Long COVID and gut candidiasis: What is the existing relationship?

Table 1 Summary of evidence on the pathophysiological mechanisms related to long coronavirus disease

Proposed etiology	Available evidence	Ref.
Immune dysregulation	The immune profiling of patients recovering from acute COVID-19 shows an up-regulation of immunological signaling molecules associated with inflammation, including ESR, CRP, TNF-α, IL-4, and IL-6	Haunhorst et al[28]
Auto-immunity	Both latent autoimmunity and PolyA have been observed in a high percentage of patients (83% and 62% of cases, respectively). The delayed resolution resulting from low-grade inflammation is evidenced by elevated levels of IL-1β, IL-6, IL-8, and TNF-α. The detection of circulating ANA/ENAs further reinforces this hypothesis	Rojas et al[31], Son et al[32]
Viral antigen persistence	The SARS-CoV-2 NP has been detected in different organs and structures of the body of patients who recovered from COVID-19, such as the gallbladder, lymph nodes, colon, appendix, ileum, hemorrhoid, and liver. In some of these cases, the presence of the viral antigen was observed in all the tissues evaluated, which may therefore predispose to the occurrence of a possible widespread involvement of multiple organs and structures	Cheung et al[33]
Latent virus reactivation	Marked differences in viral reactivities against non-SARS-CoV-2 antigens have been detected in patients with long COVID. In this respect, different herpesvirus antigens, such as the EBV minor viral capsid antigen gp23, the EBV fusion-receptor component gp42, and the varicella zoster virus glycoprotein E can be found in elevated levels in these patients	Klein et al[34]
End-organ damage	The invasive potential of SARS-CoV-2 has been shown to cause damage to different organs. A study that included a sample of young adults, most of whom were free of risk factors for severe COVID-19, found that 66% of the subjects had at least one radiological abnormality in various organs, such as the lungs, liver, pancreas, among others, thus demonstrating the possibility of multisystemic involvement. Organ damage has also been reported in the nervous system (brainstem)	Yong[18], Dennis et al[35]
Endotheliopathy	The levels of different biomarkers of endothelial damage have been observed to be changed in patients with long COVID, including Ang-1, Ang-2, sP-selectin, sICAM-1, VEGF, and vWf, demonstrating an important correlation to the presence of related symptoms	Vassiliou et al[36]
Mitochondrial dysfunction	Increased levels of blood biomarkers together with mitochondrial damage and oxidative stress have been evidenced in cases of long COVID. For example, increased levels of F2-isoprostanes, malondialdehyde, with a respective reduction in the levels of antioxidants (coenzyme Q10). Results from genomic studies have provided additional evidence in this respect. Patients with COVID-19 may exhibit altered gene expression associated with both mitochondrial function and the cellular response to viral infections	Molnar et al[37]
Microbiome dysbiosis	In addition to reduced bacterial diversity, the SCFA-producing salutary commensal bacteria are also significantly reduced in patients with previous COVID-19 history. SCFAs play a key role in regulation of the immune system response	Zhang et al[38]
Metabolic dysregulation	Metabolomic and proteomic profiling of patients with long COVID can aid in determining whether the symptoms of long COVID may be attributed to metabolic dysregulation. In this connection, higher levels of lactate, pyruvate, and total triglycerides, and significantly lower Apo-A1 and A2 levels have been observed in patients with long COVID compared to healthy individuals	Berezhnoy et al[39]
Autonomic nervous system dysfunction	Different mechanisms, such as, direct tissue damage, immune dysregulation, hormonal disturbances, persistent low-grade infection, invasion of SARS-CoV-2 into the brain, and elevated levels of cytokines have been proposed as pathways with potential to lead to reduced levels of vagal activity in patients with COVID-19. Patients with long COVID presenting neurological symptoms have been shown to exhibit higher levels of NfL and glial fibrillary acidic protein, which may be related to persistent axonal damage in such patients	Giunta et al[40], Marchegiani et al[41]

COVID-19: Coronavirus disease 2019; ESR: Erythrocyte sedimentation rate; CRP: C-reactive protein; TNF: Tumor necrosis factor; IL: Interleukin; PolyA: Polyautoimmunity; ANAs: Antinuclear-nuclear antibodies; ENAs: Extractable-nuclear antibodies; SARS-CoV-2: Severe acute respiratory syndrome coronavirus 2; NP: Nucleocapsid protein; COVID: Coronavirus disease; EBV: Epstein-Barr virus; Ang: Angiopoietin; sP-selectin: Soluble platelet selectin; sICAM-1: Soluble intercellular adhesion molecule-1; VEGF: Vascular endothelial growth factor; vWf: von Willebrand factor; SCFAs: Short-chain fatty acids; Apo: Apolipoprotein; NfL: Neurofilament light chain.

Table 2 Proposals for future research investigating the relationship between long coronavirus disease and gut candidiasis

Proposals for future research involving
Studies on the burden of gut candidiasis in patients with long COVID
More in-depth experimental investigations into the related pathophysiological mechanisms
Randomized clinical studies aimed at evaluating potential new therapies
Microbiological investigations to determine with greater predictability the predominant resident microbiota in such conditions
Studies to establish the average duration of gut candidiasis related to long COVID
Impact of using new technologies in case management

Elaborated by the authors. COVID: Coronavirus disease.