Renz-Polster et al. (2022)
- Authors: Herbert Renz-Polster, Marie-Eve Tremblay, Dorothee Bienzle, Joachim E. Fischer
- Institutes: Division of General Medicine, Center for Preventive Medicine and Digital Health Baden-Württemberg (CPD-BW), University Medicine Mannheim, Heidelberg University; Axe Neurosciences, Centre de Recherche du CHU de Québec, Université Laval; Département de Médecine Moléculaire, Université Laval.
- Publisher: Frontiers in Cellular Neuroscience
- Link: DOI
Summary
This paper offers a unifying theory that places malfunctioning brain immune cells, known as neuroglia, at the center of ME/CFS pathology. It suggests these cells are stuck in a hyper-reactive state, providing a potential biological reason for post-exertional malaise and the widespread problems with brain blood flow. This “neuroglial failure” hypothesis does not dismiss other findings like mitochondrial or vascular issues, but rather proposes a central mechanism in the brain that connects them. This provides a valuable framework that could help guide future research toward developing treatments that specifically target the neuro-immune interface of the central nervous system.
What was researched?
This paper explores the hypothesis that a dysfunction of neuroglia—the support and immune cells of the central nervous system (CNS) such as astrocytes, microglia, and oligodendrocytes—could be the common underlying cause for the wide range of biological abnormalities observed in ME/CFS. The authors reviewed existing scientific literature to test whether this “neuroglial failure” model could explain the two most defining features of the illness: post-exertional malaise (PEM) and reduced cerebral blood flow (CBF).
Why was it researched?
While numerous potential disease mechanisms for ME/CFS have been identified, including immune, metabolic, and vascular problems, it remains unclear how these different pathways are connected. Glial cell dysfunction has been previously suggested as a key feature of ME/CFS, but a comprehensive review was lacking. This paper aimed to provide a unifying hypothesis that could connect these disparate findings into a single, cohesive pathobiological framework.
How was it researched?
This study was a hypothesis and theory paper based on a non-systematic literature review. The authors analyzed and synthesized existing research on the clinical and pathobiological features of ME/CFS. They focused specifically on whether the core characteristics of PEM and abnormal CBF could be mechanistically explained by the known functions and dysfunctions of neuroglial cells.
What has been found?
The review concludes that neuroglial dysfunction provides a plausible explanation for the core features of ME/CFS. The authors propose that in ME/CFS, neuroglial cells exist in a “primed” or hyper-reactive state, which would explain the delayed onset, prolonged duration, and multi-systemic nature of PEM as a response to various stressors. Furthermore, since glial cells are central to regulating blood flow in the brain through neurovascular coupling and the baroreflex, their dysfunction would directly account for the consistently observed deficits in cerebral blood flow.
Discussion
The authors acknowledge several limitations to their hypothesis that require further investigation. The presence of CNS inflammation and blood-brain barrier (BBB) disruption in ME/CFS has not yet been definitively proven. Additionally, the specific roles and interactions of the different glial cell populations (microglia, astrocytes, oligodendrocytes) in the disease process remain to be defined.
Conclusion & Future Work
The authors conclude that regulatory failure of the CNS due to dysfunctional neuroglia may be the central process that orchestrates the clinical presentation of ME/CFS. This model links peripheral issues like immune and endothelial dysfunction to a central mechanism. The authors propose a greater research focus on the role of neuroglia in ME/CFS and suggest re-examining existing therapies that may target these cells, such as minocycline 💊, aripiprazole 💊, and low dose naltrexone 💊.