A groundbreaking study led by researchers affiliated with the University of Sydney has shed new light on the biological underpinnings of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), a debilitating condition affecting an estimated 250,000 Australians. Published in Cell Reports Medicine in December 2025, the research reveals interconnected abnormalities in energy metabolism, immune cell function, and vascular health in patients' white blood cells compared to healthy controls. This multimodal investigation, involving 61 ME/CFS patients and matched controls, challenges longstanding perceptions of the illness as purely psychological and opens doors to potential diagnostic biomarkers and targeted therapies.

ME/CFS, characterized by profound fatigue, post-exertional malaise, cognitive fog, unrefreshing sleep, and orthostatic intolerance, remains poorly understood and undiagnosed for years in many cases. In Australia, where women are twice as likely to be affected, the condition imposes significant personal and economic burdens, with diagnosis often delayed by six years or more due to the absence of specific tests. The University of Sydney's involvement through its Charles Perkins Centre and Sydney Mass Spectrometry highlights the pivotal role of Australian higher education institutions in tackling complex chronic illnesses.

🧬 The Study's Innovative Multimodal Approach

The research employed advanced techniques including metabolomics via high-performance liquid chromatography (HPLC) and gas chromatography-mass spectrometry (GC-MS), spectral flow cytometry for immune profiling, and mass spectrometry-based plasma proteomics. Peripheral blood mononuclear cells (PBMCs) from participants were analyzed for adenine nucleotides (ATP, ADP, AMP) and NAD-related metabolites, while plasma proteins were assessed for vascular and immune markers. Statistical tools like Mann-Whitney U tests and classification and regression tree (CART) modeling achieved 91% accuracy in distinguishing ME/CFS from controls.

• Metabolomics targeted the kynurenine pathway and energy nucleotides.
• Flow cytometry examined T cells, NK cells, dendritic cells (DCs), and monocytes.
• Proteomics identified over 1,000 plasma proteins, with Ingenuity Pathway Analysis revealing enriched pathways.

This integrated method underscores the value of collaborative expertise at institutions like the University of Sydney, where mass spectrometry facilities enable precise molecular insights essential for chronic disease research.

Energy Starvation in Immune Cells

Central to the findings is evidence of cellular energy stress in ME/CFS patients' immune cells. PBMCs showed elevated AMP (0.4 nM vs. 0.35 nM in controls) and ADP (1.79 nM vs. 1.25 nM), yielding a reduced ATP/ADP ratio (5.25 vs. 6.25). Higher NAD+ levels (300.3 nM vs. 257.7 nM) and NADP+/NADPH ratios (0.023 vs. 0.016) suggest impaired mitochondrial respiration and oxidative stress, limiting NADPH for antioxidant defense and immune activation.

Disruption in the de novo NAD+ synthesis via kynurenine pathway—higher 3-hydroxykynurenine (3HK, 34.29 nM vs. 26.67 nM) and lower kynurenic acid (KYNA, 23.38 nM vs. 30.26 nM), picolinic acid, and quinolinic acid—points to blocked energy production. Lead researcher Dr. Benjamin Heng noted, "Energy production in the immune cells of people with ME/CFS was low and not geared towards responding to pathogens." This metabolic exhaustion likely contributes to the hallmark post-exertional malaise, as cells prioritize survival over function.

Immune Profile Shifts Toward Immaturity

Flow cytometry revealed skewed immune subsets: reduced terminal effector memory T cells (CD45RA− CCR7− CD27− CD28− for CD4+, CD45RA+ CCR7− TEMRA for CD8+ and γδ T cells), CD56low CD16+ NK cells (p<0.05), and CD1c+ CD141− conventional dendritic cells type 2 (cDC2, p=0.001). Higher plasmacytoid DCs (pDC) suggested compensatory innate responses. These immature profiles impair pathogen clearance and maturation, heightening infection vulnerability—a common ME/CFS trigger.

Such shifts align with prior Australian and international research, indicating chronic low-grade activation exhausts adaptive immunity, forcing reliance on energy-intensive innate pathways. University of Sydney's transplantation immunobiology group contributed critical expertise here, advancing understanding of immune exhaustion in chronic conditions.

Photo by Eriksson Luo on Unsplash

Vascular and Endothelial Clues

Plasma proteomics showed elevated proteins like LYVE1 (2.1-fold), thrombospondin 1 (THBS1, 1.9-fold), von Willebrand factor (VWF, 1.3-fold), and fibronectin (FN1, 1.5-fold), linked to thrombus formation, endothelial activation, and vessel remodeling. Downregulated cadherin 5 (CDH5, -1.5-fold) and PIEZO1 (-1.4-fold) suggest impaired vascular integrity. Pathways for coagulation and integrin signaling were upregulated, while phagocytosis was downregulated. Dr. Richard Schloeffel, Clinical Senior Lecturer at University of Sydney's Macquarie Medical School, explained, "Disturbance in the vascular system... explains why people have 200 or 300 symptoms."

Read the full study in Cell Reports Medicine for detailed proteomics data.

Diagnostic Promise from CART Modeling

CART analysis using variables like FN1, VWF, LYVE1, AMP, and THBS1 predicted ME/CFS with 85.2% sensitivity, 96.7% specificity, and 91% accuracy (AUC 0.962). This biomarker panel could revolutionize diagnosis, currently reliant on exclusion criteria like the Canadian Consensus Criteria. Validation trials are underway, potentially reducing Australia's diagnostic odyssey.

University of Sydney's Pivotal Role

Affiliates from the University of Sydney's Charles Perkins Centre provided mass spectrometry and immunobiology support, exemplifying interdisciplinary collaboration with Macquarie University. Dr. Heng, with USyd ties, led the effort, while facilities enabled precise PBMC and plasma analyses. This reflects Australia's growing higher education focus on chronic diseases, bolstered by NHMRC and MRFF funding for ME/CFS and Long COVID research (over $4.7M since 2019).

Such work positions USyd as a leader in translational medicine, attracting talent to research positions in immunology and metabolomics.

Australian Research Landscape and Funding

Beyond this study, Australian universities drive ME/CFS advances: Griffith's $438K grant for progression tracking, Deakin/La Trobe/Swinburne's TRI-ME trial testing trimetazidine, and Melbourne ME/CFS Collaboration. NHMRC's $3.3M (2020) and MRFF's $23M PASC call (2026) fund overlapping Long COVID efforts, given symptom similarities. Emerge Australia advocates for $50M investment, highlighting economic costs exceeding billions annually.

ABC News coverage details patient impacts and calls for more clinicians.

Photo by Jeremy Huang on Unsplash

Challenges, Patient Stories, and Future Outlook

Patient Ella Engel's story—eight years bedbound, communicating by blinks—illustrates severity. Limitations include small cohorts and heterogeneity, but findings validate biological basis. Future: validate biomarkers, trial metabolic modulators (e.g., NAD boosters), and expand trials. Australian unis like USyd offer PhD/postdoc opportunities in this niche.

Careers in ME/CFS Research at Australian Universities

This study exemplifies demand for experts in metabolomics, immunology, and bioinformatics. Positions at USyd, Macquarie, and others via AcademicJobs Australia include research assistants, lecturers in biomedical sciences. With rising Long COVID, funding grows, positioning higher ed as key to solutions.

• Research Assistant: Immune profiling (Sydney-based).
• Postdoc: Metabolomics (Macquarie).
• Lecturer: Chronic disease pathophysiology.