This document is structured for publication: it positions the itaconate shunt hypothesis and the Gut–Liver–Autonomic (GLA) framework as non-competing explanatory layers, clarifies integration points and limits, and preserves phenotype- and phase-dependence.
Myalgic encephalomyelitis / chronic fatigue syndrome (ME/CFS) is characterized by exertion intolerance and delayed post-exertional malaise (PEM), yet mechanistic explanations remain fragmented. Immune–metabolic models, including the itaconate shunt hypothesis, and system-level control frameworks such as the Gut–Liver–Autonomic (GLA) model are often presented as competing explanations for PEM, despite operating at different levels of biological organization.
To clarify the relationship between the itaconate shunt hypothesis and the GLA framework, and to determine how immune–metabolic suppression can be integrated within a control-first architecture without collapsing distinct mechanisms or overextending causal claims.
We present a conceptual integration that situates the itaconate shunt as a contained immune–metabolic sub-layer within the broader GLA control architecture. Using phenotype- and phase-aware reasoning, we distinguish mechanisms that define vulnerability from those that shape crash expression, and illustrate how distinct upstream pathways can converge on a shared PEM endpoint.
The itaconate shunt provides a plausible intracellular mechanism for constrained oxidative throughput and delayed metabolic toxicity under sustained immune activation. The GLA framework explains how exertional load is distributed, buffered, and recovered from across vascular, autonomic, hepatic, and membrane regulatory systems. These models address complementary questions: immune–metabolic constraint operates at the level of cellular energy permission, while GLA addresses system-level control and recovery capacity. Distinct metabolic-constraint and control-failure pathways can converge on PEM without implying equivalence of upstream mechanisms. The relevance of immune–metabolic suppression varies by phenotype and disease phase, emerging as a conditional amplifier or lock-in mechanism as baseline recovery capacity erodes.
This work is conceptual and integrative rather than empirical. It does not propose a single unifying cause for ME/CFS, nor does it claim primacy of immune–metabolic suppression across all patients or disease stages. Instead, it emphasizes explanatory scope, phase dependence, and context as essential for interpreting metabolic findings and treatment responses.
Myalgic encephalomyelitis / chronic fatigue syndrome (ME/CFS) is characterized by exertion intolerance, delayed post-exertional malaise (PEM), autonomic instability, and fluctuating metabolic and vascular abnormalities that often evade detection by resting clinical tests. Despite heterogeneous initiating events—including viral infection, immune activation, and physiological stress—patients frequently converge on a shared clinical pattern in which relatively modest exertion precipitates a delayed, multi-system deterioration that may persist for days or longer.
Over the past decade, multiple mechanistic models have been proposed to explain this phenomenon. Some have emphasized immune activation and metabolic dysfunction at the cellular level, while others have focused on vascular, autonomic, hepatic, or neuroendocrine dysregulation at the system level. While these models are sometimes presented as competing explanations, such apparent conflicts often reflect differences in explanatory scope rather than mutually exclusive biological claims.
Recent metabolic models, including the Itaconate Shunt Hypothesis, have provided important insight into immune-linked constraints on cellular energy metabolism in ME/CFS. This hypothesis proposes that a normally transient innate immune program—characterized by IRG1 induction and itaconate production—may become chronically engaged following infection or inflammatory stress. Sustained itaconate signaling can inhibit succinate dehydrogenase (SDH; Complex II), constrain tricarboxylic acid (TCA) cycle throughput, and limit the capacity for oxidative energy ramping during exertion. As a consequence, cells may rely increasingly on amino-acid catabolism, generating delayed nitrogen and redox stress that could plausibly contribute to post-exertional symptom amplification.
In parallel, system-level frameworks such as the Gut–Liver–Autonomic (GLA) model have focused on how exertional stress is regulated, buffered, and recovered from across multiple interacting physiological domains. Rather than centering on energy production alone, GLA emphasizes the distinction between capacity and control: the ability of vascular perfusion, autonomic regulation, hepatic clearance, membrane stability, and related control layers to safely distribute load and restore baseline following stress. Within this framework, endoplasmic reticulum (ER) stress and related regulatory fragility define upstream vulnerability, while mitochondrial dysfunction and energetic failure emerge downstream as expressions of failed control rather than as primary initiating defects.
These approaches are often interpreted as advancing incompatible explanations for PEM—one metabolic, the other systemic. However, such a dichotomy is not required by the underlying biology. The itaconate shunt hypothesis primarily addresses cell-intrinsic metabolic state under immune activation, whereas the GLA framework addresses system-level regulation of load, buffering, and recovery across organs. As such, the two models operate at different levels of biological organization and answer different mechanistic questions.
The purpose of this paper is not to adjudicate primacy between frameworks, nor to propose a single unifying mechanism for all cases of ME/CFS. Instead, we aim to situate the itaconate shunt hypothesis within the broader GLA architecture, clarifying where immune-metabolic suppression may contribute meaningfully to disease expression, where its explanatory power is limited, and how it may interact with upstream control-layer vulnerabilities such as ER stress. By doing so, we seek to show that these models are complementary rather than competing, and that their integration can help explain phenotypic heterogeneity, phase dependence, and the variable response to metabolic interventions observed across patient populations.
In the sections that follow, we first outline the core features and scope of the itaconate shunt hypothesis, then summarize the control-first logic of the GLA framework. Using a series of conceptual diagrams, we illustrate how immune-metabolic constraints can be positioned as a contained sub-layer within a broader system-level architecture, how distinct mechanistic paths can converge on PEM, and how phenotype and disease phase modulate the relevance of metabolic suppression. This integrative framing provides a foundation for interpreting existing data without forcing false equivalence or competition between explanatory models.
The itaconate shunt hypothesis proposes that innate immune activation can induce a distinct metabolic program that constrains cellular energy production. Under inflammatory conditions, activation of the innate immune system leads to induction of immune-responsive gene 1 (IRG1), which catalyzes the production of itaconate from cis-aconitate within the tricarboxylic acid (TCA) cycle. This pathway is well described as a normally transient antimicrobial and immunomodulatory response, particularly in activated macrophages and other immune-influenced cell types.
Itaconate has been shown to inhibit succinate dehydrogenase (SDH; Complex II), thereby limiting flux through the TCA cycle and reducing mitochondrial oxidative throughput. In the context of the hypothesis as applied to ME/CFS, the critical question is not induction, but resolution. Sustained or incompletely terminated innate immune signaling is proposed to maintain IRG1 expression beyond its adaptive window, thereby constraining the capacity for oxidative energy ramping during exertion. As a result, cells may be forced to rely more heavily on amino-acid catabolism and alternative substrates to meet energetic demands.
A key feature of the model is its emphasis on delayed metabolic consequences rather than immediate energetic failure. Increased reliance on amino-acid breakdown can generate nitrogenous byproducts, redox stress, and cofactor imbalance that accumulate after exertion rather than during it, offering a potential intracellular explanation for the delayed timing of post-exertional malaise. In this framing, symptoms such as fatigue, cognitive dysfunction, and prolonged recovery emerge once exertional demand exceeds a reduced oxidative ceiling imposed upstream by immune control failure.
The principal strength of the itaconate shunt hypothesis lies in its ability to explain delayed post-exertional symptom amplification through a defined immune–metabolic mechanism operating at the cellular level. It provides a coherent account of how persistent innate immune signaling can impose ongoing limits on mitochondrial throughput without requiring primary structural mitochondrial damage.
Importantly, the explanatory scope of this hypothesis is intentionally narrow. The itaconate shunt hypothesis is primarily concerned with cell-intrinsic metabolic execution downstream of innate immune activation, rather than with the mechanisms that regulate immune signal termination, systemic load distribution, or recovery capacity. It does not, on its own, explain why antiviral signaling fails to fully shut off, how perfusion and autonomic regulation shape tissue-level demand, or how whole-system recovery is coordinated following exertion.
Recognizing this scope is essential for integrating the itaconate shunt hypothesis within broader system-level frameworks, and for avoiding overextension of a downstream metabolic mechanism into upstream control domains it was not designed to explain.
The Gut–Liver–Autonomic (GLA) framework approaches ME/CFS from a control-first perspective, focusing on how physiological systems regulate, buffer, and recover from exertional load rather than on energy production alone. A central distinction within GLA is that between capacity—the theoretical ability of tissues to generate energy or perform work—and control, defined as the system’s ability to safely distribute load, maintain stability under stress, and restore baseline following exertion.
Within this framework, exertional intolerance and post-exertional malaise arise when buffering capacity is exceeded or unevenly distributed. Key buffering domains include vascular perfusion and endothelial regulation, autonomic control of heart rate and blood pressure, hepatic clearance and metabolic processing, and membrane and signaling stability at the cellular interface. Failure in any of these domains can precipitate disproportionate downstream stress even when intrinsic metabolic machinery remains structurally intact.
GLA places particular emphasis on buffering size and distribution, rather than absolute energetic limits. Regional hypoperfusion, autonomic mismatch, impaired clearance of metabolic byproducts, or fragile membrane signaling can each create localized overload, leading to delayed symptom amplification without requiring a primary defect in mitochondrial capacity.
At the regulatory level, endoplasmic reticulum (ER) stress is treated as an upstream vulnerability within GLA. ER stress reflects reduced regulatory headroom for protein processing, signaling coordination, and cellular adaptation under load. When ER stress is persistent or incompletely resolved, the system becomes increasingly susceptible to destabilization from otherwise tolerable stressors.
In this architecture, mitochondrial dysfunction is understood primarily as a downstream crash expression rather than as an initiating cause. Energetic failure, oxidative stress, and impaired ATP generation emerge as consequences of exceeded control and buffering limits, shaped by upstream regulatory instability and load misallocation.
By centering on system-level regulation rather than intracellular throughput alone, the GLA framework addresses dimensions of ME/CFS pathophysiology that are outside the explanatory scope of cell-intrinsic metabolic models. This control-first framing provides the context in which immune–metabolic mechanisms, including the itaconate shunt, can be interpreted without overextending their causal role.
This section situates the itaconate shunt within the broader Gut–Liver–Autonomic (GLA) framework, clarifying its explanatory scope and preventing misinterpretation as a dominant or standalone mechanism.
Within the GLA architecture, the itaconate shunt is most coherently positioned as a contained immune–metabolic sub-layer that operates downstream of broader control and buffering systems. In this view, itaconate-mediated metabolic suppression does not replace system-level regulation, but may amplify energy limitation when upstream mechanisms fail to fully resolve post-infectious or exertional stress.
GLA emphasizes distributed regulation of load, perfusion, recovery, and buffering across vascular, autonomic, hepatic, and membrane domains. These systems determine how physiological stress is absorbed, routed, and resolved before cellular energy pathways are engaged. The itaconate shunt, by contrast, acts at the level of intracellular metabolic permission, constraining oxidative throughput under immune activation once stress has already reached the cellular compartment.
Figure A1 reflects this relationship visually by embedding the itaconate shunt as a boxed immune–metabolic mechanism within the larger GLA control stack rather than as a central organizing node. Downward-only arrows indicate conditional influence without implying causal primacy or closed feedback dominance. This placement preserves the explanatory strength of the itaconate model while maintaining the control-first logic of the GLA framework.
The itaconate shunt is positioned as an immune-metabolic mechanism operating within the broader GLA control architecture, potentially amplifying energy limitation when upstream buffering and recovery systems fail to resolve post-infectious stress.
This section clarifies why apparent disagreements between metabolic and systems-level models often reflect differences in explanatory scope rather than incompatible biological claims.
Apparent disagreements between metabolic and systems models often arise from differences in the level of biological organization they are designed to explain. The itaconate shunt hypothesis addresses intracellular permission for oxidative throughput under immune activation, focusing on how inflammatory signaling constrains mitochondrial energy production within cells. In contrast, the Gut–Liver–Autonomic (GLA) framework addresses how physiological load, perfusion, buffering, and recovery are regulated and coordinated across organs.
These models therefore answer different biological questions. The itaconate shunt provides a cell-centric explanation for immune-linked metabolic suppression, whereas GLA provides a system-centric explanation for how stress is distributed, absorbed, and resolved before cellular energy limits are reached. Divergent emphases should not be interpreted as competing claims about disease causality, but as complementary perspectives operating at different layers of organization.
Figure B1 makes this distinction explicit by placing the two frameworks side by side without hierarchical ordering. The comparison highlights that conclusions drawn within one explanatory layer do not invalidate those drawn within another. When interpreted within their appropriate scopes, the itaconate shunt and GLA frameworks are not mutually exclusive, but jointly informative.
The itaconate shunt focuses on intracellular metabolic state, whereas GLA addresses system-level regulation of load, recovery, and buffering.
Figure B2. Two distinct mechanistic pathways that converge on post-exertional malaise (PEM).
Distinct mechanistic pathways can converge on similar post-exertional symptom amplification. Figure B2 illustrates two such paths that lead to post-exertional malaise (PEM) while remaining mechanistically distinct upstream.
One path emphasizes metabolic constraint. In this framing, exertional demand encounters a capped oxidative ramp imposed by immune–metabolic suppression, limiting tricarboxylic acid (TCA) cycle throughput and mitochondrial respiratory flexibility. Compensation through increased amino-acid catabolism and alternative substrates may meet short-term energetic needs but generates delayed nitrogen and redox stress, producing symptom amplification after exertion rather than during it.
The second path emphasizes control and buffering failure. Here, exertion exceeds available system-level buffering capacity, leading to perfusion mismatch, regional ischemia, autonomic strain, and impaired clearance of metabolic byproducts. Symptoms emerge when recovery mechanisms fail to restore baseline, resulting in delayed and prolonged deterioration despite the absence of a primary intracellular metabolic block.
Crucially, the convergence of these paths at PEM does not imply equivalence of upstream mechanisms. The metabolic constraint–driven path and the control-failure path answer different mechanistic questions and operate at different levels of biological organization. Their shared endpoint reflects the limited number of ways complex physiological systems can fail under load, rather than a shared initiating defect.
This distinction helps explain why patients with different dominant vulnerabilities—metabolic, vascular, or autonomic—may experience clinically similar PEM while responding differently to interventions that target metabolic throughput or system-level regulation. Figure B2 therefore serves not to collapse models into a single explanation, but to clarify how distinct upstream failures can manifest as a common clinical outcome.
Distinct mechanistic paths can converge on similar post-exertional symptom amplification.
A central point of apparent tension between metabolic and control-oriented models of ME/CFS concerns the relative positioning of immune–metabolic suppression and endoplasmic reticulum (ER) stress. Within the GLA framework, ER stress is treated as an upstream control-layer vulnerability that shapes how safely exertional load can be distributed and recovered from, whereas mitochondrial dysfunction and energetic failure emerge downstream as expressions of failed control. By contrast, the itaconate shunt hypothesis emphasizes immune-linked metabolic constraint and delayed toxicity at the cellular level, raising the question of whether such processes could act upstream of, or feed into, ER stress.
Addressing this question requires careful distinction between initiation, persistence, and reinforcement. The presence of plausible biochemical couplings does not, by itself, justify reassigning primacy within a control architecture. However, several mechanistically reasonable pathways exist by which persistent innate immune signaling — particularly when signal termination is impaired — could reinforce ER stress or prevent its resolution, thereby increasing control-layer vulnerability without displacing ER stress from its upstream role.
Protein folding within the ER is exquisitely sensitive to cellular redox balance. Sustained immune–metabolic constraint associated with an itaconate-engaged state may alter NADPH availability, glutathione cycling, and overall redox tone. Such shifts can impair disulfide bond formation and slow the clearance of misfolded proteins, increasing unfolded protein response (UPR) signaling even in the absence of overt inflammation. In this context, immune–metabolic suppression does not initiate ER stress de novo, but raises the baseline difficulty of restoring ER homeostasis once stress has been engaged.
The itaconate shunt hypothesis places particular emphasis on delayed metabolic toxicity, including increased reliance on amino-acid catabolism and accumulation of nitrogenous and redox-active byproducts. These downstream consequences can impose additional demands on cellular detoxification, pH regulation, and protein processing systems. From a control-layer perspective, such delayed toxicity may act as a post-exertional stressor that prolongs ER strain after the initiating load has ceased, contributing to the delayed timing characteristic of PEM. Importantly, this effect manifests as persistence of ER stress rather than as its primary cause.
Mitochondrial and ER function are tightly coupled through calcium signaling and membrane contact sites. Even when mitochondrial dysfunction arises downstream of control failure, impaired oxidative metabolism and calcium buffering can feed back onto ER calcium stores and stress signaling pathways. An immune–metabolic constraint that limits mitochondrial adaptability may therefore indirectly exacerbate ER stress through disrupted calcium homeostasis, reinforcing vulnerability during recovery phases. This bidirectional coupling is consistent with GLA’s allowance for downstream strain to reinforce upstream fragility without collapsing the distinction between control and execution layers.
Finally, a chronically engaged innate immune program implies sustained demands on protein synthesis, trafficking, and secretion. When innate immune signaling fails to fully terminate — for example, due to impaired de-phosphorylation of key signaling intermediates — baseline ER–Golgi workload may remain elevated even in the absence of acute infection. In this scenario, the itaconate shunt reflects an immune–metabolic execution state enabled by upstream control failure, maintaining ER demand at a higher baseline and narrowing the system’s margin for safe adaptation to additional stressors.
Taken together, these couplings suggest that immune–metabolic programs such as the itaconate shunt may reinforce or prolong ER stress by preventing its resolution, thereby tightening the control-layer bottleneck that determines vulnerability to exertional load. However, they do not establish ER stress as secondary or derivative. Within the GLA framework, ER stress remains the relevant upstream determinant of system stability, while immune–metabolic suppression is best understood as a context-dependent amplifier whose persistence depends on failure of upstream immune control mechanisms.
This distinction is not merely semantic. Preserving the separation between upstream vulnerability and downstream amplification allows immune–metabolic findings to be integrated without overextending their explanatory scope, and without requiring all patients to share a single initiating mechanism. It also provides a coherent basis for understanding why immune–metabolic signatures may be prominent in some phenotypes and disease phases, while appearing secondary or inconsistent in others
Interventions targeting metabolic throughput may be stabilizing or destabilizing depending on underlying control state.
The explanatory relevance of immune–metabolic suppression, including the itaconate shunt, is not uniform across ME/CFS presentations. Within the GLA framework, exertional intolerance and post-exertional malaise arise from different dominant failure modes—referred to here as amplifier phenotypes—each characterized by distinct upstream vulnerabilities and control constraints. In parallel, patients exhibit distinct SMPDL3B regulatory phenotypes, reflecting differences in membrane stability, lipid-raft anchoring, and innate immune responsiveness. Together, these axes shape whether immune–metabolic suppression functions as a primary constraint, a persistence-enabling amplifier, or a late-stage epiphenomenon.
In metabolic-dominant (M1) presentations, limitations in oxidative throughput, substrate utilization, and recovery capacity are prominent early features. In this context, the itaconate shunt hypothesis aligns most closely with observed clinical and biochemical patterns. Sustained immune-linked suppression of TCA cycle throughput provides a plausible mechanism for reduced oxidative ramping, increased reliance on amino-acid catabolism, and delayed redox or nitrogen stress following exertion.
The relevance of immune–metabolic suppression in M1 presentations is further modulated by SMPDL3B phenotype. In SMPDL3B-deficient systems, baseline membrane and signaling fragility reduce tolerance to metabolic constraint; persistent immune–metabolic engagement enabled by impaired signal termination may therefore translate more directly into exertional intolerance and prolonged recovery once control headroom narrows. In contrast, SMPDL3B-shedding systems may tolerate transient metabolic suppression more effectively early in disease, but become vulnerable when repeated innate activation lowers execution thresholds and provokes defensive overshoot, accelerating erosion of baseline control.
Within GLA, immune–metabolic suppression in M1 presentations may meaningfully contribute to vulnerability by increasing the likelihood that exertional load exceeds available recovery capacity. Importantly, even here, this does not require immune–metabolic constraint to be the initiating defect. Rather, it acts as a dominant amplifier once upstream regulatory buffering has narrowed sufficiently to render metabolic ceilings clinically consequential.
In vascular-dominant (M2) presentations, exertional intolerance is driven primarily by failures of perfusion distribution and endothelial control rather than by intrinsic limitations in metabolic machinery. Intermittent regional under-delivery of oxygen and nutrients under load leads to ischemic metabolism, reactive oxygen species generation, and calcium stress signaling, with mitochondrial dysfunction emerging downstream during recovery.
In this phenotype, immune–metabolic suppression is more parsimoniously interpreted as a secondary lock-in mechanismrather than a primary driver. Repeated ischemic and redox stress can impair immune signal termination and promote persistence of innate-linked metabolic programs, including the itaconate shunt, which in turn delay recovery and prolong PEM. However, the initiating instability remains vascular and regulatory in nature.
SMPDL3B phenotype further differentiates how this lock-in manifests. In SMPDL3B-shedding systems, ischemia-associated stress may lower thresholds for PI-PLC–mediated shedding responses, reinforcing immune–metabolic suppression as defensive overshoot rather than deficit. In SMPDL3B-deficient systems, limited membrane reserve and reduced re-anchoring capacity make even modest metabolic suppression destabilizing once perfusion mismatch recurs. Treating immune–metabolic findings as primary in either case risks misattributing consequence to cause.
Autonomic-dominant (M3) presentations are characterized by low effective circulating volume, heart-rate and blood-pressure dysregulation, and rapid symptom escalation with posture or minimal exertion. The temporal dynamics of these symptoms—often immediate and reversible with positional or volume changes—are difficult to reconcile with immune–metabolic programs that operate on slower timescales and depend on persistence rather than instant execution.
Accordingly, immune–metabolic suppression is least explanatory in this phenotype. While repeated autonomic stress may eventually contribute to downstream metabolic or inflammatory changes, such effects are unlikely to account for primary exertional intolerance. In GLA terms, immune–metabolic signatures in M3 presentations are best understood as late or nonspecific modifiers, shaped by cumulative stress rather than defining vulnerability. SMPDL3B phenotype may influence severity or recovery trajectory but does not alter the dominant autonomic failure mode.
Disease phase further modulates the relevance of immune–metabolic suppression across both amplifier and SMPDL3B phenotypes. In early or oscillatory phases, immune–metabolic programs may serve adaptive or stabilizing roles, limiting excessive inflammatory signaling or metabolic overactivation when control remains intact. As baseline recovery capacity erodes through repeated incompletely buffered events, these same programs may become maladaptive, acting as persistence-enabled lock-in amplifiers that prolong recovery and increase symptom duration.
In advanced disease phases, distinctions between amplifier phenotypes and SMPDL3B failure modes may blur as control failure becomes global. Under these conditions, immune–metabolic suppression may appear prominent across patients regardless of original phenotype. This convergence should not be interpreted as evidence of a single initiating mechanism, but rather as a shared downstream state arising from prolonged loss of regulatory headroom.
Recognizing phenotype- and phase-dependent relevance helps reconcile heterogeneous findings in metabolic studies of ME/CFS without invoking inconsistency or contradiction. Immune–metabolic suppression may be central in some patients, contributory in others, and largely incidental in still others—depending on both the dominant amplifier phenotype and the underlying SMPDL3B regulatory state.
Within the GLA framework, this heterogeneity is expected rather than problematic. Positioning the itaconate shunt as a context-dependent execution program whose persistence depends on upstream immune control failure preserves its explanatory value where appropriate, while avoiding overgeneralization across fundamentally different control states.
The contribution of immune-metabolic suppression varies by GLA amplifier phenotype, aligning most strongly with metabolic-dominant (M1) presentations and acting as a secondary lock-in mechanism in vascular-dominant (M2) disease.
In addition to phenotype, disease phase critically shapes how immune–metabolic suppression expresses clinically and how it should be interpreted mechanistically. Within the GLA framework, disease progression is characterized by baseline threshold erosion—a gradual reduction in the system’s capacity to absorb, buffer, and recover from stress. This progression alters the functional role of mechanisms that may be adaptive or neutral early in illness but become maladaptive as control capacity diminishes.
In early or oscillatory disease phases, immune–metabolic programs such as the itaconate shunt may serve partially protective or stabilizing roles. By constraining excessive oxidative throughput during immune activation, these programs may limit acute inflammatory damage, oxidative stress, or metabolic overshoot. At this stage, exertional intolerance is often episodic, recovery between episodes is substantial, and control-layer systems—though stressed—retain sufficient headroom to restore baseline.
Within this context, immune–metabolic suppression should not be assumed to represent pathology per se. Rather, it may reflect a regulated response to unresolved immune or inflammatory signals that becomes clinically relevant only under higher loads or repeated stressors.
As illness progresses and baseline recovery becomes incomplete, immune–metabolic programs may begin to shift from adaptive modulation to conditional amplification. Repeated exertional events that exceed available buffering capacity—whether driven by metabolic, vascular, or autonomic instability—can prevent full resolution of ER stress, redox imbalance, and immune priming.
In this intermediate phase, the itaconate shunt may contribute to delayed recovery dynamics, increasing the duration or severity of PEM without serving as the primary initiating defect. Its relevance becomes increasingly context-dependent, shaped by the interaction between immune signaling, residual control capacity, and the cumulative burden of prior stress.
In advanced or severe disease phases, control-layer failure may become pervasive. Recovery windows narrow markedly, baseline vulnerability rises, and the system operates close to its stability limits even at rest. Under these conditions, immune–metabolic suppression may appear persistent and pronounced across patients, regardless of original phenotype.
Importantly, this convergence should not be interpreted as evidence that immune–metabolic suppression is the root cause of disease. Rather, it reflects a lock-in state in which downstream programs that were once transient or conditional become chronically engaged because the system can no longer reset. In this phase, immune–metabolic signatures lose mechanistic specificity: they signal severity and loss of control, but provide limited insight into the original failure mode.
Phase dependence complicates attempts to infer causality from cross-sectional metabolic measurements. Findings obtained in later disease stages may accurately describe the current physiological state while misrepresenting the pathway by which that state arose. Without phase-resolved interpretation, immune–metabolic suppression may be mistaken for a universal initiating mechanism rather than recognized as a downstream consequence of prolonged control failure.
The GLA framework accommodates this complexity by distinguishing between mechanisms that define vulnerability and those that define crash expression. Immune–metabolic programs such as the itaconate shunt may contribute meaningfully to the latter, particularly as disease advances, without displacing upstream control-layer dysfunction as the determinant of susceptibility.
Taken together, phase dependence provides a coherent explanation for why immune–metabolic suppression may be subtle, conditional, or absent early in disease, yet prominent and persistent in severe cases. Integrating the itaconate shunt hypothesis within a phase-aware control architecture preserves its relevance while preventing overgeneralization. It also underscores the importance of longitudinal, phenotype- and phase-stratified approaches when interpreting metabolic findings in ME/CFS.
Immune-metabolic suppression may emerge as a secondary stabilizing response early in disease but becomes most impactful as a lock-in amplifier once baseline recovery capacity erodes.
The integration of the itaconate shunt hypothesis within the GLA framework highlights an important principle for ME/CFS research: apparent mechanistic disagreement often reflects differences in explanatory layer rather than true biological incompatibility. Immune–metabolic models and system-level control models are frequently framed as competing explanations for post-exertional malaise (PEM), yet the analyses presented here demonstrate that they address distinct, complementary aspects of disease expression.
Metabolic studies in ME/CFS have reported heterogeneous and sometimes inconsistent findings, particularly with respect to mitochondrial function, substrate utilization, and immune-linked metabolic signatures. These discrepancies are often interpreted as methodological limitations or cohort differences. The present framework offers an alternative explanation: the relevance of immune–metabolic suppression varies by phenotype and disease phase, and similar biochemical states may arise through different upstream pathways.
When immune–metabolic suppression is treated as universally causal, downstream or phase-dependent signals risk being misclassified as primary defects. Conversely, when system-level control failure is emphasized without regard to intracellular metabolic state, important contributors to delayed recovery and symptom persistence may be overlooked. Integrating these perspectives allows both sets of findings to be interpreted without forcing false equivalence.
One of the most clinically consequential implications of this integration concerns treatment sequencing and risk, illustrated in Figure B3. Interventions designed to increase metabolic throughput or suppress immune signaling may have diametrically opposite effects depending on the underlying control state.
In patients with preserved or partially restored system-level control, metabolic modulation may improve tolerance and recovery. In patients with fragile or collapsed control layers, the same interventions may amplify instability by increasing demand without restoring buffering capacity. This distinction helps explain why metabolic interventions appear beneficial in some cohorts yet destabilizing in others, and why adverse responses are often reported in more severe or advanced disease.
Importantly, this framing does not imply that immune–metabolic approaches are misguided. Rather, it underscores the necessity of control-first or phenotype-safe sequencing, particularly in patients with vascular-dominant, autonomic-dominant, or advanced disease states. Without such sequencing, treatment responses may be misinterpreted as evidence for or against a mechanism when they instead reflect mismatched timing or context.
The integration presented here has direct implications for trial design and biomarker interpretation. Trials that enroll heterogeneous ME/CFS populations without stratification by phenotype or disease phase risk conflating primary mechanisms with secondary or downstream states. Similarly, cross-sectional metabolic measurements obtained in later disease stages may accurately reflect severity while providing limited insight into causation.
Such approaches may help reconcile divergent findings without requiring abandonment of existing models.
A central aim of this work is to preserve explanatory restraint. The itaconate shunt hypothesis offers a compelling account of immune-linked metabolic constraint and delayed toxicity, particularly in metabolically dominant or advanced disease states. The GLA framework offers a broader account of how exertional load is distributed, buffered, and recovered from across organ systems. Neither framework alone is sufficient to explain the full heterogeneity of ME/CFS, and neither needs to subsume the other.
By situating immune–metabolic suppression as a context-dependent amplifier within a control-oriented architecture, it becomes possible to recognize its contributions without overextending its scope. This positioning avoids reducing ME/CFS to a single blocked pathway while still acknowledging the real and measurable metabolic constraints experienced by many patients.
Taken together, the integration of the itaconate shunt hypothesis within the GLA framework provides a coherent way to interpret immune–metabolic findings alongside system-level control failure. It explains why similar metabolic signatures may emerge from different upstream vulnerabilities, why disease severity and phase matter for mechanistic inference, and why treatment responses vary so widely across patients.
Most importantly, this framing encourages collaboration rather than competition between research traditions. By clarifying scope, preserving causal hierarchy, and emphasizing context, it offers a foundation for more precise, safer, and more interpretable approaches to both research and care in ME/CFS.
The itaconate shunt hypothesis and the GLA framework address different but intersecting dimensions of ME/CFS pathophysiology. Immune–metabolic suppression provides a plausible account of constrained oxidative throughput and delayed recovery in a subset of patients, while the GLA framework situates these metabolic states within a broader architecture of system-level control, buffering, and recovery. Framed in this way, the two models are not competing explanations, but complementary perspectives operating at different levels of biological organization.
Positioning the itaconate shunt as a phenotype- and phase-dependent amplifier within the GLA architecture preserves its explanatory value where relevant, without extending its scope beyond the contexts in which it is most informative. This integration helps reconcile heterogeneous metabolic findings, clarifies why similar biochemical signatures may arise from distinct upstream failures, and underscores the importance of control-aware interpretation when translating mechanisms into treatment strategies.
More broadly, this work highlights the need for integrative, systems-aware approaches in ME/CFS research—approaches that respect explanatory boundaries, accommodate heterogeneity, and prioritize context over singular causation. Such framing is essential for advancing both mechanistic understanding and safe, interpretable clinical application.
The following documents provide the systems-level context used to interpret the itaconate shunt in this analysis. They clarify scope, layering, and disease-stage effects, and help prevent overextension of intracellular metabolic findings into system-level or phase-invariant claims.