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

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 recognition [10]. 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 age [11]. Leaky gut syndrome aka dysbiosis is associated with autoimmune disease [12,13,14] and is linked to LC [15,16]. Gut dysbiosis has been associated with other viral infections linked to subsequent autoimmune disease, e.g., EBV [17]. Leaky gut syndrome stimulates autoimmune pathogenesis. Probiotics containing lactobacilli and bifidobacteria suppress autoimmune risk [18].

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 health [19] 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 bacteria [21].

The gut microbiome in LC features increased F/B, decreased butyrate producing bacteria, and low biodiversity [22,23]. In AA the F/B ratio is increased [24] and butyrate decreased [25]. The F/B in the gut microbiome of psoriasis is also increased [26] with less biodiversity [27] and decreased butyrate producing bacteria [28]. The gut microbiome of vitiligo also features an increased F/B ratio (twice that of healthy controls) [29] and decreased butyrate [30].

Decreased butyrate producing bacteria have also been reported in pemphigus vulgaris [31] and bullous pemphigoid [32].

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 AA [33], psoriasis [34], and vitiligo [35].

Obesity is also a risk factor for LC [36]. The adipokines associated with obesity reflect the same cytokine triad signature (TNF-α, IL-6, IL-1β) seen in autoimmune skin disease [37]. 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 exhibit [38,39].

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 disease [40]. TNF-α upregulates IL-1β [41] and IL-6 [42]. 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 triad [44]. Viruses and fungi, especially Candida, are potent inducers of IFN-γ [45,46,47]. IFN-γ is especially effective against fungi [48] and viruses [49]. Intermediate levels of IFN-γ(20-150 pg/mL) appear to be beneficial [50] and may reflect a healthy gut microbiome [51,52], while exhausted levels (<20 pg/mL) [49] (LC) and elevated levels (>150 pg/mL) (hospitalization) appear to be unfavorable [53].

Females exhibit more robust T cell activation than males [54] and produce higher levels of interferon [55]. Furthermore, estrogen promotes Candida overgrowth [56], which fosters gut dysbiosis [57]. 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-19 [58] and LC [59,60]. This triad of TNF-α, IL-6, and IL-1β is a hallmark of autoimmune disease [61,62], cancer [63,64] and dementia [65]. Furthermore, an increased risk of Alzheimer’s disease is linked with psoriasis [66], AA [67], and vitiligo [68].

AD is also tightly linked to the triad of TNF-α, IL-6, and IL-1β [69].

4. Prevention and Therapy

A. D-mannose

D-mannose preserves intestinal barrier integrity by blocking TNF-α [70]. D-mannose can also suppress IL-1β [71], IL-6 [72], and IL-17 [73].

The presence of CD147 (the falciparum antigen) on the spike protein S of SARS CoV2 was initially reported in late 2020 [74]. Several articles challenging their report have been discredited [75]. 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 not [76]. When CD147+ T cells decrease (AIDS, Covid-19), absolute numbers of CD147- γδ T cells increase [77]. This means secretion of more TNF-α, IL-17, and especially IFN-γ [77,78]. 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 mannosidase [79], 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-17 [80]. Epidermal γδ T cells are upregulated in AA [81], psoriasis [73], and vitiligo [82,83].

The estrogen driven [55] 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 S [84] is exhausted (see Figure 1). The TNF-α and γδ T cell [80] 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 dysbiosis [85,86], tightly linked to autoimmune disease. D-mannose has proven efficacy against autoimmune disease, e.g., T1DM [87], rheumatoid arthritis, and lupus [88]. 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 LC [91]

is due to the shift of tryptophan metabolism from serotonin synthesis to the kynurenine pathway [92] (see Figure 1).

This shift is also linked to intestinal dysbiosis and increased risk of autoimmune disease [93]. The magnitude of the shift is inversely proportional to the CD8+ T cell count (T cell lymphopenia=>increased dysbiosis and autoimmune risk [94].

The kynurenine-to-tryptophan ratio is also directly predictive of Covid severity [95], AD [96], and cancer risk [97].

Butyrate has been directly linked to decreased CRC [98] and down regulation of estrogen receptor positive breast cancers [99]. The butyrate induced increase in serotonin is manifest in the hippocampus, forestalling dementia and AD [100]. Fungi, especially Candida, have been implicated in AD [101] and serotonin actively attenuates pathogenic yeast [102], as does butyrate [103]. AD related amyloid beta bodies are well described in the hippocampus and amyloid beta bodies are linked to Candida [104,105].

Butyrate also increases transcription of the vitamin D receptor gene [106] and vitamin D promotes butyrate producing gut bacteria [107].

C. Vitamin D

Vitamin D deficiency is linked with LC [108] and is prevalent in autoimmune disease [109,110]. Vitamin D downregulates NF-κB [111], 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 hypomagnesemia [114].

Deficiency is linked with immune dysfunction and risk of autoimmune disease [115].

The growing recognition of differential methylation of DNA and RNA in the pathogenesis of autoimmune disease [116,117,118] and the linkage between autoimmune disease and elevated Hcy [119,120] 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 disease [121]. According to the CDC, more than half of Americans have at least one MTHFR polymorphism.

MTHFR polymorphisms are associated with AA [122], psoriasis [123], and vitiligo [124]. Elevated Hcy is also associated with psoriasis [125].

and vitiligo [126,127].

The vital role of magnesium and B vitamin sufficiency in minimizing the deleterious effects of MTHFR polymorphisms is seen in Figure 4.