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

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.

Source: Chambers, P.W.; Chambers, S.E. Long Covid, the Gut, and Autoimmune Skin Diseases: A Novel Therapeutic Approach. Preprints 2023, 2023121881. https://doi.org/10.20944/preprints202312.1881.v2 https://www.preprints.org/manuscript/202312.1881/v2 (Full text available as PDF file)

How Patient Input Helped Create Culturally Sensitive Multinational Instruments Assessing Post Viral Symptoms

Our study involves collaboration/participation in order to develop culturally sensitive multinational tools for assessing post viral symptoms.

We discuss the creation of questionnaires using patient participation, and the translation of these questionnaires using international collaboration.

Patient engagement in collaboration on the creation and use of these types of instruments is of particular importance for patients who historically have not been true partners in collaborative efforts to understand diseases.

This has occurred for those with the post-viral illness called Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS), which has generated considerable resentment and estrangement among the patient community.

Our article reviews:

1) why participation of diverse groups/patients is important in the development of instruments to measure key symptoms of ME/CFS,

2) why the ME/CFS group of patients needs to be included specifically (as an example),

and

3) why structured health questionnaires are important/useful.

Our article also has an overall aim of demonstrating collaborative efforts with patients and others on creating multinational scales.

We provide examples of participatory processes used in developing and translating patient-driven instruments so that they can be used in non-English speaking countries.

Our article illustrates how patients and international researchers can be involved in efforts to develop and translate international assessment instruments to validly capture domains of unexplained illness like ME/CFS.

With the onset of another post-viral illness, Long COVID, there is a world-wide need to create valid and culturally sensitive assessment instruments to measure critical symptoms, many of which are similar to ME/CFS.

Source: Leonard A. Jason and Joseph A. Dorri. How Patient Input Helped Create Culturally Sensitive Multinational Instruments Assessing Post Viral Symptoms. The Australian Community Psychologist., Volume 32 No 1  https://psychology.org.au/getmedia/c300a432-c7fd-4f97-9322-ce16429067e4/ac-vol-32(1)-2023-final-draft.pdf#page=63 (Full text)

Subcortical and Default Mode Network connectivity is impaired in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

Abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a complex chronic condition with core symptoms of fatigue, and cognitive dysfunction suggesting a key role for the central nervous system, in the pathophysiology of this disease. Several studies have reported altered functional connectivity (FC) related to motor and cognitive deficits in ME/CFS patients. In this study, we compared functional connectivity differences between 31 ME/CFS and 15 healthy controls (HC) using 7 Tesla MRI. Functional scans were acquired during a cognitive Stroop color-word task and blood oxygen level-dependent (BOLD) time-series were computed for 27 regions of interest (ROIs) in the cerebellum, brainstem, and salience and default mode networks.

Region-based comparison detected reduced FC between the pontine nucleus and cerebellum vermis IX (p=0.027) for ME/CFS patients compared to HC. Our ROI-to-voxel analysis found significant impairment of FC within ponto-cerebellar regions in ME/CFS. Correlation analyses of connectivity with clinical scores in ME/CFS patients detected associations of FC with ‘duration of illness’ and ‘memory scores’ in salience network hubs and cerebellum vermis, and with ‘respiratory rate’ within medulla and the default mode network FC.

This novel investigation is the first to report extensive involvement of aberrant ponto-cerebellar connections consistent with ME/CFS symptomatology. This highlights the involvement of the brainstem and the cerebellum in the pathomechanism of ME/CFS.

Source: Maira INDERYAS, Kiran Thapaliya, Sonya Marshall-Gradisnik, Markus Barth, Leighton Barnden. Subcortical and Default Mode Network connectivity is impaired in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Front. Neurosci. Sec. Brain Imaging Methods. Volume 17 – 2023 | doi: 10.3389/fnins.2023.1318094 https://www.frontiersin.org/articles/10.3389/fnins.2023.1318094/full (Full text)

Identification of CD8 T-cell dysfunction associated with symptoms in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and Long COVID and treatment with a nebulized antioxidant/anti-pathogen agent in a retrospective case series

Highlights:

• Both Long COVID and ME/CFS are characterized by dysfunctional CD8 T-cells with severe deficiencies in their abilities to produce IFNγ and TNFα.

• In a small Long COVID and ME/CFS case series, patients’ immune deficiency and health improve during treatment period with a nebulized antioxidant, anti-pathogen and immune-modulatory pharmacological agent.

• This work provides evidence of a useful biomarker, CD8 T-cell dysfunction reminiscent of T cell exhaustion, that may assist diagnosis and have utility for tracking disease outcome during therapy, including response to a potential new treatment.

Abstract:

Background: Patients with post-acute sequelae of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection (PASC, i.e., Long COVID) have a symptom complex highly analogous to many features of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), suggesting they may share some aspects of pathogenesis in these similar disorders. ME/CFS is a complex disease affecting numerous organ systems and biological processes and is often preceded by an infection-like episode. It is postulated that the chronic manifestations of illness may result from an altered host response to infection or inability to resolve inflammation, as is being reported in Long COVID. The immunopathogenesis of both disorders is still poorly understood. Here, we show data that suggest Long COVID and ME/CFS may be due to an aberrant response to an immunological trigger-like infection, resulting in a dysregulated immune system with CD8 T-cell dysfunction reminiscent of some aspects of T-cell clonal exhaustion, a phenomenon associated with oxidative stress. As there is an urgent need for diagnostic tools and treatment strategies for these two related disabling disorders, here, in a retrospective case series, we have also identified a potential nebulized antioxidant/anti-pathogen treatment that has evidence of a good safety profile. This nebulized agent is comprised of five ingredients previously reported individually to relieve oxidative stress, attenuate NF-κB signaling, and/or to act directly to inhibit pathogens, including viruses. Administration of this treatment by nebulizer results in rapid access of small doses of well-studied antioxidants and agents with anti-pathogen potential to the lungs; components of this nebulized agent are also likely to be distributed systemically, with potential to enter the central nervous system.

Methods and Findings: We conducted an analysis of CD8 T-cell function and severity of symptoms by self-report questionnaires in ME/CFS, Long COVID and healthy controls. We developed a CD8 T-cell functional assay, assessing CD8 T-cell dysfunction by intracellular cytokine staining (ICS) in a group of ME/CFS (n = 12) and Long COVID patients (n = 8), comparing to healthy controls (HC) with similar age and sex (n = 10). Magnet-enriched fresh CD8 T-cells in both patient groups had a significantly diminished capacity to produce both cytokines, IFNγ or TNFα, after PMA stimulation when compared to HC. The symptom severity questionnaire showed similar symptom profiles for the two disorders. Fortuitously, through a retrospective case series, we were able to examine the ICS and questionnaire data of 4 ME/CFS and 4 Long COVID patients in conjunction with their treatment (3–15 months). In parallel with the treatment pursued electively by participants in this retrospective case series, there was an increase in CD8 T-cell IFNγ and TNFα production and a decrease in overall self-reported symptom severity score by 54%. No serious treatment-associated side effects or laboratory anomalies were noted in these patients.

Conclusions: Here, in this small study, we present two observations that appear potentially fundamental to the pathogenesis and treatment of Long COVID and ME/CFS. The first is that both disorders appear to be characterized by dysfunctional CD8 T-cells with severe deficiencies in their abilities to produce IFNγ and TNFα. The second is that in a small retrospective Long COVID and ME/CFS case series, this immune dysfunction and patient health improved in parallel with treatment with an immunomodulatory, antioxidant pharmacological treatment with anticipated anti-pathogen activity. This work provides evidence of the potential utility of a biomarker, CD8 T-cell dysfunction, and suggests the potential for benefit from a new nebulized antioxidant/anti-pathogen treatment. These immune biomarker data may help build capacity for improved diagnosis and tracking of treatment outcomes during clinical trials for both Long COVID and ME/CFS while providing clues to new treatment avenues that suggest potential efficacy for both conditions.

Source: Gil, A., Hoag, G.E., Salerno, J.P., Hornig, M., Klimas, N., Selin, L.K. Identification of CD8 T-cell dysfunction associated with symptoms in myalgic encephalomyelitis/ chronic fatigue syndrome (ME/CFS) and Long COVID and treatment with a nebulized antioxidant/antipathogen agent in a retrospective case series. Brain, Behavior, & Immunity – Health (2024), doi: https://doi.org/10.1016/j.bbih.2023.100720 https://www.sciencedirect.com/science/article/pii/S2666354623001345 (Full text)

The potential role of ocular and otolaryngological mucus proteins in myalgic encephalomyelitis/chronic fatigue syndrome

Abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating illness associated with a constellation of other symptoms. While the most common symptom is unrelenting fatigue, many individuals also report suffering from rhinitis, dry eyes and a sore throat.

Mucin proteins are responsible for contributing to the formation of mucosal membranes throughout the body. These mucosal pathways contribute to the body’s defense mechanisms involving pathogenic onset. When compromised by pathogens the epithelium releases numerous cytokines and enters a prolonged state of inflammation to eradicate any particular infection.

Based on genetic analysis, and computational theory and modeling we hypothesize that mucin protein dysfunction may contribute to ME/CFS symptoms due to the inability to form adequate mucosal layers throughout the body, especially in the ocular and otolaryngological pathways leading to low grade chronic inflammation and the exacerbation of symptoms.

Source: Huitsing K, Tritsch T, Arias FJC, Collado F, Aenlle KK, Nathason L, Fletcher MA, Klimas NG, Craddock TJA. The potential role of ocular and otolaryngological mucus proteins in myalgic encephalomyelitis/chronic fatigue syndrome. Mol Med. 2024 Jan 3;30(1):1. doi: 10.1186/s10020-023-00766-8. PMID: 38172662. https://molmed.biomedcentral.com/articles/10.1186/s10020-023-00766-8 (Full text)

Conceptual foundations of acetylcarnitine supplementation in neuropsychiatric long COVID syndrome: a narrative review

Abstract:

Post-acute sequelae of COVID-19 can present as multi-organ pathology, with neuropsychiatric symptoms being the most common symptom complex, characterizing long COVID as a syndrome with a significant disease burden for affected individuals. Several typical symptoms of long COVID, such as fatigue, depressive symptoms and cognitive impairment, are also key features of other psychiatric disorders such as myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and major depressive disorder (MDD). However, clinically successful treatment strategies are still lacking and are often inspired by treatment options for diseases with similar clinical presentations, such as ME/CFS.

Acetylcarnitine, the shortest metabolite of a class of fatty acid metabolites called acylcarnitines and one of the most abundant blood metabolites in humans can be used as a dietary/nutritional supplement with proven clinical efficacy in the treatment of MDD, ME/CFS and other neuropsychiatric disorders. Basic research in recent decades has established acylcarnitines in general, and acetylcarnitine in particular, as important regulators and indicators of mitochondrial function and other physiological processes such as neuroinflammation and energy production pathways.

In this review, we will compare the clinical basis of neuropsychiatric long COVID with other fatigue-associated diseases. We will also review common molecular disease mechanisms associated with altered acetylcarnitine metabolism and the potential of acetylcarnitine to interfere with these as a therapeutic agent. Finally, we will review the current evidence for acetylcarnitine as a supplement in the treatment of fatigue-associated diseases and propose future research strategies to investigate the potential of acetylcarnitine as a treatment option for long COVID.

Source: Helbing DL, Dommaschk EM, Danyeli LV, Liepinsh E, Refisch A, Sen ZD, Zvejniece L, Rocktäschel T, Stabenow LK, Schiöth HB, Walter M, Dambrova M, Besteher B. Conceptual foundations of acetylcarnitine supplementation in neuropsychiatric long COVID syndrome: a narrative review. Eur Arch Psychiatry Clin Neurosci. 2024 Jan 3. doi: 10.1007/s00406-023-01734-3. Epub ahead of print. PMID: 38172332. https://link.springer.com/article/10.1007/s00406-023-01734-3 (Full text)

KombOver: Efficient k-core and K-truss based characterization of perturbations within the human gut microbiome

Abstract:

The microbes present in the human gastrointestinal tract are regularly linked to human health and disease outcomes. Thanks to technological and methodological advances in recent years, metagenomic sequencing data, and computational methods designed to analyze metagenomic data, have contributed to improved understanding of the link between the human gut microbiome and disease. However, while numerous methods have been recently developed to extract quantitative and qualitative results from host-associated microbiome data, improved computational tools are still needed to track microbiome dynamics with short-read sequencing data.

Previously we have proposed KOMB as a de novo tool for identifying copy number variations in metagenomes for characterizing microbial genome dynamics in response to perturbations. In this work, we present KombOver (KO), which includes four key contributions with respect to our previous work: (i) it scales to large microbiome study cohorts, (ii) it includes both k-core and K-truss based analysis, (iii) we provide the foundation of a theoretical understanding of the relation between various graph-based metagenome representations, and (iv) we provide an improved user experience with easier-to-run code and more descriptive outputs/results.

To highlight the aforementioned benefits, we applied KO to nearly 1000 human microbiome samples, requiring less than 10 minutes and 10 GB RAM per sample to process these data. Furthermore, we highlight how graph-based approaches such as k-core and K-truss can be informative for pinpointing microbial community dynamics within a myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) cohort. KO is open source and available for download/use at: https://github.com/treangenlab/komb.

Source: Sapoval N, Tanevski M, Treangen TJ. KombOver: Efficient k-core and K-truss based characterization of perturbations within the human gut microbiome. Pac Symp Biocomput. 2024;29:506-520. PMID: 38160303; PMCID: PMC10764071. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10764071/ (Full text)

Muscle abnormalities worsen after post-exertional malaise in long COVID

Abstract:

A subgroup of patients infected with SARS-CoV-2 remain symptomatic over three months after infection. A distinctive symptom of patients with long COVID is post-exertional malaise, which is associated with a worsening of fatigue- and pain-related symptoms after acute mental or physical exercise, but its underlying pathophysiology is unclear.

With this longitudinal case-control study (NCT05225688), we provide new insights into the pathophysiology of post-exertional malaise in patients with long COVID. We show that skeletal muscle structure is associated with a lower exercise capacity in patients, and local and systemic metabolic disturbances, severe exercise-induced myopathy and tissue infiltration of amyloid-containing deposits in skeletal muscles of patients with long COVID worsen after induction of post-exertional malaise. This study highlights novel pathways that help to understand the pathophysiology of post-exertional malaise in patients suffering from long COVID and other post-infectious diseases.

Source: Appelman, B., Charlton, B.T., Goulding, R.P. et al. Muscle abnormalities worsen after post-exertional malaise in long COVID. Nat Commun 15, 17 (2024). https://doi.org/10.1038/s41467-023-44432-3 https://www.nature.com/articles/s41467-023-44432-3 (Full text)

Heterogenous circulating miRNA changes in ME/CFS converge on a unified cluster of target genes: A computational analysis

Abstract:

Myalgic Encephalomyelitis / Chronic Fatigue Syndrome is a debilitating, multisystem disease of unknown mechanism, with a currently ongoing search for its endocrine mediators. Circulating microRNAs (miRNA) are a promising candidate for such a mediator and have been reported as significantly different in the patient population versus healthy controls by multiple studies. None of these studies, however, agree with each other on which specific miRNA are under- or over-expressed.

This discrepancy is the subject of the computational study presented here, in which a deep dive into the predicted gene targets and their functional interactions is conducted, revealing that the aberrant circulating miRNAs in ME/CFS, although different between patients, seem to mainly target the same specific set of genes (p ≈ 0.0018), which are very functionally related to each other (p ≲ 0.0001).

Further analysis of these functional relations, based on directional pathway information, points to impairments in exercise hyperemia, angiogenic adaptations to hypoxia, antioxidant defenses, and TGF-β signaling, as well as a shift towards mitochondrial fission, corroborating and explaining previous direct observations in ME/CFS. Many transcription factors and epigenetic modulators are implicated as well, with currently uncertain downstream combinatory effects.

As the results show significant similarity to previous research on latent herpesvirus involvement in ME/CFS, the possibility of a herpesvirus origin of these miRNA changes is also explored through further computational analysis and literature review, showing that 8 out of the 10 most central miRNAs analyzed are known to be upregulated by various herpesviruses. In total, the results establish an appreciable and possibly central role for circulating microRNAs in ME/CFS etiology that merits further experimental research.

Source: Kaczmarek MP. Heterogenous circulating miRNA changes in ME/CFS converge on a unified cluster of target genes: A computational analysis. PLoS One. 2023 Dec 29;18(12):e0296060. doi: 10.1371/journal.pone.0296060. PMID: 38157384; PMCID: PMC10756525. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10756525/ (Full text)

Role of pharmacological activity of autoantibodies in ME/CFS

Abstract:

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a condition characterised by extreme fatigue, memory impairment, pain and other symptoms that vary from patient to patient. It affects about 0.9% of the population and is often triggered by an acute viral or bacterial infection, such as Epstein-Barr virus. The underlying physiological and molecular basis of ME/CFS is unknown, and no effective treatments exist.

One proposed mechanism is that the blood flow is altered by autoantibodies against receptors involved in blood flow regulation. Antibodies are generated by the immune system to recognise intruders and under normal conditions, our immune system is trained not to attack our own tissues. However, during a severe infection, the immune system adopts an “all hands on deck” approach, which results in some of the newly-produced antibodies escaping quality control and targeting our own tissues, autoantibodies. Receptors regulation blood flow are located in walls of blood vessels and cause a blood vessel to dilate or contract as the demand for oxygen and nutrients to tissues such as the brain or muscles changes. Research has found increased levels of these autoantibodies in ME/CFS patients and initial trials removing these autoantibodies from the blood using a technique called immunoadsorption have shown improvement in symptoms.

In this project, we will test the hypothesis that autoantibodies can activate or inhibit the receptors responsible for the blood flow regulation, in a similar way medical drugs are used to regulate blood pressure.
We aim to profile serum samples from 325 ME/CFS patients and 130 healthy individuals to determine the presence of autoantibodies against all thirty receptors involved in blood pressure regulation. Importantly, we will study the ability of autoantibodies detected in each sample to activate or inhibit these receptors in order to test the hypothesis that the activity of these autoantibodies is a decisive factor in the disease.
If our hypothesis is correct, we will be able to develop an accurate blood test that may be able to detect ME/CFS earlier or to independently confirm the diagnosis. Ultimately, we hope that these results may also indicate a possible route for therapeutic intervention to counteract the effects of autoantibodies and alleviate the ME/CFS symptoms using a combination of already existing drugs, specific for each individual case.

 

Technical Summary:

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a condition of extreme tiredness and brain fog, often triggered by an acute infection. Its prevalence is ca 0.9% and here is no effective treatment. Competing theories for the root cause of ME/CFS include metabolic or redox homeostasis disruption, and presence of autoantibodies (AABs) against G protein coupled receptors (GPCRs) involved in regulation of blood flow.
Triggered by acute infection, autoimmunity is a result of reduced immuno-vigilance during severe infections, when an “all hands on deck” approach confers survival advantage. About 30% of ME/CFS patients show increased titre of autoantibodies against beta2-adrenoceptor and M3/4 muscarinic receptors controlling vasodilation/vasoconstriction, but this could become higher if all 30 receptors controlling blood flow would be taken into account.
In this project, we will test a hypothesis that the pharmacological activity of AABs against GPCRs is the key to their involvement in ME/CFS. Similar to medical drugs, AABs can be stimulatory (agonistic) or inhibitory (antagonistic) and induce a therapeutic or an undesired side effect.
We will profile 325 patient samples and 130 control plasma samples for AABs and their pharmacological activity using a state-of-the art GPCR drug screening pipeline we have established, against all 30 GPCRs involved in blood pressure regulation. We also have machine learning expertise that would allow us to interpret this extensive dataset, extract the most salient features. This will advance the understanding of the molecular basis of ME/CFS and could form the basis of a robust diagnostic blood test for ME/CFS. Ultimately, our findings may point in the direction of developing combination therapy using repurposed drugs to counteract the effects of autoantibodies and mitigate ME/CFS symptoms and stimulate the development of specific B-cell elimination strategy to cure ME/CFS.
Source: Lead Research Organisation: University of Nottingham, Department Name: School of Life Sciences. https://gtr.ukri.org/projects?ref=MR%2FY003667%2F1&pn=0&fetchSize=25&selectedSortableField=date&selectedSortOrder=ASC