Tag: Vernon

Deficient butyrate-producing capacity in the gut microbiome of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome patients is associated with fatigue symptoms

Abstract:

Background Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a complex, debilitating disease of unknown cause for which there is no specific therapy. Patients suffering from ME/CFS commonly experience persistent fatigue, post-exertional malaise, cognitive dysfunction, sleep disturbances, orthostatic intolerance, fever and irritable bowel syndrome (IBS). Recent evidence implicates gut microbiome dysbiosis in ME/CFS. However, most prior studies are limited by small sample size, differences in clinical criteria used to define cases, limited geographic sampling, reliance on bacterial culture or 16S rRNA gene sequencing, or insufficient consideration of confounding factors that may influence microbiome composition. In the present study, we evaluated the fecal microbiome in the largest prospective, case-control study to date (n=106 cases, n=91 healthy controls), involving subjects from geographically diverse communities across the United States.

Results Using shotgun metagenomics and qPCR and rigorous statistical analyses that controlled for important covariates, we identified decreased relative abundance and quantity of Faecalibacterium, Roseburia, and Eubacterium species and increased bacterial load in feces of subjects with ME/CFS. These bacterial taxa play an important role in the production of butyrate, a multifunctional bacterial metabolite that promotes human health by regulating energy metabolism, inflammation, and intestinal barrier function. Functional metagenomic and qPCR analyses were consistent with a deficient microbial capacity to produce butyrate along the acetyl-CoA pathway in ME/CFS. Metabolomic analyses of short-chain fatty acids (SCFAs) confirmed that fecal butyrate concentration was significantly reduced in ME/CFS. Further, we found that the degree of deficiency in butyrate-producing bacteria correlated with fatigue symptom severity among ME/CFS subjects. Finally, we provide evidence that IBS comorbidity is an important covariate to consider in studies investigating the microbiome of ME/CFS subjects, as differences in microbiota alpha diversity, some bacterial taxa, and propionate were uniquely associated with self-reported IBS diagnosis.

Conclusions Our findings indicate that there is a core deficit in the butyrate-producing capacity of the gut microbiome in ME/CFS subjects compared to healthy controls. The relationships we observed among symptom severity and these gut microbiome disturbances may be suggestive of a pathomechanistic linkage, however, additional research is warranted to establish any causal relationship. These findings provide support for clinical trials that explore the utility of dietary, probiotic and prebiotic interventions to boost colonic butyrate production in ME/CFS.

Source: Cheng Guo, Xiaoyu Che, Thomas Briese, Orchid Allicock, Rachel A. Yates, Aaron Cheng, Amit Ranjan, Dana March, Mady Hornig, Anthony L. Komaroff, Susan Levine, Lucinda Bateman, Suzanne D. Vernon, Nancy G. Klimas, Jose G. Montoya, Daniel L. Peterson, W. Ian Lipkin, Brent L. Williams. Deficient butyrate-producing capacity in the gut microbiome of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome patients is associated with fatigue symptoms. medRxiv 2021.10.27.21265575; doi: https://doi.org/10.1101/2021.10.27.21265575 https://www.medrxiv.org/content/10.1101/2021.10.27.21265575v1?fbclid=IwAR16pb6by73xZx5lZM3j-5dOc_YT2JapILaRS-DcUZj5EHZxnoSa2fAAIuE (Full text available to download)

Multi-omics of host-microbiome interactions in short- and long-term Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)

Abstract:

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a complex, multi-system, debilitating disability manifesting as severe fatigue and post-exertional malaise. The chronic dysfunctions in ME/CFS are increasingly recognized as significant health factors with potential parallels with “long COVID”. However, the etiology of ME/CFS remains elusive with limited high-resolution human studies. In addition, reliable biomarker-based diagnostics have not been well-established, but may assist in disease classification, particularly during different temporal phases of the disease. Here, we performed deep multi-omics (shotgun metagenomics of gut microbiota and plasma metabolomics) and clinical phenotyping of healthy controls (n=79) vs. two cohorts of ME/CFS patients: those with short-term disease (<4 years, n=75), and patients with long-term disease (>10y, n=79).

Overall, ME/CFS was characterized by reduced gut microbiome diversity and richness with high heterogeneity, and depletion of sphingomyelins and short-chain fatty acids in the plasma. We found significant differences when stratifying by cohort; short-term ME/CFS was associated with more microbial dysbiosis, but long-term ME/CFS was associated with markedly more severe phenotypic and metabolic abnormalities. We identified a reduction in the gene-coding capacity (and relative abundance of butyrate producers) of microbial butyrate biosynthesis together with a reduction in the plasma concentration of butyrate, especially in the short-term group. Global co-association and detailed gene pathway correlation analyses linking the microbiome and metabolome identified additional potential biological mechanisms underlying host-microbiome interactions in ME/CFS, including bile acids and benzoate pathways.

Finally, we built multiple state-of-the-art classifiers to identify microbes, microbial gene pathways, metabolites, and clinical features that individually or together, were most able to differentiate short or long-term MECFS, or MECFS vs. healthy controls. Taken together, our study presents the highest resolution, multi-cohort and multi-omics analysis to date, providing an important resource to facilitate mechanistic hypotheses of host-microbiome interactions in ME/CFS.

Source: Ruoyun Xiong, Courtney Gunter, Elizabeth Fleming, Suzanne Vernon, Lucinda Bateman, Derya Unutmaz, Julia Oh. Multi-omics of host-microbiome interactions in short- and long-term Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). bioRxiv 2021.10.27.466150; doi: https://doi.org/10.1101/2021.10.27.466150 https://www.biorxiv.org/content/10.1101/2021.10.27.466150v1 (Full study available for download)

Acute Corticotropin-Releasing Factor Receptor Type 2 Agonism Results in Sustained Symptom Improvement in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

Abstract:

Background: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a complex multi-symptom disease with widespread evidence of disrupted systems. The authors hypothesize that it is caused by the upregulation of the corticotropin-releasing factor receptor type 2 (CRFR2) in the raphé nuclei and limbic system, which impairs the ability to maintain homeostasis. The authors propose utilizing agonist-mediated receptor endocytosis to downregulate CRFR2.

Materials and Methods: This open-label trial tested the safety, tolerability and efficacy of an acute dose of CT38s (a short-lived, CRFR2-selective agonist, with no known off-target activity) in 14 ME/CFS patients. CT38s was subcutaneously-infused at one of four dose-levels (i.e., infusion rates of 0.01, 0.03, 0.06, and 0.20 μg/kg/h), for a maximum of 10.5 h. Effect was measured as the pre-/post-treatment change in the mean 28-day total daily symptom score (TDSS), which aggregated 13 individual patient-reported symptoms.

Results: ME/CFS patients were significantly more sensitive to the transient hemodynamic effects of CRFR2 stimulation than healthy subjects in a prior trial, supporting the hypothesized CRFR2 upregulation. Adverse events were generally mild, resolved without intervention, and difficult to distinguish from ME/CFS symptoms, supporting a CRFR2 role in the disease. The acute dose of CT38s was associated with an improvement in mean TDSS that was sustained (over at least 28 days post-treatment) and correlated with both total exposure and pre-treatment symptom severity. At an infusion rate of 0.03 μg/kg/h, mean TDSS improved by −7.5 ± 1.9 (or −25.7%, p = 0.009), with all monitored symptoms improving.

Conclusion: The trial supports the hypothesis that CRFR2 is upregulated in ME/CFS, and that acute CRFR2 agonism may be a viable treatment approach warranting further study.

Clinical Trial Registration: ClinicalTrials.gov, identifier NCT03613129.

Source: Gerard Pereira, Hunter Gillies, Sanjay Chanda, Michael Corbett, Suzanne D. Vernon, Tina Milani and Lucinda Bateman. Acute Corticotropin-Releasing Factor Receptor Type 2 Agonism Results in Sustained Symptom Improvement in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Front. Syst. Neurosci., 01 September 2021. https://doi.org/10.3389/fnsys.2021.69824 https://www.frontiersin.org/articles/10.3389/fnsys.2021.698240/full (Full text)

Dissecting the nature of post-exertional malaise

Abstract:

Background: Post-exertional malaise (PEM) is a defining characteristic of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) but there is insufficient research dissecting the nature of PEM from the patients’ perspective.

Methods: A PEM questionnaire administered to 150 ME/CFS patients. It included open-ended questions about triggers, experiences, recovery, and prevention. Responses were re-coded into concise, representative topics. Chi-Square tests of independence were then used to test for differences and relationships between duration of ME/CFS illness (<4 years and >10 years), PEM onset and duration, and gender with PEM trigger, experience, recovery, and prevention.

Results: Physical exertion was the most common trigger of PEM. The onset of PEM occurred within minutes after physical exertion compared to within hours after cognitive exertion (<0.05). ME/CFS patients sick for <4 years reported stress as a trigger significantly more often than those sick for >10 years (<0.001). ME/CFS patients sick for <4 years experienced more orthostatic symptoms during PEM than those sick for >10 years. ME/CFS patients sick for >10 years reported using medications to recover from PEM significantly more that those sick for <4 years (<0.01). Pacing and avoiding specific triggers were common approaches to prevent PEM.

Conclusions: There are differences in PEM triggers, experiences and recovery based on duration of illness. Asking about PEM is important for diagnosis and to understand how to manage PEM. Given that PEM occurs more quickly after physical versus cognitive exertion, these results should instigate research on the relationship of upright posture, hypoperfusion and PEM.

Source: Megan Hartle, Lucinda Bateman & Suzanne D. Vernon (2021) Dissecting the nature of post-exertional malaise, Fatigue: Biomedicine, Health & Behavior, DOI: 10.1080/21641846.2021.1905415 https://www.tandfonline.com/doi/full/10.1080/21641846.2021.1905415 (Full text)

Accurate and objective determination of myalgic encephalomyelitis/chronic fatigue syndrome disease severity with a wearable sensor

Abstract:

Background: Approximately 2.5 million people in the U.S. suffer from myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). This disease negatively impacts patients’ ability to function, often resulting in difficulty maintaining employment, sustaining financial independence, engaging socially with others, and in particularly severe cases, consistently and adequately performing activities of daily living. The focus of this research was to develop a sensor-based method to measure upright activity defined as time with feet on the floor and referred to as UpTime, as an indicator of ME/CFS disease severity.

Methods: A commercially available inertial measurement unit (IMU), the Shimmer, was selected for this research. A Kalman filter was used to convert IMU data collected by the Shimmer to angle estimates. Angle estimate accuracy was confirmed by comparison to a motion capture system. Leg angle estimates were then converted to personalized daily UpTime scores using a critical angle of 39º from vertical to differentiate between upright (feet on the floor) and not upright. A 6-day, case-control study with 15 subjects (five healthy controls, five moderate-level ME/CFS, and five severe-level ME/CFS) was conducted to determine the utility of UpTime for assessing disease severity.

Results: UpTime was found to be a significant measure of ME/CFS disease severity. Severely ill ME/CFS patients spend less than 20% of each day with feet on the floor. Moderately ill ME/CFS patients spend between 20-30% of each day with feet on the floor. Healthy controls have greater than 30% UpTime. IMU-measured UpTime was more precise than self-reported hours of upright activity which were over-estimated by patients.

Conclusions: UpTime is an accurate and objective measure of upright activity, a measure that can be used to assess disease severity in ME/CFS patients. Due to its ability to accurately monitor upright activity, UpTime can also be used as a reliable endpoint for evaluating ME/CFS treatment efficacy. Future studies with larger samples and extended data collection periods are required to fully confirm the use of UpTime as a measure of disease severity in ME/CFS. With the added perspective of large-scale studies, this sensor-based platform could provide a recovery path for individuals struggling with ME/CFS.

Source: Palombo T, Campos A, Vernon SD, Roundy S. Accurate and objective determination of myalgic encephalomyelitis/chronic fatigue syndrome disease severity with a wearable sensor. J Transl Med. 2020 Nov 10;18(1):423. doi: 10.1186/s12967-020-02583-7. PMID: 33168001. https://translational-medicine.biomedcentral.com/articles/10.1186/s12967-020-02583-7 (Full text)

Hemodynamics during the 10-minute NASA Lean Test: evidence of circulatory decompensation in a subset of ME/CFS patients

Abstract:

Background: Lightheadedness, fatigue, weakness, heart palpitations, cognitive dysfunction, muscle pain, and exercise intolerance are some of the symptoms of orthostatic intolerance (OI). There is substantial comorbidity of OI in ME/CFS (Myalgic Encephalomyelitis/Chronic Fatigue Syndrome). The 10-minute NASA Lean Test (NLT) is a simple, point-of-care method that can aid ME/CFS diagnosis and guide management and treatment of OI. The objective of this study was to understand the hemodynamic changes that occur in ME/CFS patients during the 10-minute NLT.

Methods: A total of 150 ME/CFS patients and 75 age, gender and race matched healthy controls (HCs) were enrolled. We recruited 75 ME/CFS patients who had been sick for less than 4 years (< 4 ME/CFS) and 75 ME/CFS patients sick for more than 10 years (> 10 ME/CFS). The 10-minute NLT involves measurement of blood pressure and heart rate while resting supine and every minute for 10 min while standing with shoulder-blades on the wall for a relaxed stance. Spontaneously reported symptoms are recorded during the test. ANOVA and regression analysis were used to test for differences and relationships in hemodynamics, symptoms and upright activity between groups.

Results: At least 5 min of the 10-minute NLT were required to detect hemodynamic changes. The < 4 ME/CFS group had significantly higher heart rate and abnormally narrowed pulse pressure compared to > 10 ME/CFS and HCs. The < 4 ME/CFS group experienced significantly more OI symptoms compared to > 10 ME/CFS and HCs. The circulatory decompensation observed in the < 4 ME/CFS group was not related to age or medication use.

Conclusions: Circulatory decompensation characterized by increased heart rate and abnormally narrow pulse pressure was identified in a subgroup of ME/CFS patients who have been sick for < 4 years. This suggests inadequate ventricular filling from low venous pressure. The 10-minute NLT can be used to diagnose and treat the circulatory decompensation in this newly recognized subgroup of ME/CFS patients. The > 10 ME/CFS group had less pronounced hemodynamic changes during the NLT possibly from adaptation and compensation that occurs over time. The 10-minute NLT is a simple and clinically useful point-of-care method that can be used for early diagnosis of ME/CFS and help guide OI treatment.

Source: Lee J, Vernon SD, Jeys P, et al. Hemodynamics during the 10-minute NASA Lean Test: evidence of circulatory decompensation in a subset of ME/CFS patients. J Transl Med. 2020;18(1):314. Published 2020 Aug 15. doi:10.1186/s12967-020-02481-y https://pubmed.ncbi.nlm.nih.gov/32799889/

Clinically Accessible Tools for Documenting the Impact of Orthostatic Intolerance on Symptoms and Function in ME/CFS

Abstract:

Background: Clinical observations have indicated that hours of upright activity (HUA) reported by Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) patients correlated with orthostatic symptoms and impaired physical function. This study examined the relationship between HUA and orthostatic intolerance (OI).

Methods: Twenty-five female ME/CFS subjects and 25 age and race matched female healthy controls (HCs) were enrolled. Subjects reported HUA (defined as hours per day spent with feet on the floor) and completed questionnaires to assess the impact of OI on daily activities and symptoms. ME/CFS patients were categorized into those with <5 HUA and ≥5 HUA and analyzed by employment status. Data analysis used one-way ANOVA.

Results: ME/CFS patients had fewer HUA, worse symptoms and greater interference with daily activities due to OI than HCs. The <5 HUA ME/CFS subjects had more severe OI related symptoms than ≥5 HUA ME/CFS subjects even though OI interfered with daily activities similarly. Only 33% of ME/CFS subjects were employed and all were ≥5 HUA ME/CFS subjects with an average HUA of 8.

Conclusions: ME/CFS subjects experienced more frequent and severe OI symptoms, higher interference with daily activities, and reduced ability to work than HCs. Reported HUA and assessment of OI using standardized instruments may be useful clinical tools for physicians in the diagnosis, treatment and management of ME/CFS patients.

Source: Lee J, Wall P, Kimler C, Bateman L, Vernon SD. Clinically accessible tools for documenting the impact of orthostatic intolerance on symptoms and function in ME/CFS [published online ahead of print, 2020 Jun 16]. Work. 2020;10.3233/WOR-203169. doi:10.3233/WOR-203169 https://pubmed.ncbi.nlm.nih.gov/32568144/

Perturbation of effector and regulatory T cell subsets in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)

Abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating disorder of unknown etiology, and diagnosis of the disease is largely based on clinical symptoms. We hypothesized that immunological disruption is the major driver of this disease and analyzed a large cohort of ME/CFS patient or control blood samples for differences in T cell subset frequencies and functions.

We found that the ratio of CD4+ to CD8+ T cells and the proportion of CD8+ effector memory T cells were increased, whereas NK cells were reduced in ME/CFS patients younger than 50 years old compared to a healthy control group. Remarkably, major differences were observed in Th1, Th2, Th17 and mucosal-associated invariant T (MAIT) T cell subset functions across all ages of patients compared to healthy subjects. While CCR6+ Th17 cells in ME/CFS secreted less IL-17 compared to controls, their overall frequency was higher. Similarly, MAIT cells from patients secreted lower IFNγ, GranzymeA and IL-17 upon activation.

Together, these findings suggest chronic stimulation of these T cell populations in ME/CFS patients. In contrast, the frequency of regulatory T cells (Tregs), which control excessive immune activation, was higher in ME/CFS patients. Finally, using a machine learning algorithm called random forest, we determined that the set of T cell parameters analyzed could identify more than 90% of the subjects in the ME/CFS cohort as patients (93% true positive rate or sensitivity).

In conclusion, these multiple and major perturbations or dysfunctions in T cell subsets in ME/CFS patients suggest potential chronic infections or microbiome dysbiosis. These findings also have implications for development of ME/CFS specific immune biomarkers and reveal potential targets for novel therapeutic interventions.

Source: Ece Karhan, Courtney L Gunter, Vida Ravanmehr, Meghan Horne, Lina Kozhaya, Stephanie Renzullo, Lindsey Placek, Joshy George, Peter N Robinson, Suzanne D Vernon, Lucinda Bateman, Derya Unutmaz. Perturbation of effector and regulatory T cell subsets in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)
bioRxiv 2019.12.23.887505; doi: https://doi.org/10.1101/2019.12.23.887505 https://www.biorxiv.org/content/10.1101/2019.12.23.887505v1 (Full text available as PDF file)

Integration of DNA methylation & health scores identifies subtypes in myalgic encephalomyelitis/chronic fatigue syndrome

Abstract:

AIM: To identify subtypes in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) based on DNA methylation profiles and health scores.

METHODS: DNA methylome profiles in immune cells were integrated with symptomatology from 70 women with ME/CFS using similarity network fusion to identify subtypes.

RESULTS: We discovered four ME/CFS subtypes associated with DNA methylation modifications in 1939 CpG sites, three RAND-36 categories and five DePaul Symptom Questionnaire measures. Methylation patterns of immune response genes and differences in physical functioning and postexertional malaise differentiated the subtypes.

CONCLUSION: ME/CFS subtypes are associated with specific DNA methylation differences and health symptomatology and provide additional evidence of the potential relevance of metabolic and immune differences in ME/CFS with respect to specific symptoms.

Source: de Vega WC, Erdman L, Vernon SD, Goldenberg A, McGowan PO. Integration of DNA methylation & health scores identifies subtypes in myalgic encephalomyelitis/chronic fatigue syndrome. Epigenomics. 2018 Apr 25. doi: 10.2217/epi-2017-0150. [Epub ahead of print] https://www.ncbi.nlm.nih.gov/pubmed/29692205

Markers of non-coeliac wheat sensitivity in patients with myalgic encephalomyelitis/chronic fatigue syndrome

We recently reported in Gut that non-coeliac wheat sensitivity (NCWS) is associated with a state of systemic immune activation in conjunction with a compromised intestinal epithelium.1 Patients with NCWS experience GI symptoms, most commonly including abdominal pain and bloating, as well as extraintestinal symptoms, among which fatigue, headache and cognitive difficulties feature prominently.1 2 A principal component analysis of the generated data from our study, including markers of antibody reactivity to wheat gluten, intestinal cell damage and systemic innate and adaptive immune responses to microbial components, found clustering of the patients and controls into discernible groups and demonstrated the potential utility of the identified biomarkers for identifying patients with NCWS.1

Extreme fatigue, in particular one that does not improve with rest, is a hallmark of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS).3 Immune system abnormalities have been found to be associated with symptoms in a substantial number of patients with ME/CFS.4 5 Furthermore, many patients complain of GI symptoms of unknown aetiology.6–8 We considered whether a subset of patients with ME/CFS may exhibit serologic markers associated with NCWS, which might explain some of the corresponding symptoms. We screened serum samples from 131 patients with ME/CFS and 86 healthy controls (table 1), recruited as previously described,9 for the same markers as those in the above-mentioned study on NCWS.1 Questionnaires were used to assess GI symptoms within the past 6 months, including abdominal pain, bloating and nausea. Severity of individual symptoms was scored from 1 to 5 (1=absent; 2=mild; 3=moderate; 4=severe; 5=very severe), and a total score, based on the sum of individual symptom scores, was calculated for each subject.

Read full article HERE.

Source: Melanie Uhde, Alyssa C Indart, Xuechen B Yu, Sophie S Jang, Roberto De Giorgio, Peter H R Green, Umberto Volta, Suzanne D Vernon, Armin Alaedini. Markers of non-coeliac wheat sensitivity in patients with myalgic encephalomyelitis/chronic fatigue syndrome. http://dx.doi.org/10.1136/gutjnl-2018-316133