL-1β is a hallmark of autoimmune disease61,62, cancer63,64 and dementia65. Furthermore, an increased risk of Alzheimer’s disease is linked with psoriasis66, AA67, and vitiligo68.
AD is also tightly linked to the triad of TNF-α, IL-6, and IL-1β69.
4. Prevention and Therapy
A. D-mannose
D-mannose preserves intestinal barrier integrity by blocking TNF-α70. D-mannose can also suppress IL-1β71, IL-672, and IL-1773.
The presence of CD147 (the falciparum antigen) on the spike protein S of SARS CoV2 was initially reported in late 202074. Several articles challenging their report have been discredited75. The immune dysfunction in Covid-19 cannot be explained in the absence of CD147 on the spike protein S. The surface expression of CD147 v ACE2 on CD4+ and CD8+ T cells is overwhelming. This is important, as the immune dysfunction subsequent to the SARS CoV2 induced loss of CD 147+ CD8+ T cells (increased CD4+/CD8+) impacts cytokines prominent in LC.
There are two kinds of T cells - αβ T cells and γδ T cells. The majority are αβ (95% of circulating T cells and 80% of tissue T cells). All αβ T cells express surface CD147. γδ T cells do not76. When CD147+ T cells decrease (AIDS, Covid-19), absolute numbers of CD147- γδ T cells increase77. This means secretion of more TNF-α, IL-17, and especially IFN-γ77,78. Persistent spike protein S (LC) triggers consumption of CD147+ CD8+ T cells with a consequent increase in IFN-γ producing γδ T cells.
TNF-α inhibits mannosidase79, thereby limiting mannose trimming of glycans in the Golgi and increasing oligomannose glycans. Oligomannose glycan shields induced by TNF-α also activate pathogenic γδ T cells to secrete IL-1780. Epidermal γδ T cells are upregulated in AA81, psoriasis73, and vitiligo82,83.
The estrogen driven55 increase in type I interferons (α and β) induces additional STAT dependent IFN-γ secretion that drives the altered tryptophan metabolism until IFN-γ production in the face of persistent spike protein S84 is exhausted (see figure 1). The TNF-α and γδ T cell80 driven IL-17 completes a vicious loop with TNF-α and the triad. By suppressing TNF-α producing T cells and IL-17 producing epidermal γδ T cells d-mannose does double duty in suppressing autoimmune skin disease risk.
D-mannose is considered a prebiotic, because consuming it stimulates the growth of good microbiota. Probiotic capsules contain “good” microbiota, e.g., bifidobacteria and lactobacilli. D-mannose may be especially helpful in preventing gut dysbiosis85,86, tightly linked to autoimmune disease. D-mannose has proven efficacy against autoimmune disease, e.g., T1DM87, rheumatoid arthritis, and lupus88. This prebiotic/probiotic approach is complemented by the postbiotic butyrate.
B. Butyrate
Butyrate is considered a postbiotic because it is produced by gut microbiota. Short chain fatty acids, especially butyrate, suppress IDO and increase serotonin (see figure 1)89,90
The altered tryptophan metabolism seen in Covid-19 and LC91 is due to the shift of tryptophan metabolism from serotonin synthesis to the kynurenine pathway92 (see Figure 1).
This shift is also linked to intestinal dysbiosis and increased risk of autoimmune disease93. The magnitude of the shift is inversely proportional to the CD8+ T cell count (T cell lymphopenia=>increased dysbiosis) and autoimmune risk94.
The kynurenine-to-tryptophan ratio is also directly predictive of Covid severity95, AD96, and cancer risk97.
Butyrate has been directly linked to decreased CRC98 and down regulation of estrogen receptor positive breast cancers99. The butyrate induced increase in serotonin is manifest in the hippocampus, forestalling dementia and AD100. Fungi, especially Candida, have been implicated in AD101 and serotonin actively attenuates pathogenic yeast102, as does butyrate103. AD related amyloid beta bodies are well described in the hippocampus and amyloid beta bodies are linked to Candida104,105. Butyrate also increases transcription of the vitamin D receptor gene106 and vitamin D promotes butyrate producing gut bacteria107.
C. Vitamin D
Vitamin D deficiency is linked with LC108 and is prevalent in autoimmune disease109,110. Vitamin D downregulates NF-κB111, a pro inflammatory cytokine linked to overproduction of the triad. It also suppresses almost all cytokines associated with psoriasis and psoriatic arthritis (see Figure 2 and Figure 3).
D. Magnesium and B Vitamins
Magnesium is a vital cofactor required for the synthesis of both the storage and active forms of vitamin D. Many of the symptoms of LC are associated with hypomagnesemia114.
Deficiency is linked with immune dysfunction and risk of autoimmune disease115.
The growing recognition of differential methylation of DNA in the pathogenesis of autoimmune disease116,117,118 and the linkage between autoimmune disease and elevated Hcy119,120 raises the specter of increased autoimmune disease in those with MTHFR (methylenetetrahydrofolate reductase) variants afflicted with LC. Indeed a recent meta analysis demonstrated a direct connection between MTHFR 677 C/T and 1298 A/C polymorphisms and increased risk of autoimmune disease121. According to the CDC, more than half of Americans have at least one MTHFR polymorphism. MTHFR polymorphisms are associated with AA122, psoriasis123, and vitiligo124. Elevated Hcy is also associated with psoriasis125 and vitiligo126,127. The vital role of magnesium and B vitamin sufficiency in minimizing the deleterious effects of MTHFR polymorphisms is seen in Figure 4. They enhance both the recycling and the degradation of homocysteine. Glutathione is the “master“ antioxidant.

Conclusions

In the most recent reviews on treatment for AA128, psoriasis129, and vitiligo130 TNF-α, IL-6, IL-1β, and IFN-γ have been targets of immunotherapy. These targets may be more comprehensively addressed without toxic side effects by addressing the gut dysbiosis associated with these autoimmune diseases. A regimen of prebiotics, probiotics, postbiotics, vitamin D, and magnesium is at the top of this approach (see Figure 5). This novel therapeutic approach to autoimmune skin diseases outlined in this review is in part theoretical and awaits an appropriately structured randomized controlled trial on the efficacy of d-mannose and butyrate in this regard. It may enhance or possibly replace immunotherapy in some who are so afflicted. Relief would flow to women (LC/autoimmune diseases), especially those of color (AA131, psoriasis132, vitiligo133).

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Figure 1. Roles and relationships of the major players in the altered metabolism of tryptophan, essential to gut dysbiosis, COVID-19, LC, autoimmune disease, AD, and cancer risks. As mitochondrial dysfunction mounts, tryptophan metabolism pivots from serotonin synthesis to the kynurenine pathway and NAD+ synthesis to counter the loss of ATP production.
Figure 1. Roles and relationships of the major players in the altered metabolism of tryptophan, essential to gut dysbiosis, COVID-19, LC, autoimmune disease, AD, and cancer risks. As mitochondrial dysfunction mounts, tryptophan metabolism pivots from serotonin synthesis to the kynurenine pathway and NAD+ synthesis to counter the loss of ATP production.
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Figure 2. Figure discloses a wide range of commercial products targeting cytokines and receptors that promote psoriasis, Crohn’s, RA, MS112.
Figure 2. Figure discloses a wide range of commercial products targeting cytokines and receptors that promote psoriasis, Crohn’s, RA, MS112.
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Figure 3. Figure discloses that all the immunotherapies involving psoriasis and other autoimmune diseases in figure 2 and more are covered by vitamin D113.
Figure 3. Figure discloses that all the immunotherapies involving psoriasis and other autoimmune diseases in figure 2 and more are covered by vitamin D113.
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Figure 4. MTHFR is the rate limiting step. Magnesium is a required cofactor or ATP conjugate and B2,3,6,9,12 are required cofactors for many involved enzymes.
Figure 4. MTHFR is the rate limiting step. Magnesium is a required cofactor or ATP conjugate and B2,3,6,9,12 are required cofactors for many involved enzymes.
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Figure 5. Figure discloses the healthful benefits (green) of a prebiotic, probiotic, postbiotic, vitamin D, and magnesium approach. Triad=TNF-α, IL-6, IL-1β, CRC=colorectal cancer, NF-kB=nuclear factor kappa B. Estrogen promotes Candida overgrowth56.
Figure 5. Figure discloses the healthful benefits (green) of a prebiotic, probiotic, postbiotic, vitamin D, and magnesium approach. Triad=TNF-α, IL-6, IL-1β, CRC=colorectal cancer, NF-kB=nuclear factor kappa B. Estrogen promotes Candida overgrowth56.
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