Tag: 2023

The direct correlation between microbiota and SARS-CoV-2 infectious disease

Abstract:

The human microbiota is the good part of the human organism and is a collection of symbiotic microorganisms which aid in human physiological functions. Diseases that can be generated by an altered microbiota are continuously being studied, but it is quite evident how a damaged microbiota is involved in chronic inflammatory diseases, psychiatric diseases, and some bacterial or viral infections. However, the role of the microbiota in the host immune response to bacterial and viral infections is still not entirely understood.

Metabolites or components which are produced by the microbiota are useful in mediating microbiota-host interactions, thus influencing the host’s immune capacity. Recent evidence shows that the microbiota is evidently altered in patients with viral infections such as post-acute COVID-19 syndrome (PACS).

In this review, the associations between microbiota and COVID-19 infection are highlighted in terms of biological and clinical significance by emphasizing the mechanisms through which metabolites produced by the microbiota modulate immune responses to COVID-19 infection.

Source: Vitiello A, Ferrara F, Zovi A. The direct correlation between microbiota and SARS-CoV-2 infectious disease. Inflammopharmacology. 2023 Feb 1:1–8. doi: 10.1007/s10787-023-01145-9. Epub ahead of print. PMID: 36725821; PMCID: PMC9891758. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9891758/ (Full text)

Symptom-based clusters in people with ME/CFS: an illustration of clinical variety in a cross-sectional cohort

Abstract:

Background: Myalgic encephalomyelitis (ME)/chronic fatigue syndrome (CFS) is a complex, heterogenous disease. It has been suggested that subgroups of people with ME/CFS exist, displaying a specific cluster of symptoms. Investigating symptom-based clusters may provide a better understanding of ME/CFS. Therefore, this study aimed to identify clusters in people with ME/CFS based on the frequency and severity of symptoms.

Methods: Members of the Dutch ME/CFS Foundation completed an online version of the DePaul Symptom Questionnaire version 2. Self-organizing maps (SOM) were used to generate symptom-based clusters using severity and frequency scores of the 79 measured symptoms. An extra dataset (n = 252) was used to assess the reproducibility of the symptom-based clusters.

Results: Data of 337 participants were analyzed (82% female; median (IQR) age: 55 (44–63) years). 45 clusters were identified, of which 13 clusters included ≥ 10 patients. Fatigue and PEM were reported across all of the symptom-based clusters, but the clusters were defined by a distinct pattern of symptom severity and frequency, as well as differences in clinical characteristics. 11% of the patients could not be classified into one of the 13 largest clusters. Applying the trained SOM to validation sample, resulted in a similar symptom pattern compared the Dutch dataset.

Conclusion: This study demonstrated that in ME/CFS there are subgroups of patients displaying a similar pattern of symptoms. These symptom-based clusters were confirmed in an independent ME/CFS sample. Classification of ME/CFS patients according to severity and symptom patterns might be useful to develop tailored treatment options.

Source: Vaes, A.W., Van Herck, M., Deng, Q. et al. Symptom-based clusters in people with ME/CFS: an illustration of clinical variety in a cross-sectional cohort. J Transl Med 21, 112 (2023). https://doi.org/10.1186/s12967-023-03946-6 https://translational-medicine.biomedcentral.com/articles/10.1186/s12967-023-03946-6 (Full text)

Persistent short nighttime sleep duration is associated with a greater post-COVID risk in fully mRNA-vaccinated individuals

Abstract:

Short nighttime sleep duration impairs the immune response to virus vaccination, and long nighttime sleep duration is associated with poor health status. Thus, we hypothesized that short (<6 h) and long (>9 h) nighttime sleepers have a higher post-COVID risk than normal nighttime sleepers, despite two doses of mRNA vaccine (which has previously been linked to lower odds of long-lasting COVID-19 symptoms). Post-COVID was defined as experiencing at least one core COVID-19 symptom for at least three months (e.g., shortness of breath).

Multivariate logistic regression adjusting for age, sex, BMI, and other factors showed in 9717 respondents (age span 18-99) that two mRNA vaccinations lowered the risk of suffering from post-COVID by about 21% (p < 0.001). When restricting the analysis to double-vaccinated respondents (n = 5918), short and long sleepers exhibited a greater post-COVID risk than normal sleepers (adjusted OR [95%-CI], 1.56 [1.29, 1.88] and 1.87 [1.32, 2.66], respectively). Among respondents with persistent sleep duration patterns during the pandemic compared to before the pandemic, short but not long sleep duration was significantly associated with the post-COVID risk (adjusted OR [95%-CI], 1.59 [1.24, 2.03] and 1.18 [0.70, 1.97], respectively). No significant association between sleep duration and post-COVID symptoms was observed in those reporting positive SARS-CoV-2 test results (n = 538).

Our findings suggest that two mRNA vaccinations against SARS-CoV-2 are associated with a lower post-COVID risk. However, this protection may be less pronounced among those sleeping less than 6 h per night. Our findings warrant replication in cohorts with individuals with confirmed SARS-CoV-2 infection.

Source: Xue P, Merikanto I, Chung F, Morin CM, Espie C, Bjorvatn B, Cedernaes J, Landtblom AM, Penzel T, De Gennaro L, Holzinger B, Matsui K, Hrubos-Strøm H, Korman M, Leger D, Mota-Rolim S, Bolstad CJ, Nadorff M, Plazzi G, Reis C, Chan RNY, Wing YK, Yordanova J, Bjelajac AK, Inoue Y, Partinen M, Dauvilliers Y, Benedict C. Persistent short nighttime sleep duration is associated with a greater post-COVID risk in fully mRNA-vaccinated individuals. Transl Psychiatry. 2023 Feb 1;13(1):32. doi: 10.1038/s41398-023-02334-4. PMID: 36726008; PMCID: PMC9890416. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9890416/ (Full text)

Multi-‘omics of gut microbiome-host interactions in short- and long-term myalgic encephalomyelitis/chronic fatigue syndrome patients

Highlights

  • Multi-‘omics identified phenotypic, gut microbial, and metabolic biomarkers for ME/CFS.
  • Reduced gut microbial diversity and increased plasma sphingomyelins in ME/CFS.
  • Short-term patients had more severe gut microbial dysbiosis with decreased butyrate.
  • Long-term patients had more significant metabolic and clinical aberrations

Summary

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a complex, debilitating disorder manifesting as severe fatigue and post-exertional malaise. The etiology of ME/CFS remains elusive.

Here, we present a deep metagenomic analysis of stool combined with plasma metabolomics and clinical phenotyping of two ME/CFS cohorts with short-term (<4 years, n = 75) or long-term disease (>10 years, n = 79) compared with healthy controls (n = 79).

First, we describe microbial and metabolomic dysbiosis in ME/CFS patients. Short-term patients showed significant microbial dysbiosis, while long-term patients had largely resolved microbial dysbiosis but had metabolic and clinical aberrations.

Second, we identified phenotypic, microbial, and metabolic biomarkers specific to patient cohorts. These revealed potential functional mechanisms underlying disease onset and duration, including reduced microbial butyrate biosynthesis and a reduction in plasma butyrate, bile acids, and benzoate.

In addition to the insights derived, our data represent an important resource to facilitate mechanistic hypotheses of host-microbiome interactions in ME/CFS.

Source: Ruoyun Xiong, Courtney Gunter, Elizabeth Fleming, Suzanne D. Vernon, Lucinda Bateman, Derya Unutmaz, Julia Oh. Multi-‘omics of gut microbiome-host interactions in short- and long-term myalgic encephalomyelitis/chronic fatigue syndrome patients. Cell Host & Microbe 31, 273–287. https://www.cell.com/cell-host-microbe/fulltext/S1931-3128(23)00021-5 (Full text)

Evaluating the ability of patient reported outcome measures to represent the functional limitation of people living with myalgic encephalomyelitis/chronic fatigue syndrome

Abstract:

Aim: To identify activities which people with Myalgic Encephalomyelitis (ME)/Chronic Fatigue Syndrome (CFS) report are impacted by their condition, and evaluate the ability of measures of function used by National Health Service (NHS) ME/CFS Services to represent these experiences.

Method: 122 participants completed ME/CFS Service questionnaires reporting activities that they had reduced or stopped doing, as well as Patient Reported Outcome Measures (PROMs). These data were coded using the International Classification of Functioning, Disability and Health (ICF) using established linking rules. Matrices identified the agreement rate between the outcome measures and the participant-generated list. Activities which could not be coded against the ICF were grouped using content analysis.

Results: Responses from participants related to codes from nine subsections of the ICF. The PROMs used by the ME/CFS service had agreement rates between 58% and 62.5% with the participant-generated list. The content analysis identified a range of activities that were meaningful to participants that they could no longer do. These included holidays and day trips, accessing the community independently, and sustaining activity into the evening. These were not captured in either the ICF or the service’s outcome measures.

Conclusion: The list generated by participants referred to a wide range of activities, including some not captured by the ICF. Comparison against the outcome measures suggests that the measures used in many NHS ME/CFS services nationally capture patients’ experiences moderately well. However, there are activities that patients value that are not captured by these measures.

Source: Bethan Jones, Corin Bourne & Peter Gladwell. Evaluating the ability of patient reported outcome measures to represent the functional limitation of people living with myalgic encephalomyelitis/chronic fatigue syndrome. Fatigue: Biomedicine, Health & Behavior, DOI: 10.1080/21641846.2023.2175579 (Full text)

Impact of Misdiagnosis in Case-Control Studies of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

Abstract:

Misdiagnosis of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) can occur when different case definitions are used by clinicians (relative misdiagnosis) or when failing the genuine diagnosis of another disease (misdiagnosis in a strict sense). This problem translates to a recurrent difficulty in reproducing research findings.

To tackle this problem, we simulated data from case-control studies under misdiagnosis in a strict sense. We then estimated the power to detect a genuine association between a potential causal factor and ME/CFS. A minimum power of 80% was obtained for studies with more than 500 individuals per study group.

When the simulation study was extended to the situation where the potential causal factor could not be determined perfectly (e.g., seropositive/seronegative in serological association studies), the minimum power of 80% could only be achieved in studies with more than 1000 individuals per group.

In conclusion, current ME/CFS studies have suboptimal power under the assumption of misdiagnosis. This power can be improved by increasing the overall sample size using multi-centric studies, reporting the excluded illnesses and their exclusion criteria, or focusing on a homogeneous cohort of ME/CFS patients with a specific pathological mechanism where the chance of misdiagnosis is reduced.

Source: Malato J, Graça L, Sepúlveda N. Impact of Misdiagnosis in Case-Control Studies of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Diagnostics. 2023; 13(3):531. https://doi.org/10.3390/diagnostics13030531 https://www.mdpi.com/2075-4418/13/3/531 (Full text)

Investigating Immune Reactivity to the Intestinal Microbiome in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

Abstract:

Introduction: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) pathogenesis is thought to be multisystemic, including the immune and gastrointestinal systems. A proportion of patients experience gastrointestinal disturbances with evidence suggesting a leaky gut. It was hypothesised that a leaky gut and microbial translocation causes a breach in immune tolerance, promoting inflammation and autoimmunity.

Aims: A) determine whether severe ME/CFS patients have increased systemic and mucosal immunoglobulin (Ig) reactivity to the intestinal microbiome, and B) determine which intestinal microbes serum IgG was directed against.

Methods: Serum and stool samples were collected from five pairs of severe ME/CFS patients and matched household controls. Enzyme linked immunosorbent assays were developed to quantify IgG in serum, bound and non-bound IgA in stool and serum IgG levels reactive with autologous and heterologous stool bacteria. Flow cytometry methods were developed to quantify both stool microbial load and the proportion of stool microbes reactive with mucosal IgA and serum IgG. A ‘bug FACS’ method was developed to identify and quantify serum IgG reactivity to stool bacteria and fungi.

Results: The main finding was that severe ME/CFS patients have significantly lower levels of serum IgG reactive to heterologous stool bacteria compared to their matched household controls. In addition, severe ME/CFS patients do not have higher levels of serum IgG reactive to heterologous stool bacteria than autologous stool bacteria. Severe ME/CFS patients also have a non-significant increase of IgG binding to Campylobacter jejuni and Pseudomonas viridiflava compared to their matched household controls. Analysis of mucosal IgA found ME/CFS patients with a long disease duration had higher microbe bound IgA concentrations compared to their matched household controls.

Conclusion: This thesis presents results from the first ME/CFS study to investigate serum IgG immune reactivity to stool microbes. Findings suggest ME/CFS patients have an impaired serum IgG immune response to the intestinal microbiome.

Source: Seton, Katharine.  Investigating Immune Reactivity to the Intestinal Microbiome in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome.  Doctoral thesis, University of East Anglia. https://ueaeprints.uea.ac.uk/id/eprint/90862/

No Causal Effects Detected in COVID-19 and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A Two Sample Mendelian Randomization Study

Abstract

New clinical observational studies suggest that Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a sequela of COVID-19 infection, but whether there is an exact causal relationship between COVID-19 and ME/CFS remains to be verified. To investigate whether infection with COVID-19 actually causes ME/CFS, this paper obtained pooled data from the Genome Wide Association Study (GWAS) and analyzed the relationship between COVID susceptibility, hospitalization and severity of COVID and ME/CFS, respectively, using two-sample Mendelian randomization (TSMR).
TSMR analysis was performed by inverse variance weighting (IVW), weighted median method, MR-Egger regression and weighted mode and simple mode methods, respectively, and then the causal relationship between COVID-19 and ME/CFS was further evaluated by odds ratio (OR). Eventually, we found that COVID-19 severity, hospitalization and susceptibility were all not significantly correlated with ME/CFS (OR:1.000,1.000,1.000; 95% CI:0.999–1.000, 0.999–1.001, 0.998–1.002; p = 0.333, 0.862, 0.998, respectively). We found the results to be reliable after sensitivity analysis.
These results suggested that SARS-CoV-2 infection may not significantly contribute to the elevated risk of developing CFS, and therefore ME/CFS may not be a sequela of COVID-19, but may simply present with symptoms similar to those of CFS after COVID-19 infection, and thus should be judged and differentiated by physicians when diagnosing and treating the disease in clinical practice.
Source: Xu W, Cao Y, Wu L. No Causal Effects Detected in COVID-19 and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A Two Sample Mendelian Randomization Study. International Journal of Environmental Research and Public Health. 2023; 20(3):2437. https://doi.org/10.3390/ijerph20032437 https://www.mdpi.com/1660-4601/20/3/2437 (Full text)

Studies find that microbiome changes may be a signature for ME/CFS

Researchers have found differences in the gut microbiomes of people with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) compared to healthy controls. Findings from two studies, published in Cell Host & Microbe and funded by the National Institutes of Health add to growing evidence that connects disruptions in the gut microbiome, the complete collection of bacteria, viruses, and fungi that live in our gastrointestinal system, to ME/CFS.

“The microbiome has emerged as a potential contributor to ME/CFS. These findings provide unique insights into the role the microbiome plays in the disease and suggest that certain differences in gut microbes could serve as biomarkers for ME/CFS,” said Vicky Whittemore, Ph.D., program director at NIH’s National Institute of Neurological Disorders and Stroke (NINDS).

ME/CFS is a serious, chronic, and debilitating disease characterized by a range of symptoms, including fatigue, post-exertional malaise, sleep disturbance, cognitive difficulties, pain, and gastrointestinal issues. The causes of the disease are unknown and there are no treatments.

In one study, senior author Brent L. Williams, Ph.D., assistant professor, W. Ian Lipkin, M.D., John Snow Professor of Epidemiology and director of the Center for Infection and Immunity at the Columbia University Mailman School of Public Health, in New York City, and their collaborators analyzed the genetic makeup of gut bacteria in fecal samples collected from a geographically diverse cohort of 106 people with ME/CFS and 91 healthy controls. The results revealed key differences in microbiome diversity, quantity, metabolic pathways, and interactions between species of gut bacteria.

Dr. Williams and his colleagues found that people with ME/CFS had abnormally low levels of several bacterial species compared to healthy controls, including Faecalibacterium prausnitzii (F. prausnitzii) and Eubacterium rectale. These health-promoting bacteria produce a short chain fatty acid called butyrate, a bacterial metabolite, or by-product, that plays an important role in maintaining gut health. An acetate-producing bacterium was also reduced in samples obtained from people with ME/CFS.

More detailed metabolomic analyses confirmed that a reduction in these bacteria was associated with reduced butyrate production in ME/CFS. Butyrate is the primary energy source for cells that line the gut, providing up to 70% of their energy requirements, support for the gut immune system, and protection against diseases of the digestive tract. Butyrate, tryptophan, and other metabolites detected in the blood are important for regulating immune, metabolic, and endocrine functions.

While species of butyrate-producing bacteria decreased, there were increased levels of nine other species in ME/CFS, including Enterocloster bolteae and Ruminococcus gnavus, which are associated with autoimmune diseases and inflammatory bowel disease, respectively.

Dr. Williams’ group also reported that an abundance of F. prausnitzii was inversely associated with fatigue severity in ME/CFS, suggesting a possible link between gut bacteria and disease symptoms. More research is needed to determine if differences in the gut microbiome are a consequence or cause of symptoms.

The findings indicate that imbalances in these 12 species of bacteria could be used as biomarkers for ME/CFS classification, potentially providing consistent, measurable targets to improve diagnosis.

The gut microbiome is an ecosystem with complex interactions between bacteria, where microbes can exchange or compete for nutrients, metabolites, or other molecular signals. Researchers found notable differences in the network of species interactions in people with ME/CFS—including unique interactions between F. prausnitzii and other species. This indicates that there is an extensive rewiring of bacterial networks in ME/CFS.

“In addition to differences in individual species in ME/CFS, focusing a lens on community interaction dynamics may add greater specificity to the broad definition of dysbiosis, distinguishing between other diseases in which the gut microbiome becomes imbalanced,” said Dr. Williams. “This is also important for generating new testable hypotheses about the underlying mechanisms and mediators of dysbiosis in ME/CFS and may eventually inform strategies to correct these imbalances.”

A balanced microbiome is also essential for a variety of neural systems, especially immune regulation and coupling between energy metabolism and blood supply in the brain, as well as the function of the nerves that supply the gut.

In another study at the Jackson Laboratory in Farmington, Connecticut, Julia Oh, Ph.D.(link is external), associate professor, and Derya Unutmaz, M.D., professor, teamed up with other ME/CFS experts to study microbiome abnormalities in different phases of ME/CFS. Dr. Oh’s team collected and analyzed clinical data, fecal samples, and blood samples from 149 people with ME/CFS who had been diagnosed within the previous four years (74 short-term) or who had been diagnosed more than 10 years ago (75 long-term) and 79 healthy controls.

The results showed that the short-term group had less microbial diversity, while the long-term group established a stable, but individualized gut microbiome similar to healthy controls. Dr. Oh and her colleagues found lower levels of several butyrate-producing species, including F. prausnitzii, especially in the short-term participants. There was also a reduction in species associated with tryptophan metabolism in all ME/CFS participants compared to controls.

Dr. Oh’s group also collected detailed clinical and lifestyle data from participants. By combining these data with genetic and metabolome data, the team developed a way to accurately classify and differentiate ME/CFS from healthy controls. Using this approach, they found that individuals with long-term ME/CFS had a more balanced microbiome but showed more severe clinical symptoms and progressive metabolic irregularities compared to the other groups.

Both studies identify potential biomarkers for ME/CFS, which may inform diagnostic tests and disease classification. Understanding the connection between disturbances in the gut microbiome and ME/CFS may also guide the development of new therapeutics.

Additional research is required to learn more about the pathophysiological implications of butyrate and other metabolite deficiencies in ME/CFS. Future studies will determine how gut microbe disturbances contribute to symptoms, including changes during disease progression.

The studies were funded in part by the NIH’s ME/CFS Collaborative Research Network(link is external), a consortium supported by multiple institutes and centers at NIH, consisting of three collaborative research centers and a data management coordinating center. The research network was established in 2017 to help advance research on ME/CFS. The research was supported by NINDS grant U54NS105539, National Institute of Allergy and Infectious Diseases grants U54AI138370 and R56AI120724, and anonymous donors through the Crowdfunding Microbe Discovery Project.

SARS-CoV-2 infection and persistence in the human body and brain at autopsy

Abstract:

Coronavirus disease 2019 (COVID-19) is known to cause multi-organ dysfunction1-3 during acute infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), with some patients experiencing prolonged symptoms, termed post-acute sequelae of SARS-CoV-2 (refs. 4,5). However, the burden of infection outside the respiratory tract and time to viral clearance are not well characterized, particularly in the brain3,6-14.

Here we carried out complete autopsies on 44 patients who died with COVID-19, with extensive sampling of the central nervous system in 11 of these patients, to map and quantify the distribution, replication and cell-type specificity of SARS-CoV-2 across the human body, including the brain, from acute infection to more than seven months following symptom onset.

We show that SARS-CoV-2 is widely distributed, predominantly among patients who died with severe COVID-19, and that virus replication is present in multiple respiratory and non-respiratory tissues, including the brain, early in infection. Further, we detected persistent SARS-CoV-2 RNA in multiple anatomic sites, including throughout the brain, as late as 230 days following symptom onset in one case. Despite extensive distribution of SARS-CoV-2 RNA throughout the body, we observed little evidence of inflammation or direct viral cytopathology outside the respiratory tract.

Our data indicate that in some patients SARS-CoV-2 can cause systemic infection and persist in the body for months.

Source: Stein SR, Ramelli SC, Grazioli A, Chung JY, Singh M, Yinda CK, Winkler CW, Sun J, Dickey JM, Ylaya K, Ko SH, Platt AP, Burbelo PD, Quezado M, Pittaluga S, Purcell M, Munster VJ, Belinky F, Ramos-Benitez MJ, Boritz EA, Lach IA, Herr DL, Rabin J, Saharia KK, Madathil RJ, Tabatabai A, Soherwardi S, McCurdy MT; NIH COVID-19 Autopsy Consortium; Peterson KE, Cohen JI, de Wit E, Vannella KM, Hewitt SM, Kleiner DE, Chertow DS. SARS-CoV-2 infection and persistence in the human body and brain at autopsy. Nature. 2022 Dec;612(7941):758-763. doi: 10.1038/s41586-022-05542-y. Epub 2022 Dec 14. PMID: 36517603; PMCID: PMC9749650. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9749650/ (Full text)