AI-driven multi-omics modeling of myalgic encephalomyelitis/chronic fatigue syndrome

Abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a chronic illness with a multifactorial etiology and heterogeneous symptomatology, posing major challenges for diagnosis and treatment. Here we present BioMapAI, a supervised deep neural network trained on a 4-year, longitudinal, multi-omics dataset from 249 participants, which integrates gut metagenomics, plasma metabolomics, immune cell profiling, blood laboratory data and detailed clinical symptoms.

By simultaneously modeling these diverse data types to predict clinical severity, BioMapAI identifies disease- and symptom-specific biomarkers and classifies ME/CFS in both held-out and independent external cohorts. Using an explainable AI approach, we construct a unique connectivity map spanning the microbiome, immune system and plasma metabolome in health and ME/CFS adjusted for age, gender and additional clinical factors.

This map uncovers altered associations between microbial metabolism (for example, short-chain fatty acids, branched-chain amino acids, tryptophan, benzoate), plasma lipids and bile acids, and heightened inflammatory responses in mucosal and inflammatory T cell subsets (MAIT, γδT) secreting IFN-γ and GzA.

Overall, BioMapAI provides unprecedented systems-level insights into ME/CFS, refining existing hypotheses and hypothesizing unique mechanisms—specifically, how multi-omics dynamics are associated to the disease’s heterogeneous symptoms.

Source: Xiong, R., Aiken, E., Caldwell, R. et al. AI-driven multi-omics modeling of myalgic encephalomyelitis/chronic fatigue syndrome. Nat Med (2025). https://doi.org/10.1038/s41591-025-03788-3  https://www.nature.com/articles/s41591-025-03788-3

Steroid dynamics in myalgic encephalomyelitis / chronic fatigue syndrome: a case-control study using ultra performance supercritical fluid chromatography tandem mass spectrometry

Abstract:

Background: Myalgic encephalomyelitis / chronic fatigue syndrome (ME/CFS) is a multisystem disorder characterised by unrelenting fatigue, post-exertional malaise, and dysfunction across immune, nervous, metabolism, and endocrine systems. Given the broad role of steroid hormones in regulating these systems, this study investigated differences in the steroid metabolome and network dynamics between ME/CFS patients and matched controls.

Methods: Blood plasma steroid levels were quantified using Ultra-Performance Supercritical Fluid Chromatography- Tandem Mass Spectrometry (UPSFC-MS/MS) in ME/CFS patients (n = 24) and age and gender matched controls (n = 24). Group comparisons of absolute steroid concentrations were performed using Mann-Whitney U tests. Partial Spearman correlation networks were evaluated to examine direct associations between steroids within each group, and centrality metrics were used to evaluate structural differences. Steroid-steroid ratios were analysed to reflect biochemical relationships. Multivariate analysis with Orthogonal Partial Least Squares Discriminant Analysis (OPLS-DA) was also conducted.

Results: No significant group differences in absolute steroid concentrations were observed following FDR correction. However, network analysis revealed a marked reduction in direct steroid-steroid relationships in ME/CFS, with controls exhibiting 52 significant partial correlations, while the ME/CFS group retained only one (cortisol – corticosterone). Centrality analysis further revealed a shift in network structure, with cortisone emerging as highly central in ME/CFS (degree = 7, betweenness = 16.7), despite being peripheral in controls, and progesterone showing reduced integration in ME/CFS (degree = 3 vs. 12, eigenvector = 0.40 vs. 0.93). Steroid-steroid ratio analysis revealed a higher cortisol-to-pregnanolone ratio and a lower pregnanolone-to-progesterone ratio in ME/CFS, although these findings did not remain significant after FDR correction. OPLS-DA indicated a modest relationship between steroid levels and group classification (R²Y = 22.8%), but negative Q² values suggested poor predictive power.

Conclusions: Despite no significant differences in absolute steroid levels, network analysis revealed profound disruptions in steroid-steroid relationships in ME/CFS compared to controls, suggesting disrupted steroid homeostasis. Collectively the results suggest dysregulation of HPA axis function and progestogen pathways, as demonstrated by altered partial correlations, centrality profiles, and steroid ratios. These findings illustrate the importance of hormone network dynamics in ME/CFS pathophysiology and underscores the need for more research into steroid metabolism.

Source: Thomas, N., Ubhayasekera, S.J.K.A., Armstrong, C.W. et al. Steroid dynamics in myalgic encephalomyelitis / chronic fatigue syndrome: a case-control study using ultra performance supercritical fluid chromatography tandem mass spectrometry. J Transl Med 23, 829 (2025). https://doi.org/10.1186/s12967-025-06841-4 https://link.springer.com/article/10.1186/s12967-025-06841-4 (Full text)

Pyridostigmine and low-dose naltrexone for ME/CFS: study protocol for the Life Improvement Trial (LIFT), a randomized, double-blind, placebo-controlled clinical trial

Abstract:

Background: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a complex, chronic disease with no FDA-approved treatments. This report describes a protocol for the Life Improvement Trial (LIFT), a randomized, double-blind, placebo-controlled clinical trial investigating the impact of low-dose naltrexone (LDN) and pyridostigmine (Mestinon) on physiological response, symptoms, and functionality of ME/CFS patients.

Methods: Participants (target n = 160) are recruited through clinics at Massachusetts General Hospital and Brigham and Women’s Hospital, and through Open Medicine Foundation’s StudyME registry. They are then randomized into one of four arms: LDN/pyridostigmine, LDN/placebo, placebo/pyridostigmine, placebo/placebo. Treatment is administered for 13 weeks after an initial screening period of up to 4 weeks. Primary outcomes are FUNCAP-55 score, peak oxygen utilization, heart rate recovery, and oxygen uptake efficiency slope. Secondary outcomes are scores from DSQ-PEM and PROMIS-29 surveys, DANA Brain Vital score, step count, heart rate, and heart rate variability.

Discussion: The results of this trial will provide novel insights into the efficacy of and predictors of response to LDN and pyridostigmine in ME/CFS. This may inform future treatment strategies for ME/CFS. The trial will also validate what primary and secondary outcomes to use in similar clinical trials.

Source: Danielle Meadows, Johanna Squires, Joshua Dibble et al. Pyridostigmine and low-dose naltrexone for ME/CFS: study protocol for the Life Improvement Trial (LIFT), a randomized, double-blind, placebo-controlled clinical trial, 04 March 2025, PREPRINT (Version 1) available at Research Square [https://doi.org/10.21203/rs.3.rs-5626167/v1]

A Signal for Voice and Speech Abnormalities in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

Abstract:

Background/Objectives: Patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) may report abnormalities in voice and speech; however, no formal research has been conducted in this area.
Methods: An online mixed-methods survey was completed by 685 people with ME/CFS. A total of 302 respondents completed the qualitative component (44.09%). Questions assessed disease experience with ME/CFS and post-exertional malaise without prompting on specific symptoms. Within the qualitative results, a search of the terms “speech, voice,” “words,” and “speak” was conducted.
Results: Excluding neurocognitive associations, colloquial phrases, and “speech therapy,” there were 38 mentions of the terms in the context of voice or speech changes across 28 unique qualitative survey responses (9.27%).
Conclusions: A notable portion of respondents reported voice or speech changes when responding to open-ended qualitative questions about their disease experience. More research is needed regarding the implications of voice and speech anomalies in ME/CFS pathology and disease monitoring.
Source: Grach SL, Seltzer J, Orbelo DM. A Signal for Voice and Speech Abnormalities in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Journal of Clinical Medicine. 2025; 14(14):4847. https://doi.org/10.3390/jcm14144847 https://www.mdpi.com/2077-0383/14/14/4847 (Full text)

Rate of 4.5% Post-COVID ME/CFS Onset Cited in Recent RECOVER Study is Based on Biased Cohort

Letter:

The recent paper by Vernon, et al.1 predicts that 4.5% of adult COVID sufferers in the United States experience subsequent onset of Myalgic Encephalomyelitis / Chronic Fatigue Syndrome (ME/CFS). While the degree of ME/CFS onset is indeed significant, the figure of 4.5% cannot be justified from the provided data.

Vernon, et al. compute a male onset rate of 3.41% (107/3134, see Table 1 of paper) and a female onset rate of 4.91% (422/8600). They then take a weighted average based on the gender breakdown of their cohort, which is 27.7% male and 72.3% female, to arrive at 4.5% overall.

The problem here is that their cohort, which is nearly three-quarters female, is not representative of the adult gender prevalence of COVID in the United States. One can estimate the gender breakdown using the CDC Household Pulse Survey,2 which shows 61.6% of US adults having gotten COVID, 58.6% of males and 64.4% of females. These numbers are consistent with an assumed gender breakdown of the adult population of 48.3% male and 51.7% female, from which can be deduced an adult COVID breakdown of 46% male and 54% female, leading to an ME/CFS onset rate of 4.22%. While significant, this is less than the 4.5% published conclusion.

Source: Mirin AA. Rate of 4.5% Post-COVID ME/CFS Onset Cited in Recent RECOVER Study is Based on Biased Cohort. J Gen Intern Med. 2025 Jul 22. doi: 10.1007/s11606-025-09711-3. Epub ahead of print. PMID: 40696227.  https://link.springer.com/article/10.1007/s11606-025-09711-3 (Full text)

Intelligent Eye Tracker Integrated with Cylindrical Capacitive Sensors for Chronic Fatigue Assessment

Abstract:

Fatigue negatively impacts health, safety, and productivity, yet current monitoring methods are often subjective, labor-intensive, and inaccurate. To address these challenges, this study presents a capacitive sensor-based eye tracker leveraging cylindrical carbon nanotube-paper composite (CCPC) sensors for chronic fatigue (CF) assessment.

Fabricated by novel wet-fracture and paper-rolling methods, CCPC sensors demonstrate superior proximity sensitivity with a small form factor. These one-dimensional sensors are seamlessly integrated into an eyeglass frame for noncontact monitoring of blink rates and eye closures. A 15-minute testing protocol, combining cognitive tasks and noise exposure, is designed to induce acute fatigue and identify CF. By analyzing changes in the digital markers against established fatigue indicators, CF is assessed with the aid of machine learning models for the evaluation of accuracy, sensitivity, and specificity.

This real-time, wearable monitoring platform provides an objective, effortless, and noncontact approach to fatigue assessment. With further testing and optimization, it holds the potential for user-friendly evaluation of acute fatigue or fatigue-associated diseases, such as myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS).

Source: Li T, Park SH, Lee C, Kim S, Kwon Y, Kim H, Chung JH. Intelligent Eye Tracker Integrated with Cylindrical Capacitive Sensors for Chronic Fatigue Assessment. Adv Sens Res. 2025 Jul;4(7):e00027. doi: 10.1002/adsr.202500027. Epub 2025 May 22. PMID: 40662140; PMCID: PMC12259227. https://pmc.ncbi.nlm.nih.gov/articles/PMC12259227/ (Full text)

Cytokine profiles associated with persisting symptoms of post-acute sequelae of COVID-19

Abstract:

Background/aims: Post-acute sequelae of COVID-19 (PASC) are highly heterogeneous; therefore, the pathophysiological mechanisms for PASC remain unclear. In this study, we aimed to examine the immunologic aspects of various PASC symptoms.

Methods: We prospectively enrolled adults aged ≥ 18 years who were diagnosed with COVID-19 between August 2022 and September 2023. Blood samples were collected from all participants, who were interviewed using a questionnaire for PASC symptoms at least once between 1 and 6 months after the COVID-19 diagnosis. For immunological evaluation, plasma concentrations of SARS-CoV-2 spike subunit 1-specific IgG and 33 cytokines were measured using enzyme-linked immunosorbent assays and multiplex-based immunoassay, respectively.

Results: In total, 156 pairs of blood samples and symptom reports from 79 participants were eligible for analysis. The most frequent symptom was fatigue, followed by post exertional malaise, chronic cough, thirst, and brain fog. Gastrointestinal symptoms, chest pain, post exertional malaise, smell/taste change, fatigue, brain fog, abnormal movement, and palpitation were accompanied by significant increases in IL-10, VEGF, and inflammatory cytokines like MIP-1α, IL-1β, IL-6, IL-8, MIG, granzyme A, and CX3CL1 levels, while chronic cough, dizziness, dyspnea, and hair loss were not accompanied by significant differences in cytokine levels.

Conclusion: Symptoms classified into different categories based on the dysfunctional organs may share a common pathophysiology regarding elevation of certain cytokines. Although PASC symptoms are heterogeneous, our findings suggest that T-cell recruitment, thrombosis, and increased vascular permeability might contribute to various symptom clusters sharing common pathophysiological mechanisms.

Source: Kwon JS, Chang E, Jang HM, Kim JY, Kim W, Son JY, Cha J, Jang CY, Bae S, Jung J, Kim MJ, Chong YP, Lee SO, Choi SH, Kim YS, Kim SH. Cytokine profiles associated with persisting symptoms of post-acute sequelae of COVID-19. Korean J Intern Med. 2025 Jul;40(4):667-675. doi: 10.3904/kjim.2024.217. Epub 2025 Jul 1. PMID: 40635493. https://kjim.org/journal/view.php?doi=10.3904/kjim.2024.217 (Full text)

Assessing the influence of lived-experience experts on healthcare providers in a virtual community of practice: a qualitative study

Abstract:

Long COVID, myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), and other poorly understood post-acute infection syndromes (PAIS) can present with unexplained symptoms or conditions that may be misunderstood by healthcare providers, causing delays in diagnosis and care. To address these issues, the Centers for Disease Control and Prevention (CDC) funded the Long COVID and Fatiguing Illness Recovery Program (LC&FIRP), initiated as a pilot project to assess whether providing tele-mentoring and other online education for primary care providers could help them improve the quality of life and support the recovery of their patients with these conditions.

The LC&FIRP multi-disciplinary team-based care approach is built on the Extension for Community Healthcare Outcomes (ECHO) learning model, which is an evidence-based virtual learning framework developed by the University of New Mexico and designed to disseminate and implement best practices, especially in under-resourced areas. A distinctive feature of LC&FIRP was the inclusion of lived-experience experts. To explore the influence of lived-experience experts on the care patients received, we collected the educational recommendations provided by the lived-experience experts during webinar sessions (January 2022-March 2024) and grouped these by themes.

The major themes that emerged included validation of patients’ illness experience; attitudes and beliefs about Long COVID, ME/CFS, and PAIS; understanding patients’ challenges and communicating with empathy; navigating referrals; recognizing and supporting disability; and supporting self-care. Investigators also interviewed patients of the Family Health Centers of San Diego (FHCSD) about their experiences receiving care from participating primary care providers and employed content analysis methods to code interview transcripts to identify themes among patients’ perspectives. Positive comments from the patients about topics emphasized by the lived-experience experts provided evidence of providers’ uptake and application of the experts’ recommendations and support the value of involving lived-experience experts in medical education to improve health services.

Source: Weaver SS, Carry M, Bertolli J, Godino J, Struminger B, Taren D, Scott JD, Sharp SP, Samaniego J, Bean DR, Issa A, Lin JS, Unger ER, Ramers CB. Assessing the influence of lived-experience experts on healthcare providers in a virtual community of practice: a qualitative study. Front Health Serv. 2025 Jun 27;5:1562651. doi: 10.3389/frhs.2025.1562651. PMID: 40656206; PMCID: PMC12245761. https://pmc.ncbi.nlm.nih.gov/articles/PMC12245761/ (Full text)

Brain and muscle chemistry in myalgic encephalitis/chronic fatigue syndrome (ME/CFS) and long COVID: a 7T magnetic resonance spectroscopy study

Abstract:

Myalgic encephalitis/chronic fatigue syndrome (ME/CFS) is a common debilitating medical condition, whose main symptoms – fatigue, post-exertional malaise and cognitive dysfunction – are also present in many cases of long COVID. Magnetic resonance spectroscopy (MRS) allows the insight into their pathophysiology through exploration of a range of biochemicals putatively relevant to aetiological processes, in particular mitochondrial dysfunction and energy metabolism.

24 patients with ME/CFS, 25 patients with long COVID and 24 healthy controls (HC) underwent brain (pregenual and dorsal anterior cingulate cortex, respectively, pgACC and dACC) and calf muscle MRS scanning at 7 Tesla, followed by a computerised cognitive assessment. Compared to HC, ME/CFS patients had elevated levels of lactate in both pgACC and dACC, while long COVID patients had lowered levels of total choline in dACC. By contrast, skeletal muscle metabolites at rest did not significantly differ between the groups.

The changes in lactate in ME/CFS are consistent with the presence of energetic stress and mitochondrial dysfunction. A reduction in total choline in long COVID is of interest in the context of the recently reported association between blood clots and ‘brain fog’, and earlier animal studies showing that choline might prevent intravascular coagulation.

Importantly, differences in findings between ME/CFS and long COVID suggest that the underlying neurobiological mechanisms, while leading to similar clinical presentations, may differ. An important implication is that patients with ME/CFS and those with fatigue in the course of long COVID should not be studied as a single group, at least until the mechanisms are better understood.

Source: Godlewska BR, Sylvester AL, Emir UE, Sharpley AL, Clarke WT, Williams SR, Gonçalves AJ, Raman B, Valkovič L, Cowen PJ. Brain and muscle chemistry in myalgic encephalitis/chronic fatigue syndrome (ME/CFS) and long COVID: a 7T magnetic resonance spectroscopy study. Mol Psychiatry. 2025 Jul 12. doi: 10.1038/s41380-025-03108-8. Epub ahead of print. PMID: 40652046. https://www.nature.com/articles/s41380-025-03108-8 (Full text)

The impact of leading questions on ME/CFS research: bias and stigma in study design

Abstract:

Background: Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a complex and often misunderstood illness, characterized by post-exertional malaise, unrefreshing sleep, and cognitive impairments.

Objective: To investigate how question phrasing in ME/CFS research may influence participant attributions of fatigue/energy problems and unintentionally reinforce psychosomatic assumptions.

Methods: A total of 2248 individuals with ME/CFS from an international sample completed a survey assessing fatigue-related attributions. We analyzed how question wording influenced whether participants attributed their symptoms to physical or psychosocial causes. Particular focus was given to a fatigue attribution item that framed causes in terms of ‘personal life’ or ‘environmental factors.’

Results: Participants were significantly more likely to attribute their fatigue/energy problems to psychosocial factors when prompted with psychosocial framing. Many respondents who previously indicated physical causes as the primary source of their symptoms shifted to psychosocial explanations in response to the differently phrased item. This shift was especially pronounced among participants reporting higher levels of psychological distress.

Conclusions: Leading or biased question phrasing may distort participant responses in ME/CFS research, potentially inflating psychosomatic interpretations of the illness. Researchers should critically examine survey language to avoid introducing unintended bias that could compromise research validity and reinforce stigma.

Source: Campolattara, A. T. T., Jason, L. A., & Tuzzolino, K. C. (2025). The impact of leading questions on ME/CFS research: bias and stigma in study design. Fatigue: Biomedicine, Health & Behavior, 1–16. https://doi.org/10.1080/21641846.2025.2530338 https://www.tandfonline.com/doi/full/10.1080/21641846.2025.2530338