Patient-led, research-grounded framework — exploratory tools

GLA Axis Questionnaires for ME/CFS & Long COVID

Patient-led questionnaires and explainers for ME/CFS and Long COVID, built around the Gut–Liver–Autonomic (GLA) framework and SMPDL3B-linked vascular fragility. The goal is to help patients, clinicians, and researchers explore why post-exertional malaise (PEM), exertion intolerance, and multi-system symptoms can become amplified and unstable.

These questionnaires do not diagnose ME/CFS or Long COVID. They translate published research and biomarker signals into a testable, falsifiable model that can be refined — or disproven — over time.

About the author & project background
Update — Jan 25, 2026
GLA v2.6 Patient & Clinician Guide — recovery failure framing, PEM timeline, muscle execution surface, calcium reset, immune surveillance, SMPDL3B termination, persistence amplifiers, and systems-level synthesis to explain delayed PEM and recovery-phase instability in ME/CFS.

About the author — background and framework development context updated for clarity.
Update — Jan 23, 2026
Cell Danger Response × GLA v2.6 — new framework-positioning paper added, clarifying the Cell Danger Response as a downstream execution state and defining control-layer and clearance-limited failure mechanisms that explain delayed PEM and recovery-phase collapse in ME/CFS.

Welcome

ME is a complex condition, but it becomes clearer when explained through the Gut–Liver–Autonomic (GLA) framework — a systems-biology approach that links circulation, metabolism, immunity, and autonomic regulation into a single, integrated picture.

The GLA model is not a competing theory of ME/CFS or Long COVID. Instead, it helps explain why mechanisms described in other models — such as neuroimmune activation, energy failure, microclots, autonomic dysfunction, or muscle ion imbalance — are so easily triggered, how strongly symptoms amplify, and why recovery can be slow or unstable.

Start by completing the full questionnaire and saving your results. You can then explore the Understanding My Subtype section to see how your pattern is interpreted within the GLA context. For readers who want deeper biological detail, the Disease Concept section below explains the GLA hypothesis and how it integrates current research into a testable model.

What is Myalgic Encephalomyelitis (brief overview)

Myalgic encephalomyelitis (ME/CFS) is a biological illness in which the body cannot safely increase blood flow, energy production, and autonomic stability in response to stress, leading to post-exertional malaise, delayed recovery, and multi-system symptoms.

GLA v2.6 — Updated systems-level explanation (optional deeper view)

In ME/CFS, an initial infection or physiological stressor in a biologically vulnerable individual perturbs particle coronas (RBC-derived extracellular vesicles and oxidized lipids) and endothelial surface signaling in the setting of limited clearance bandwidth. These corona-encoded signals persist beyond pathogen resolution and bias circulating particles toward near-wall residence, corrupting endothelial timing and organ-level coordination without requiring inflammation or structural damage.

Because near-wall signaling fails to terminate cleanly during recovery, exertion repeatedly exposes this latent control defect as post-exertional malaise (PEM). Each PEM episode further erodes recovery reliability by prolonging unresolved endothelial timing noise, increasing clearance demand, and progressively lowering baseline recovery headroom.

As this state persists, endothelial Ca²⁺ dysregulation sustains low-grade immune signaling and drives divergence into SMPDL3B failure modes according to control state: in high-gain systems, PI-PLC–mediated cleavage produces oscillatory SMPDL3B shedding, while in rebuild-limited systems, chronic ER–Golgi stress progressively restricts membrane reconstruction, leading to anchoring deficiency. In both cases, loss of membrane-anchored SMPDL3B further impairs signal termination, amplifies mistimed signaling, and accelerates illness severity.

Thus, ME/CFS progression reflects a self-reinforcing failure of recovery termination in a clearance-limited system, with phenotype expression determined by the balance between signaling gain and membrane rebuild capacity, rather than by ongoing infection, immune hyperactivation, or primary tissue damage.

Recovery implication: Within this framework, recovery depends on protecting recovery-phase stability rather than increasing exertional capacity. Avoiding post-exertional malaise, reducing repeated recovery failures, and minimizing physiological stressors that increase clearance demand are expected to preserve remaining recovery headroom and improve the likelihood of stabilization or gradual improvement over time.

What is ME? (Patient Guide) What is ME? (Research Overview)

Choose your questionnaire

You can start with the broader 30+ question pattern questionnaire or the shorter SMPDL3B-focused quiz. You can always come back later and do the other one.

Option 1 – Full Pattern Questionnaire (30+ questions)

A broader questionnaire that looks at multiple dimensions of your illness pattern, including:

  • Baseline vs deep-crash PEM pattern
  • Vascular and autonomic features (POTS/OI, brain fog, dizziness)
  • Metabolic load, recovery, and “energy envelope” behaviour
  • GI / liver / bile-acid–type symptoms
  • How your overall pattern fits the GLA amplifier model

Recommended if you have the energy to answer more questions and want a more complete pattern overview.

Start Full Pattern Questionnaire V2.4

Option 2 – SMPDL3B-Focused Questionnaire

A shorter quiz that concentrates on SMPDL3B-linked vascular and inflammatory features, including:

  • Signs of endothelial fragility and microcirculatory issues
  • Volume / kidney-type symptoms (low blood volume, salt/fluid responses)
  • Inflammatory/reactive features that line up with SMPDL3B biology

Recommended if you are mainly interested in how SMPDL3B-linked vascular instability might fit your presentation, or if you’re too fatigued for the longer questionnaire.

Start SMPDL3B Questionnaire V2.4

If you’re unsure where to start, begin with the Full Pattern Questionnaire and come back to the SMPDL3B-focused quiz later.

Understanding Your Subtype

Understanding My Subtype – Patient Understanding My Subtype – Researcher SMPDL3B Phenotype Hub

These pages expand on how your subtype is interpreted using the GLA model, with separate paths for patients and clinicians.

What is the GLA Concept?

The sections below are written for readers who want deeper biological context. You can safely skip or skim detailed sections without missing the main ideas.

The Gut–Liver–Autonomic (GLA) framework is an upstream systems-biology model designed to explain why people with ME/CFS and Long COVID are so vulnerable to stress — and why recovery from exertion can become delayed, amplified, or unstable.

The GLA model did not begin as a competing theory of post-exertional malaise (PEM). It emerged from attempts to understand the physiological constraints that make PEM possible across many different biological pathways.

Early work by Wirth & Scheibenbogen was foundational in showing that post-exertional malaise reflects a failure of adequate blood flow, ion handling, and autonomic compensation during exertion. Building on this insight, the GLA framework explores the upstream conditions that make vascular instability and impaired perfusion persist — and why relatively small stressors can trigger multi-system destabilization simultaneously. Rather than proposing a single broken pathway, GLA proposes that PEM is not driven by a single broken mechanism, but by a loss of buffering capacity across interconnected regulatory systems. When metabolic stress, endothelial instability, membrane vulnerability, and autonomic regulation converge, the body loses its ability to adapt safely to load — making crashes more likely, more prolonged, and more system-wide.

How the GLA framework is structured

The model integrates three interacting biological domains.

1. SMPDL3B → Membrane Fragility → Endothelial Instability

SMPDL3B is positioned as a key context-setting biomarker linking inflammation, ceramide metabolism, and membrane stability. When SMPDL3B function is reduced or dysregulated, endothelial cells and microvasculature become more reactive and fragile.

This increases susceptibility to:

  • microvascular collapse
  • impaired oxygen delivery
  • exaggerated inflammatory and stress responses

In this way, SMPDL3B biology helps explain why the endothelial sensitivity described by Wirth & Scheibenbogen can become persistent rather than transient.

2. Liver & Bile-Acid Signalling as “Load Controllers”

The liver and bile-acid system act as metabolic load regulators, shaping how well the body tolerates stress, food intake, inflammation, and exertion. Bile acids, FGF-21 signalling, and hepatic metabolic strain function as upstream amplifiers, not root causes.

When this axis becomes overloaded:

  • Ang-2/Tie2 signalling becomes easier to destabilize
  • blood-flow regulation weakens
  • autonomic compensation becomes less reliable

This creates the metabolic context that makes vascular and autonomic models of ME/CFS more fragile and more easily triggered.

3. Autonomic Nervous System (ANS) Vulnerability

Wirth & Scheibenbogen describe autonomic failure as central to PEM expression. The GLA framework agrees — but adds that ANS dysregulation is best understood as the final common pathway.

In GLA, autonomic instability emerges after upstream:

  • metabolic strain
  • endothelial fragility
  • membrane instability
  • hepatic signalling stress

have narrowed the system’s capacity to maintain equilibrium. This explains why autonomic symptoms can:

  • fluctuate over time
  • worsen after exertion, illness, or dietary stress
  • improve when upstream load is reduced

rather than behaving as a fixed primary defect.

The mechanistic chain (step-by-step biology)

This model proposes the following cascade:

  1. Viral or inflammatory trigger activates innate immune receptors (e.g. TLR4).
  2. PKC → PI-PLC signalling is upregulated.
  3. SMPDL3B is cleaved from the cell membrane, reducing membrane stability.
  4. Endothelial flow control becomes fragile (barrier leak + heterogeneous microconstriction) with NO signaling that is mis-timed/mislocalized and often functionally unavailable under shear.).
  5. Perfusion drops and tissues shift toward ischemic metabolism.
  6. Calcium overload and ROS bursts occur in stressed cells and mitochondria.
  7. ROS further increases PI-PLC and SMPDL3B loss, deepening the loop.
  8. Kidney volume regulation becomes unstable, worsening low blood volume and hypoperfusion.
  9. Hepatic strain and FGF21 elevation signal ongoing metabolic stress in the liver.
  10. Autonomic dysfunction (POTS/OI, sympathetic bias) further reduces stable perfusion.

These interlocking loops may help explain why symptoms can become chronic, and why exertion can trigger delayed post-exertional crashes.

Framework documents

Core architecture and definitions that anchor the GLA model.

Disease Concept — GLA v2.1 GLA v2.3 update / addition DecodeME × GLA v2.4 — Genetic Synthesis GLA v2.6 — Patient & Clinician Guide to ME/CFS and PEM

Papers

Longer, paper-format documents (reader narrative + figures).

Itaconate Shunt Hypothesis x GLA (v2.4) HS Genetics & Shear Signaling (GLA v2.5) Shear-Activated PEM — GLA Paper I v2.5 Skeletal Muscle as the Primary Generator of (PEM) v2.5
Cell Danger Response × GLA v2.6

Modules (v2.1 → v2.6)

Modular “building blocks” used across the site. Organized by version and topic.

Shear Stress — A PEM Activator (GLA v2.4) ER–Mitochondrial Calcium Routing (GLA v2.5) PEM Generation — GLA v2.5 Initiation & Lock-In — GLA v2.5 PEM at a Glance — BioMapAI (GLA v2.5) Recovery-Phase Persistence Amplifier — GLA v2.6

SMPDL3B phenotype frameworks

Phenotype-specific models (shedding vs deficient) and the mechanistic chain framework.

SMPDL3B Phenotypes: Deficient vs Shedding v2.3 SMPDL3B-Shedding Systems Framework (v2.4) Feedback-Loop Architecture (Shedding, v2.4) SMPDL3B-Shedding Mechanistic Chain (v2.4) V2.3 — SMPDL3B Deficient mechanistic chain

System modulators & control-state modifiers

Documents that shape interpretation of the core framework and control-state behavior.

ER Stress — Control-Layer Failure in ME/CFS v2.4 Innate Immune Control Layer — GLA v2.4 Polygenic Control-Layer — GLA v2.4 Disease Progression & Baseline Threshold Erosion v2.4 Haptoglobin Phenotypes — GLA v2.5

How the GLA Model Interacts With Other ME/CFS Disease Concepts

The Gut–Liver–Autonomic (GLA) framework is not a competing theory of ME/CFS or Long COVID.

Instead, it acts as a systems-level layer that explains why the well-known mechanisms in other models become so easily triggered — and why they persist.

Across the major published theories of ME/CFS, GLA provides the upstream regulatory context

Show detailed view: how GLA interacts with other ME/CFS disease models

Across the major published theories of ME/CFS, GLA provides the upstream regulatory context:

  1. Neuroinflammation models (vagal sensitization, microglial priming) describe how symptoms amplify.

    GLA identifies the peripheral triggers — ischemia, ROS, DAMPs, SMPDL3B-related TLR4 sensitivity — that activate those neural pathways.

  2. Metabolic and mitochondrial dysfunction models explain what fails inside the cell.

    GLA explains why cells are under strain in the first place — impaired perfusion, hepatic metabolic load, bile-acid dysregulation, and elevated FGF21.

  3. Microclot and coagulopathy models describe one amplifier inside the vasculature.

    GLA provides the broader microvascular instability (SMPDL3B loss, Ang-2/Tie2 drift, tissue hypoxia) that makes microclots form and persist.

  4. Autonomic dysfunction models (POTS, OI, cerebral hypoperfusion) describe the circulatory collapse.

    GLA shows why autonomic buffering becomes fragile, linking low-volume states, hepatic strain, and endothelial instability into a single loop.

  5. CDR / metabolic-trap theories describe intracellular “locked” steady states.

    GLA supplies the chronic stress inputs — ischemia, ROS, inflammatory signalling — that could maintain such states.

  6. Wirth & Scheibenbogen describe post-exertional malaise (PEM) as a perfusion-limited failure of exertional adaptation.

    GLA builds on this framework by examining why this perfusion vulnerability persists — endothelial fragility, hepatic load, SMPDL3B-linked membrane instability, and weakened autonomic buffering.

  7. Nunes (endothelial senescence / clearance failure) describes persistent damaged vascular targets that are not effectively cleared.
    GLA interpretation: SMPDL3B-related membrane instability, bile-acid–biased immune tolerance, and autonomic hypoperfusion favor incomplete repair over clearance.

  8. Itaconate shunt (resolution brake) describes prolonged immunometabolic suppression that delays recovery.
    GLA interpretation: Protective acutely, but maladaptive when repeatedly re-engaged by unresolved ischemia, endothelial stress, and oxidative signaling—prolonging PEM.

  9. Carnac (phosphatidylcholine / membrane turnover pressure) describes repair fragility when membrane demand exceeds phosphatidylcholine resupply.
    GLA interpretation: Reduced lipid-raft stability, impaired signal termination, and lower endothelial/RBC shear tolerance lower crash threshold and delay recovery without initiating persistence.

  10. Nitrogen hypothesis (NO/RNS stress) describes nitrosative stress as a recovery-cost amplifier.
    GLA interpretation: Mis-timed and mis-localized NO under shear-sensing error and ischemia–reperfusion cycles inhibits enzymes and extends PEM duration (OMF Canada: Missailidis, Phair, Gooley, Annesley, Armstrong).

In short: GLA describes the system that links existing ME/CFS disease models. It does not replace them — it explains when they trigger, how strongly they amplify, and how long recovery takes.

Open: GLA as a Systems-Level Integration Layer Across ME/CFS Disease Models

Framework archive & technical references

The documents below represent earlier or deeper mechanistic layers of the GLA framework. They remain scientifically relevant, but are not required reading to use the questionnaires or understand your subtype.

V2.3 — shedding mechanistic light. V2.3 — Shedding mechanistic technical.
  • These questionnaires are exploratory tools built around a patient-led hypothesis (the GLA / SMPDL3B model).
  • They are not diagnostic tests and do not replace medical advice, investigation, or treatment.
  • No medication (including UDCA or TUDCA) should be started, stopped, or adjusted based on these results without discussing it with a qualified healthcare professional.
  • If you have worrying or rapidly worsening symptoms, please seek medical care and do not rely on this site.