Tag: 2024

An approach to finding specific forms of dysbiosis that associate with different disorders

Abstract:

Background Many disorders display dysbiosis of the enteric microbiome, compared with healthy controls. Different disorders share a pattern of dysbiosis that may reflect ‘reverse causation’, due to non-specific effects of illness-in-general. Combining a range of disorders into an ‘aggregate non-healthy active control’ (ANHAC) group should highlight such non-specific dysbiosis. Differential dysbiosis between the ANHAC group and specific disorders may then reflect effects of treatment or bowel dysfunction, or may potentially be causal. Here, we illustrate this logic by testing if individual genera can differentiate an ANHAC group from two specific diagnostic groups.

Methods We constructed an ANAHC group (n=17) that had 14 different disorders. We then used random forest analyses to test differential dysbiosis between the ANHAC group and two other disorders that have no known pathology, but: (i) symptoms of illness (Myalgic Encephalomyelitis / Chronic Fatigue Syndrome – ME/CFS – n = 38); or (ii) both illness and bowel dysfunction (ME/CFS comorbid with Irritable Bowel Syndrome – IBS – n=27).

Results Many genera differentiated the ANHAC group from co-morbid IBS. However, only two genera – Roseburia and Dialister – discriminated the ANHAC group from ME/CFS.

Conclusions Different disorders can associate with specific forms of dysbiosis, over-and-above non-specific effects of illness-in-general. Bowel dysfunction may contribute to dysbiosis in IBS via reverse causation. However, ME/CFS has symptoms of illness-in-general, but lacks known pathology or definitive treatment that could cause dysbiosis. Therefore, the specific dysbiosis in ME/CFS may be causal. [230 words]

Contribution to the field Many disorders associate with enteric dysbiosis. The pattern of dysbiosis is largely consistent between unrelated disorders, which suggests that it mainly reflects non-specific secondary effects of illness-in-general (e.g. due to changes in activity levels, or diet). However, faecal microbiome transplantation (FMT) can be therapeutic in some disorders. This implies that unique features of dysbiosis may cause those specific disorders. Here, we propose a way to assess causal effects of dysbiosis, by testing if individual genera can discriminate individual disorders from an ‘aggregate non-healthy active control’ (ANHAC) group. Dysbiosis in the ANHAC group can control for non-specific effects of illness-in-general on the microbiome and so highlight potentially-causal forms of dysbiosis in specific disorders. This approach may provide insight into pathogenetic mechanisms of individual disorders and help to design specific forms of FMT to counteract them.

Source: Jonathan Williams, Inga Williams, Karl Morten, Julian Kenyon. An approach to finding specific forms of dysbiosis that associate with different disorders. medRxiv 2024.04.23.24306162; doi: https://doi.org/10.1101/2024.04.23.24306162 https://www.medrxiv.org/content/10.1101/2024.04.23.24306162v1 (Full text available as PDF file)

Development of an expert system for the classification of myalgic encephalomyelitis/chronic fatigue syndrome

Abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a severe condition with an uncertain origin and a dismal prognosis. There is presently no precise diagnostic test for ME/CFS, and the diagnosis is determined primarily by the presence of certain symptoms. The current study presents an explainable artificial intelligence (XAI) integrated machine learning (ML) framework that identifies and classifies potential metabolic biomarkers of ME/CFS.

Metabolomic data from blood samples from 19 controls and 32 ME/CFS patients, all female, who were between age and body mass index (BMI) frequency-matched groups, were used to develop the XAI-based model. The dataset contained 832 metabolites, and after feature selection, the model was developed using only 50 metabolites, meaning less medical knowledge is required, thus reducing diagnostic costs and improving prognostic time. The computational method was developed using six different ML algorithms before and after feature selection. The final classification model was explained using the XAI approach, SHAP.

The best-performing classification model (XGBoost) achieved an area under the receiver operating characteristic curve (AUCROC) value of 98.85%. SHAP results showed that decreased levels of alpha-CEHC sulfate, hypoxanthine, and phenylacetylglutamine, as well as increased levels of N-delta-acetylornithine and oleoyl-linoloyl-glycerol (18:1/18:2)[2], increased the risk of ME/CFS. Besides the robustness of the methodology used, the results showed that the combination of ML and XAI could explain the biomarker prediction of ME/CFS and provided a first step toward establishing prognostic models for ME/CFS.

Source: Yagin FH, Shateri A, Nasiri H, Yagin B, Colak C, Alghannam AF. Development of an expert system for the classification of myalgic encephalomyelitis/chronic fatigue syndrome. PeerJ Comput Sci. 2024 Mar 20;10:e1857. doi: 10.7717/peerj-cs.1857. PMID: 38660205; PMCID: PMC11041999. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11041999/ (Full text)

SARS-CoV-2 Mitochondrial Metabolic and Epigenomic Reprogramming in COVID-19

Abstract:

To determine the effects of SARS-CoV-2 infection on cellular metabolism, we conducted an exhaustive survey of the cellular metabolic pathways modulated by SARS-CoV-2 infection and confirmed their importance for SARS-CoV-2 propagation by cataloging the effects of specific pathway inhibitors. This revealed that SARS-CoV-2 strongly inhibits mitochondrial oxidative phosphorylation (OXPHOS) resulting in increased mitochondrial reactive oxygen species (mROS) production.

The elevated mROS stabilizes HIF-1α which redirects carbon molecules from mitochondrial oxidation through glycolysis and the pentose phosphate pathway (PPP) to provide substrates for viral biogenesis. mROS also induces the release of mitochondrial DNA (mtDNA) which activates innate immunity. The restructuring of cellular energy metabolism is mediated in part by SARS-CoV-2 Orf8 and Orf10 whose expression restructures nuclear DNA (nDNA) and mtDNA OXPHOS gene expression.

These viral proteins likely alter the epigenome, either by directly altering histone modifications or by modulating mitochondrial metabolite substrates of epigenome modification enzymes, potentially silencing OXPHOS gene expression and contributing to long-COVID.

Source: Guarnieri JW, Haltom JA, Albrecht YES, Lie T, Olali AZ, Widjaja GA, Ranshing SS, Angelin A, Murdock D, Wallace DC. SARS-CoV-2 Mitochondrial Metabolic and Epigenomic Reprogramming in COVID-19. Pharmacol Res. 2024 Apr 11:107170. doi: 10.1016/j.phrs.2024.107170. Epub ahead of print. PMID: 38614374. https://www.sciencedirect.com/science/article/pii/S1043661824001142 (Full text)

Long COVID-19 and Peripheral Serotonin: A Commentary and Reconsideration

Abstract:

We believe there are serious problems with a recently published and highly publicized paper entitled “Serotonin reduction in post-acute sequelae of viral infection.” The blood centrifugation procedure reportedly used by Wong et al would produce plasma that is substantially (over 95%) depleted of platelets. Given this, their published mean plasma serotonin values of 1.2 uM and 2.4 uM for the control/contrast groups appear to be at least 30 to 60 times too high and should be disregarded. The plasma serotonin values reported for the long COVID and viremia patients also should be disregarded, as should any comparisons to the control/contrast groups.

We also note that the plasma serotonin means for the two control/contrast groups are not in good agreement. In the “Discussion” section, Wong et al state that their results tend to support the use of selective serotonin reuptake inhibitors (SSRIs) for the treatment of COVID-19, and they encourage further clinical trials of SSRIs. While they state that, “Our animal models demonstrate that serotonin levels can be restored and memory impairment reversed by precursor supplementation or SSRI treatment”, it should be noted that no data are presented showing an increase or restoration in circulating serotonin with SSRI administration.

In fact, one would expect a marked decline in platelet serotonin due to SSRIs’ effective inhibition of the platelet serotonin transporter. Wong et al hypothesize that problems of long COVID arise from too little peripheral serotonin. However, given the frequent presence of a hyperaggregation state in long COVID, and the known augmenting effects of platelet serotonin on platelet aggregation, it is plausible to suggest that reductions in platelet serotonin might be associated with a lessening of the cardiovascular sequelae of COVID-19.

Source: Anderson GM, Cook EH, Blakely RD, Sutcliffe JS, Veenstra-VanderWeele J. Long COVID-19 and Peripheral Serotonin: A Commentary and Reconsideration. J Inflamm Res. 2024 Apr 11;17:2169-2172. doi: 10.2147/JIR.S456000. PMID: 38628604; PMCID: PMC11019386. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11019386/ (Full text)

Recovery of neurophysiological measures in post-COVID fatigue: a 12-month longitudinal follow-up study

Abstract:

One of the major consequences of the COVID-19 pandemic has been the significant incidence of persistent fatigue following resolution of an acute infection (i.e. post-COVID fatigue). We have shown previously that, in comparison to healthy controls, those suffering from post-COVID fatigue exhibit changes in muscle physiology, cortical circuitry, and autonomic function. Whether these changes preceded infection, potentially predisposing people to developing post-COVID fatigue, or whether the changes were a consequence of infection was unclear.

Here we present results of a 12-month longitudinal study of 18 participants from the same cohort of post-COVID fatigue sufferers to investigate these correlates of fatigue over time. We report improvements in self-perception of the impact of fatigue via questionnaires, as well as significant improvements in objective measures of peripheral muscle fatigue and autonomic function, bringing them closer to healthy controls. Additionally, we found reductions in muscle twitch tension rise times, becoming faster than controls, suggesting that the improvement in muscle fatigability might be due to a process of adaptation rather than simply a return to baseline function.

Source: Maffitt NJ, Germann M, Baker AME, Baker MR, Baker SN, Soteropoulos DS. Recovery of neurophysiological measures in post-COVID fatigue: a 12-month longitudinal follow-up study. Sci Rep. 2024 Apr 17;14(1):8874. doi: 10.1038/s41598-024-59232-y. PMID: 38632415; PMCID: PMC11024107. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11024107/ (Full text)

Exploring the Experience of Healthcare-Related Epistemic Injustice among People with Myalgic Encephalomyelitis / Chronic Fatigue Syndrome

Abstract:

Myalgic encephalomyelitis / chronic fatigue syndrome (ME/CFS) is a chronic, disabling yet clinically “contested” condition, previously theorised through a lens of epistemic injustice. Phenomena conceptually close to epistemic injustice, including stigma, are known to have deleterious consequences on a person’s health and life-world. Yet, no known primary studies have explored how people with ME/CFS experience healthcare through a lens of epistemic injustice, whilst a dearth of research explicitly exploring healthcare-related injustice from a patient perspective has been noted. This qualitative study seeks to address this gap.

Semi-structured interviews and interpretative phenomenological analysis (IPA) were used to explore the experiences of five people with ME/CFS in the UK, vis-à-vis healthcare-related epistemic injustice. One superordinate theme is presented, “Being de-centred in patient-centred care,” alongside two sub-themes: “Struggling for epistemic-existential validation” and “Negotiating socio-epistemic hierarchies, politics and ‘power’.”

Findings suggest that healthcare-related epistemic injustice may differentially impact according to the patient’s social positionality (here, notably gender), and that a potential pathway of existential harm operates through threats to identity and personhood. Findings also indicate that cultural and political factors may further epistemic injustice in healthcare. Finally, epistemic injustice impacting as a chronic stressor cannot be ruled out and is worthy of further research.

The experience of healthcare-related epistemic injustice can carry far-reaching yet varied consequences for patients. Future research should consider drawing upon more socio-demographically diverse samples and an intersectional approach is recommended. Further exploration of structural drivers of epistemic injustice may highlight a need for politically and socio-culturally cognisant clinical approaches.

Source: Hunt, J., Runacres, J., Herron, D., & Sheffield, D. (2024). Exploring the Experience of Healthcare-Related Epistemic Injustice among People with Myalgic Encephalomyelitis / Chronic Fatigue Syndrome. The Qualitative Report, 29(4), 1125-1148. https://doi.org/10.46743/2160-3715/2024.6519 https://nsuworks.nova.edu/tqr/vol29/iss4/15/ (Full text available as PDF file)

Fibroblast growth factor receptor inhibitors mitigate the neuropathogenicity of Borrelia burgdorferi or its remnants ex vivo

Abstract:

In previous studies, we showed that fibroblast growth factor receptors (FGFRs) contribute to inflammatory mediator output from primary rhesus microglia in response to live Borrelia burgdorferi. We also demonstrated that non-viable B. burgdorferi can be as pathogenic as live bacteria, if not more so, in both CNS and PNS tissues.

In this study we assessed the effect of live and non-viable B. burgdorferi in inducing FGFR expression from rhesus frontal cortex (FC) and dorsal root ganglion (DRG) tissue explants as well as their neuronal/astrocyte localization. Specific FGFR inhibitors were also tested for their ability to attenuate inflammatory output and apoptosis in response to either live or non-viable organisms.

Results show that in the FC, FGFR2 was the most abundantly expressed receptor followed by FGFR3 and FGFR1. Non-viable B. burgdorferi significantly upregulated FGFR3 more often than live bacteria, while the latter had a similar effect on FGFR1, although both treatments did affect the expressions of both receptors. FGFR2 was the least modulated in the FC tissues by the two treatments. FGFR1 expression was more prevalent in astrocytes while FGFR2 and FGFR3 showed higher expression in neurons.

In the DRG, all three receptor expressions were also seen, but could not be distinguished from medium controls by immunofluorescence. Inhibition of FGFR1 by PD166866 downregulated both inflammation and apoptosis in both FC and DRG in response to either treatment in all the tissues tested.

Inhibition of FGFR1-3 by AZD4547 similarly downregulated both inflammation and apoptosis in both FC and DRG in response to live bacteria, while with sonicated remnants, this effect was seen in one of the two FC tissues and 2 of 3 DRG tissues tested. CCL2 and IL-6 were the most downregulated mediators in the FC, while in the DRG it was CXCL8 and IL-6 in response to FGFR inhibition. Downregulation of at least two of these three mediators was observed to downregulate apoptosis levels in general.

We show here that FGFR inhibition can be an effective anti-inflammatory treatment in antibiotic refractive neurological Lyme. Alternatively, two biologics may be needed to effectively curb neuroinflammation and pathology in the CNS and PNS.

Source: Parthasarathy G. Fibroblast growth factor receptor inhibitors mitigate the neuropathogenicity of Borrelia burgdorferi or its remnants ex vivo. Front Immunol. 2024 Apr 4;15:1327416. doi: 10.3389/fimmu.2024.1327416. PMID: 38638441; PMCID: PMC11024320. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11024320/ (Full study)

Case-Control Study of Individuals With Small Fiber Neuropathy After COVID-19

Abstract:

Objectives: To report a case-control study of new-onset small fiber neuropathy (SFN) after COVID-19 with invasive cardiopulmonary exercise testing (iCPET). SFN is a critical objective finding in long COVID and amenable to treatment.

Methods: A retrospective chart review was conducted on patients seen in the NeuroCOVID Clinic at Yale who developed new-onset SFN after a documented COVID-19 illness. We collected demographics, symptoms, skin biopsy, iCPET testing, treatments, and clinical response to treatment or no intervention.

Results: Sixteen patients were diagnosed with SFN on skin biopsy (median age 47, 75% female, 75% White). 92% of patients reported postexertional malaise characteristic of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), and 7 patients underwent iCPET, which demonstrated neurovascular dysregulation and dysautonomia consistent with ME/CFS. Nine patients underwent treatment with IVIG, and 7 were not treated with IVIG. The IVIG group experienced significant clinical response in their neuropathic symptoms (9/9) compared with those who did not receive IVIG (3/7; p = 0.02).

Discussion: Here, we present preliminary evidence that after COVID-19, SFN is responsive to treatment with IVIG and linked with neurovascular dysregulation and dysautonomia on iCPET. A larger clinical trial is indicated to further demonstrate the clinical utility of IVIG in treating postinfectious SFN.

Classification of evidence: This study provides Class III evidence. It is a retrospective cohort study.

Source: McAlpine L, Zubair AS, Joseph P, Spudich S. Case-Control Study of Individuals With Small Fiber Neuropathy After COVID-19. Neurol Neuroimmunol Neuroinflamm. 2024 May;11(3):e200244. doi: 10.1212/NXI.0000000000200244. Epub 2024 Apr 17. PMID: 38630952. https://www.neurology.org/doi/10.1212/NXI.0000000000200244 (Full text)

Exploring Cognitive Dysfunction in Long COVID Patients: Eye Movement Abnormalities and Frontal-Subcortical Circuits Implications via Eye-Tracking and Machine Learning

Abstract:

Background: Cognitive dysfunction is regarded as one of the most severe aftereffects following coronavirus disease 2019 (COVID-19). Eye movements, controlled by various brain regions, including the dorsolateral prefrontal cortex and frontal-thalamic circuits, offer a potential metric for evaluating cognitive dysfunction. We aimed to examine the utility of eye movement measurements in identifying cognitive impairments in long COVID patients.

Methods: We recruited 40 long COVID patients experiencing subjective cognitive complaints and 40 healthy controls and used a certified eye-tracking medical device to record saccades and antisaccades. Machine learning was applied to enhance the analysis of eye movement data.

Results: Patients did not differ from the healthy controls regarding age, sex, and years of education. However, the patients’ Montreal Cognitive Assessment total score was significantly lower than healthy controls. Most eye movement parameters were significantly worse in patients: the latencies, gain, and velocity of visually and memory-guided saccades, the number of correct memory saccades, the latencies and duration of reflexive saccades, and the number of errors in the antisaccade test. Machine learning permitted distinguishing between long COVID patients experiencing subjective cognitive complaints and healthy controls.

Conclusion: Our findings suggest impairments in frontal subcortical circuits in long COVID patients experiencing subjective cognitive complaints. Eye-tracking, combined with machine learning, offers a novel, efficient way to assess and monitor long COVID patients’ cognitive dysfunctions, suggesting its utility in clinical settings for early detection and personalized treatment strategies. Further research is needed to determine the long-term implications of these findings and the reversibility of cognitive dysfunctions.

Source: Benito-León J, Lapeña J, García-Vasco L, Cuevas C, Viloria-Porto J, Calvo-Córdoba A, Arrieta-Ortubay E, Ruiz-Ruigómez M, Sánchez-Sánchez C, García-Cena C. Exploring Cognitive Dysfunction in Long COVID Patients: Eye Movement Abnormalities and Frontal-Subcortical Circuits Implications via Eye-Tracking and Machine Learning. Am J Med. 2024 Apr 5:S0002-9343(24)00217-1. doi: 10.1016/j.amjmed.2024.04.004. Epub ahead of print. PMID: 38583751. https://pubmed.ncbi.nlm.nih.gov/38583751/

Long COVID and post-acute sequelae of SARS-CoV-2 pathogenesis and treatment: A Keystone Symposia report

Abstract:

In 2023, the Keystone Symposia held the first international scientific conference convening research leaders investigating the pathology of post-acute sequelae of COVID-19 (PASC) or Long COVID, a growing and urgent public health priority. In this report, we present insights from the talks and workshops presented during this meeting and highlight key themes regarding what researchers have discovered regarding the underlying biology of PASC and directions toward future treatment.

Several themes have emerged in the biology, with inflammation and other immune alterations being the most common focus, potentially related to viral persistence, latent virus reactivation, and/or tissue damage and dysfunction, especially of the endothelium, nervous system, and mitochondria.

In order to develop safe and effective treatments for people with PASC, critical next steps should focus on the replication of major findings regarding potential mechanisms, disentangling pathogenic mechanisms from downstream effects, development of cellular and animal models, mechanism-focused randomized, placebo-controlled trials, and closer collaboration between people with lived experience, scientists, and other stakeholders.

Ultimately, by learning from other post-infectious syndromes, the knowledge gained may help not only those with PASC/Long COVID, but also those with other post-infectious syndromes.

Source: Matthew S. Durstenfeld, Shannon Weiman, Michael Holtzman, Catherine Blish, Resia Pretorius, Steven G. Deeks. Long COVID and post-acute sequelae of SARS-CoV-2 pathogenesis and treatment: A Keystone Symposia report. First published: 09 April 2024 https://doi.org/10.1111/nyas.15132 https://nyaspubs.onlinelibrary.wiley.com/doi/10.1111/nyas.15132 (Full text)