The Gut–Liver–Autonomic (GLA) framework is not a competing explanation for ME/CFS or Long COVID. Instead, it acts as a systems-level integration layer: a regulatory architecture that connects vascular, metabolic, immune, and autonomic pathways described across many established disease concepts. This section outlines how the core GLA components — SMPDL3B signalling, endothelial–microvascular stability, liver and bile-acid regulation, and autonomic control — intersect with the major published hypotheses of ME/CFS and PEM.
The goal is not to force links where none exist. Only biologically coherent, evidence-supported intersections are included.
(Brainstem immune activation, dorsal root ganglia sensitization, microglial priming)
These models propose that PEM arises when peripheral exertion triggers delayed central neuroimmune activation, producing symptom flares (brain fog, sensory intolerance, malaise, sleep disruption). In GLA v2.6, neuroinflammation is treated primarily as a downstream amplifier of a recovery-phase control failure, not the initiating defect.
GLA intersects by specifying peripheral recovery-phase triggers that can bias vagal and brainstem circuits:
In this view, neuroinflammation and vagal sensitization can explain how symptoms amplify centrally, while GLA explains why peripheral recovery signals fail to terminate cleanly and repeatedly re-engage these circuits.
(Metabotypes, redox/ATP recovery failure, impaired substrate routing, β-oxidation constraints)
Metabolic models emphasize altered energy handling during and after exertion: impaired ATP recovery reliability, abnormal redox state, and constrained fatty-acid oxidation or substrate flexibility. In GLA v2.6, these findings are integrated as downstream execution consequences of perfusion instability and recovery-phase signaling that fails to resolve.
GLA adds upstream drivers that can produce “metabolic fragility” without requiring a primary mitochondrial lesion:
So metabolic dysfunction remains real and central — but within GLA it is best interpreted as the execution-layer signature of a recovery-phase control problem, rather than the primary initiating cause.
(Platelet hyperactivation, fibrinaloid microclots, capillary obstruction)
Microclot models propose that abnormal fibrin(ogen) structures and platelet activation impede capillary flow. GLA aligns strongly with this vascular amplifier, but positions it inside a broader control architecture. In GLA v2.6, the key sequencing principle is: clearance or clot-targeting should follow improved shear tolerance, otherwise flow-topology shifts can increase shear variability and worsen recovery-phase instability.
In short: microclots can amplify PEM by increasing flow heterogeneity and recovery burden, but they are not treated as the sole cause of PEM or the primary driver of persistence.
(POTS, orthostatic intolerance, low circulating volume, cerebral hypoperfusion)
These models demonstrate reproducible reductions in cerebral and peripheral blood flow and impaired orthostatic compensation. GLA embeds this directly but adds an important framing: autonomic dysfunction is often the final common pathway through which upstream vascular and recovery failures become symptoms.
The two frameworks fit naturally: autonomic models describe what fails at the system level, while GLA explains why the system loses buffering and timing reliability during recovery.
(Stress-induced state-locking, altered purinergic signaling, impaired exit/termination)
These concepts focus less on the specific metabolic phenotype and more on the problem of exit: how cells can enter stable “locked” signaling/metabolic states that persist after the initiating stressor. This is related to Section 2 but distinct: Section 2 summarizes observed metabolic dysfunction; Section 5 describes why it can become self-maintaining.
In GLA v2.6, CDR/trap logic is treated as a subordinate intracellular program that may be repeatedly re-engaged when recovery-phase stress does not terminate:
GLA does not assume CDR is universal or primary. It provides mechanistic conditions under which CDR-like lock-in may emerge and explains why simply targeting one intracellular node may not restore recovery control if upstream termination and clearance remain constrained.
(Muscle Na+ accumulation, Ca2+ overload, mitochondrial injury)
The Wirth & Scheibenbogen model explains PEM through muscle-centric ionic instability and mitochondrial injury under exertional load. GLA aligns strongly, but adds an upstream systems framing: W&S describe a proximal execution mechanism of PEM in muscle, while GLA explains the vulnerability context that makes that mechanism easy to trigger and hard to resolve.
In this integrated view, PEM is not primarily an exertion-time failure of energy production. It is a recovery-phase failure in which muscle stress collides with unstable perfusion control and persistence-amplifying signals that delay termination and repair.
(Endothelial senescence, immunometabolic resolution brakes, membrane repair fragility, NO/RNS recovery cost)
Several recent hypotheses focus less on how ME/CFS begins and more on why physiological stress fails to terminate cleanly during recovery. These models emphasize persistence, impaired repair, and recovery inhibition rather than acute immune hyperactivation or primary mitochondrial failure. In GLA v2.6, they are interpreted as persistence-layer consequences of upstream regulatory instability (vascular–autonomic timing, membrane signal termination, and clearance bandwidth limits), not as independent disease-initiating mechanisms.
The virus-induced endothelial senescence and clearance failure hypothesis proposed by Nunes et al. frames ME/CFS persistence as the accumulation of long-lived dysfunctional vascular and barrier targets that are not effectively cleared. This model does not require ongoing cytokine storm or overt immune hyperactivation. Instead, it emphasizes impaired resolution: endothelial and barrier cells enter durable “dysfunctional” states, immune surveillance remains permissive/tolerant, and unresolved targets persist as chronic sources of physiological stress.
GLA v2.6 alignment: GLA supports this persistence logic but adds a mechanistic recovery layer: persistence pressure is amplified by clearance-limited circulating signals (e.g., RBC-derived extracellular vesicles and oxidized lipid coronas) that bias toward near-wall residence and sustain endothelial “timing noise” during recovery. Combined with membrane-context instability (SMPDL3B anchoring loss or shedding) and autonomic hypoperfusion, the system can stabilize around a fragile equilibrium where repair is incomplete and termination is unreliable.
The immunometabolic itaconate shunt hypothesis describes a protective, inflammation-linked adaptation that can function as a resolution brake. Acutely, itaconate signaling can limit oxidative damage and excessive immune activation. In ME/CFS, the key risk is not that the shunt exists, but that the “brake” is repeatedly re-engaged or fails to release, suppressing full metabolic recovery after stress.
GLA v2.6 framing: The itaconate shunt is not treated as a primary driver of disease. It becomes maladaptive when upstream recovery stressors (patchy ischemia–reperfusion, endothelial instability, and persistence-amplifying near-wall signals) repeatedly force the system back into a “protective low-throughput” mode, preventing clean termination and restoration of baseline control.
The phosphatidylcholine hypothesis emphasizes membrane repair economics: PEM vulnerability can increase when membrane turnover demand exceeds phosphatidylcholine resupply. This is framed less as primary energy failure and more as repair/termination fragility at the membrane execution surface.
GLA v2.6 integration: This is treated as a membrane-level vulnerability amplifier that shapes crash threshold and recovery duration. Phosphatidylcholine availability reflects the balance between repair demand and routing/timing of lipid resupply (hepatic–lipoprotein dynamics), influencing SMPDL3B anchoring stability, endothelial shear sensing, and RBC deformability. When turnover demand exceeds resupply, the system becomes easier to destabilize and slower to re-stabilize — amplifying PEM without being required as the initiating cause of persistence.
The nitrogen hypothesis proposes dysregulated nitrogen metabolism and nitric oxide / reactive nitrogen species (NO/RNS) signaling, contributing to nitrosative stress, impaired recovery, and abnormal vascular responses. In GLA v2.6, nitrogen stress is treated primarily as a downstream recovery-cost amplifier, emerging from perfusion instability and recovery-phase signaling failure rather than initiating disease persistence.
GLA v2.6 constraint: GLA avoids “NO deficiency” framing and instead emphasizes NO timing and localization noise under conditions of endothelial shear-sensing error, membrane instability, and persistence-amplified near-wall signaling. Nitrogen stress therefore amplifies post-exertional recovery burden and prolongs symptoms, but does not define the initiating lesion.
Related work (OMF Canada): Nitrogen metabolism and testing the nitrogen hypothesis in ME/CFS (Daniel Missailidis; Robert Phair; Paul Gooley; Sarah Annesley; Christopher Armstrong).
Taken together, these persistence-focused models describe why ME/CFS can become self-maintaining over time. The core problem is not simply an inability to generate immune responses or produce energy, but a failure to terminate stress responses, restore membrane signaling fidelity, clear persistent signals/targets, and re-establish stable flow control during recovery. The GLA framework integrates these mechanisms by identifying upstream regulatory instability that repeatedly engages and sustains them, with clearance bandwidth acting as a critical rate-limiter that determines whether recovery resolves cleanly or amplifies into delayed PEM.
Across the major disease concepts proposed for ME/CFS, a consistent division of explanatory roles emerges:
The GLA framework does not replace any of these models. Instead, it identifies the upstream regulatory architecture that governs how these mechanisms are engaged, coordinated, and sustained. By focusing on membrane signaling context (SMPDL3B stability), microvascular flow control, hepatic metabolic and bile-acid routing, clearance bandwidth, and autonomic timing, GLA explains:
GLA is therefore best understood not as a competing hypothesis, but as a systems-level coordination and timing model. It explains when established mechanisms activate, how strongly they amplify, and why they fail to resolve—providing a coherent architecture that links existing ME/CFS disease models through recovery-phase control failure rather than through a single initiating lesion.