How ME/CFS begins, stabilizes, and becomes hard to escape
Author: Michael Daniels · Framework: GLA v2.5 · Date: January 16th 2026 · This document presents a systems-level interpretation and is not clinical guidance or a treatment recommendation.
This module defines where ME/CFS begins in the GLA v2.5 hierarchy, how early vulnerability is established, and how that vulnerability becomes stabilized into a persistent disease state. It explains initiation, convergence, and lock-in — not the detailed mechanics of post-exertional malaise (PEM) itself.
This module does not attempt to catalog symptoms, prescribe interventions, or re-explain downstream PEM mechanics. Its goal is to prevent causal inversion: ME/CFS is not initiated at the point of symptom expression.
This section provides a compressed recap of the GLA v2.5 control layers to orient the reader before discussing initiation pathways and lock-in mechanisms. No new claims are introduced here. The intent is to clarify where disease initiation lives and where post-exertional malaise (PEM) is later expressed, so that causality is not reversed or conflated.
(Susceptibility, not symptoms)
Layer 0 consists of polygenic modifiers that shape baseline regulatory headroom across immune, metabolic, vascular, and recovery systems. These variants influence signal gain, buffering capacity, membrane maintenance, and recovery bandwidth, but do not produce symptoms on their own.
Critically, Layer 0 determines:
Key constraint: Layer 0 explains susceptibility and failure mode, not disease expression.
(Duration failure, not inflammatory excess)
Layer 1 governs how immune and stress signals end. In healthy physiology, innate activation is time-limited and followed by orderly termination through phosphatase braking, ER recovery, and transcriptional exit.
In ME/CFS, immune activation may be modest, but termination is incomplete. Signals persist longer than intended, producing a state of prolonged priming and low-grade ER coupling without overt inflammation or cytokine excess.
Key clarifications:
GLA v2.5 clarification: impaired immune termination (Layer 1) and constrained recovery bandwidth (Layer 3) represent parallel upstream initiation sites that bias distinct failure modes.
(Constraint failure, not acute injury)
Layer 3 governs the system’s capacity to recover after stress. It coordinates endoplasmic- reticulum support, redox restoration, substrate routing, and cellular maintenance needed to return signaling platforms to baseline.
In healthy physiology, Layer 3 ensures that each stressor is followed by sufficient recovery depth. In ME/CFS, recovery bandwidth may be chronically constrained. Stress is tolerated in the moment, but recovery is incomplete, leaving a small residue after each episode.
Key clarifications:
Placement: Alongside Layer 1, this layer defines the upstream control space where disease initiation can occur.
When instability in Layer 1 and/or Layer 3 persists, downstream execution surfaces become increasingly fragile. Signals overlap instead of resolving, recovery windows shorten, and normal physiological stressors begin to carry disproportionate impact.
At this stage:
Boundary definition: This transition marks the boundary between upstream control failure and downstream execution vulnerability.
The execution layers translate upstream instability into physical consequences only when the system is stressed.
Layer 2 governs the structural and temporal reliability of signaling platforms, including lipid rafts and mechanosensitive complexes. SMPDL3B plays a central role in anchoring and timing control. Instability here increases signal gain and noise but does not cause symptoms on its own. This is where failure modes diverge (shedding vs deficient).
Layer 3 determines how substrates and redox resources are routed during demand and recovery. Constraints at this layer reduce flexibility and increase the cost of recovery, shaping how much stress can be absorbed before injury risk rises.
Layer 4 governs endothelial signal timing, nitric-oxide spatial precision, microvascular flow topology, and buffering. When destabilized, normal shear stress is misinterpreted, producing heterogeneous perfusion and oxygen-extraction mismatch. This is where shear becomes pathogenic.
Layer 5 determines whether tissues can resolve calcium flux, restore redox balance, and reset mitochondrial and ER function. When constrained, injury is encoded during recovery, explaining delayed PEM and cumulative baseline erosion.
Summary constraint: Together, Layers 4–5 explain where and when PEM is expressed, not where disease begins.
Figure 1. This schematic situates ME/CFS within the GLA v2.5 control hierarchy. Disease initiation occurs upstream, primarily through impaired immune signal termination (Layer 1) and constrained recovery bandwidth (Layer 3). Downstream execution layers (Layers 2–5) do not initiate disease but express vulnerability once stress is applied. Post-exertional malaise (PEM) is generated at the execution level—predominantly within endothelial timing (Layer 4) and recovery processes (Layer 5)—after upstream control failure has already occurred.
The shared pathway underlying diverse onsets
ME/CFS does not begin with post-exertional malaise itself. It begins when the body fails to fully reset after a real stressor, leaving core control systems in a fragile, unresolved state. This shared sequence — the common trunk — is what allows many different entry routes to converge into the same illness.
The starting point is always a legitimate physiological challenge, such as:
Nothing in this model requires the trigger to be unusual or extreme. What matters is what happens afterward. In healthy systems, this kind of stress is followed by resolution, recovery, and reset. In ME/CFS, that reset does not fully occur.
This is the decisive moment in ME/CFS initiation. After the stressor has passed, two upstream control processes fail to return to baseline:
Crucially, this is not ongoing inflammation and not tissue damage yet. It is a control failure — signals that should end do not fully end. This creates vulnerability without obvious symptoms or abnormal labs.
When immune signals linger and recovery bandwidth narrows, downstream execution surfaces gradually lose precision. This conditioning happens quietly across multiple layers:
At this stage, nothing dramatic may be felt yet. But the system has lost its margin for error.
Once this conditioning is established, the body enters a new state:
This is why early ME/CFS can feel confusing:
This section establishes that:
This sets the stage for understanding why different entry routes exist, and why they all converge on the same downstream failure pattern.
Figure 2. Distinct initiating stressors—such as infection, exertion during incomplete recovery, or autonomic shock—converge on a shared upstream failure sequence. The critical transition is failure to reset: immune signals persist (Layer 1) and recovery bandwidth narrows (Layer 3). This conditions downstream execution surfaces (Layers 2–5) toward fragility, creating a “stress-test positive” state in which post-exertional malaise becomes possible but not inevitable. Initiation establishes vulnerability; PEM requires later activation.
Where heterogeneity lives — without fragmenting the disease
ME/CFS presents with diverse onsets, but these differences reflect distinct entry routes into the same upstream failure sequence, not separate diseases. The routes below describe where stress first lands, not where illness ultimately resides. Each route converges back into the common trunk described in Section 2, and none can bypass the requirement for impaired immune termination and recovery capacity.
Early execution-surface destabilization
In some individuals, the earliest vulnerability appears at the endothelial execution interface. Infection or inflammatory stress can disrupt glycocalyx and heparan sulfate integrity, impairing mechanosensing and nitric-oxide spatial timing.
This route can produce early shear sensitivity and exertional intolerance, but on its own it does not explain persistence. For transient endothelial injury to become chronic ME/CFS, the upstream trunk must fail: immune signals must linger (Layer 1) and recovery bandwidth must narrow (Layer 3). Without that failure to reset, endothelial surfaces can recover.
Immune termination failure → membrane destabilization
In this route, initiation begins upstream with poor immune signal termination. After a trigger, innate activation does not fully shut down, increasing signal duration and priming overlap.
This creates a high-gain, overshoot-prone system in which endothelial timing becomes fragile and shear stress more readily converts into injury during recovery. PEM thresholds drop quickly, and baseline control can erode rapidly. Severity here reflects poor damping, not excessive inflammation.
Maintenance erosion and slow baseline collapse
In other cases, initiation reflects a gradual erosion of recovery capacity rather than acute cleavage events. Repeated stress with incomplete recovery places sustained load on ER function and redox maintenance.
This route produces low-maintenance, predictable fragility rather than dramatic overshoot. PEM may develop more slowly, but recovery remains incomplete and baseline gradually shifts downward. Progression is often steadier and less episodic than in shedding-dominant dynamics.
Figure 3. ME/CFS onset may enter through multiple pathways, reflecting where stress first lands within the system rather than distinct diseases. Early endothelial surface disruption (Layer 4), SMPDL3B shedding driven by immune termination failure (Layers 1→2), or gradual SMPDL3B deficiency due to recovery erosion (Layers 3→2) represent different entry routes. All routes rejoin the same upstream trunk and require impaired termination and recovery to persist. No route bypasses the failure-to-reset transition.
Explaining real-world diversity without fragmenting disease
In clinical reality, ME/CFS onset is often described in ways that do not fit neatly into a single initiating event. This section accounts for that diversity without multiplying disease mechanisms. The stressors below are convergent contributors: they describe where load first lands in the GLA hierarchy, not independent causes. Each feeds into the same common trunk (Section 2) and requires failure of immune termination (Layer 1) and/or recovery bandwidth (Layer 3) to persist.
First stressed: Layer 3 — Recovery bandwidth (ER/mitochondrial reset)
Sustained or repeated exertion without adequate recovery compresses recovery windows. Folding, trafficking, redox reset, and clearance fall behind demand, gradually narrowing recovery bandwidth. Over time, this load predisposes to incomplete immune termination (Layer 1) and membrane fragility (Layer 2), lowering the threshold at which normal stress later activates PEM.
First stressed: Layer 4 — Distribution, timing & buffering
Severe or prolonged autonomic stress (e.g., illness, heat, dehydration, trauma) increases vascular gain and timing noise. Baseline shear variability rises, making endothelial interpretation of normal forces less reliable. Recovery-phase calcium/ROS stress accumulates (Layer 5), and upstream termination and recovery controls erode secondarily (Layers 1–3).
First stressed: Layer 4 — Distribution, timing & buffering
Impaired volume regulation increases heterogeneity of microvascular flow and reduces perfusion stability. This does not initiate disease by itself, but it lowers the activation threshold for PEM by amplifying shear variability. Once recovery becomes error-prone (Layer 5), upstream fragility consolidates.
First stressed: Layer 1 — Immune control & signal termination (gain bias only)
Sex hormones and life-stage transitions modulate immune and vascular gain, influencing signal visibility and damping. These factors bias failure mode (e.g., overshoot-prone vs fragility-prone) without determining phenotype or severity. They expose pre-existing vulnerabilities rather than create pathology.
First stressed: Layer 1 — Immune control & signal termination
Multiple modest immune activations can accumulate signal-duration load even in the absence of overt inflammation. Overlapping priming windows prolong activation, couple to ER stress (Layer 3), and gradually destabilize membrane timing (Layer 2), setting the stage for shear-activated injury downstream.
What turns episodes into persistence
Once the common trunk is established and execution surfaces are conditioned, a separate mechanism is required to explain why ME/CFS stabilizes instead of resolving. In GLA v2.5, that mechanism is bile acid signalling acting through circadian timing. This layer does not initiate disease and does not generate symptoms directly. Its role is to govern whether the system is allowed to exit activation and enter recovery.
Within the GLA framework, bile acids function as low-noise, system-wide regulatory signals originating from the liver and recirculating through the enterohepatic loop.
This distinction matters because it explains how persistence can occur with normal labs and without ongoing inflammation.
When upstream control layers (Layers 1–3) are compromised, otherwise normal bile-acid signaling becomes maladaptive. The bias shifts in three interlocking ways:
In short, BA-GLA stabilizes the failure state by continuously instructing the system to remain tolerant, responsive, and alert—without ever fully standing down.
A defining feature of BA-GLA signaling is that it is circadian-gated. In healthy physiology, bile-acid signals are state markers: they rise during feeding and daytime activity, then fall quiet during fasting and sleep. This quiet period is not passive. It is the body’s permission to shut systems down and repair.
Key principles
In ME/CFS, the circadian gate does not close properly. Autonomic dysfunction keeps the body in a daytime, alert, responsive state even when it should be transitioning into rest and repair. Sympathetic tone remains elevated, parasympathetic dominance is delayed or incomplete, and the nervous system continues to signal readiness rather than shutdown.
As a result:
Importantly, this is not because bile-acid signaling is excessive, and not because of eating behavior. It is because the autonomic system fails to signal that it is safe to stand down, so bile-acid–mediated regulatory cues arrive at the wrong time.
Because the circadian gate never fully closes, the system cannot enter true recovery. Exertion itself creates ordinary physiological stress. In healthy systems, that stress is resolved during circadian shutdown. In ME/CFS, shutdown does not occur. Recovery programs fail to engage, and cellular stress is encoded rather than repaired.
Figure 4. Bile-acid signaling acts as a low-noise, circadian-gated regulator that determines whether the system may enter recovery. In healthy physiology, bile-acid activity pulses during feeding and falls silent during fasting and sleep, permitting shutdown and repair. In ME/CFS, autonomic dysfunction disrupts this gating: regulatory signals persist into periods that should be silent. The result is a failure to enter true recovery. BA-GLA signaling does not initiate disease but stabilizes persistence once upstream control layers are compromised.
How vulnerability becomes self-reinforcing
Once the lock-in mechanisms described above are established, ME/CFS does not remain a static condition. The system begins to accumulate structural vulnerability, making future episodes easier to trigger and harder to recover from. Each episode of post-exertional malaise does more than cause transient symptoms — it alters the physical and functional baseline from which recovery must occur.
When recovery entry repeatedly fails, physiological stress is resolved incompletely. Calcium handling, redox balance, and mitochondrial–ER coordination do not fully reset before the next demand is imposed. Over time, this leads to:
Constraint: Layer 5, which governs recovery depth and reset capacity, becomes the dominant bottleneck. The system can still respond to stress, but it cannot reliably return to baseline afterward.
Crucially, repeated PEM does not leave tissues unchanged. Across episodes, there is incremental structural and functional damage to key execution interfaces:
These changes do not need to be catastrophic to matter. Even subtle degradation reduces tolerance to normal shear stress and oxygen-delivery demands. As a result, the same level of exertion now produces greater perfusion mismatch and recovery stress than before.
Critical transition: PEM begins to reshape the terrain on which future PEM occurs.
As endothelial timing and microvascular distribution degrade, skeletal muscle increasingly becomes the primary site where failure is expressed. Muscle is uniquely vulnerable because it combines:
When these systems are compromised, muscle becomes the tissue where exertion most reliably converts into delayed injury. Over time, PEM shifts from a conditional risk to a predictable outcome of ordinary activity.
Within stressed muscle and vascular beds, repeated post-exertional episodes reinforce a self-feeding loop:
Key implication: Each cycle leaves the system slightly less able to recover. Importantly, this loop lowers the activation threshold, not just the recovery speed — less stress is required to provoke the next episode.
The combined effect is a gradual downward shift in baseline tolerance:
This is not simply disease progression in the traditional sense. It is baseline erosion driven by repeated recovery failure, where structural vulnerability accumulates faster than it can be repaired.
At this stage, the explanatory focus shifts from why ME/CFS persists to how PEM is generated once persistence exists. The detailed mechanisms by which:
are addressed in the following modules:
ME/CFS begins when the body fails to fully reset after a real stressor (such as infection, exertion during incomplete recovery, or autonomic shock). The decisive transition is upstream: immune signals do not terminate cleanly (Layer 1) and recovery bandwidth narrows (Layer 3). This prolonged, low-grade activation quietly conditions downstream execution surfaces—membrane timing (Layer 2), endothelial shear interpretation (Layer 4), and recovery reliability (Layer 5)—without requiring overt inflammation or abnormal baseline labs. Initiation therefore creates vulnerability, not symptoms. Only after this vulnerability is established does normal physiology become capable of triggering post-exertional malaise (PEM).
Persistence arises when BA-GLA signaling and circadian gating prevent clean entry into recovery. Bile acids act as low-noise, state-setting regulators; when their timing is misaligned—often reinforced by autonomic dysfunction—the system remains in a “daytime/alert” regulatory mode when it should be silent. This blocks the permission to shut down and repair, so recovery programs fail to engage. Repeated PEM then encodes injury during recovery (Layer 5), progressively damaging endothelial glycocalyx, microcirculatory flow topology, and skeletal muscle. Each episode lowers future tolerance by tightening Ca²⁺/ROS loops and narrowing recovery bandwidth, shifting the baseline downward and making PEM easier to trigger. BA-GLA does not start ME/CFS; it stabilizes the failure state once control layers are compromised.
The documents listed below define the conceptual and methodological framework used to interpret genetic signals and physiological mechanisms in this paper. Collectively, they establish layer boundaries, phenotype discipline, and phase dependence within the Gut–Liver–Autonomic (GLA) system architecture.
These materials are provided for transparency and interpretive context only. They are not cited as evidentiary sources and should be read as evolving systems-biology models used to organize and constrain interpretation, rather than as claims of mechanism or causation.
Core GLA framework documents
SMPDL3B phenotype frameworks
Control layers & system modulators