NEW SECTION (v2.2): 7.4 Bile-Acid Modulation — UDCA & TUDCA

Although no ME/CFS clinical trials have evaluated ursodeoxycholic acid (UDCA) or tauroursodeoxycholic acid (TUDCA), their mechanisms overlap with validated abnormalities in the hepatic metabolic stress axis, FGF21 elevation, mitochondrial fragility, and gut–liver microcirculatory strain observed in ME/CFS (Hoel et al., 2021; Beentjes et al., 2025; Azimi et al., 2025).

Because the ME/CFS hepatic signature resembles:

• hypoxia-like amino-acid patterns
• abnormal β-oxidation
• oxidative stress signaling
• FGF21 upregulation

…modulating bile-acid composition and hepatocyte stress responses may theoretically help restore the GLA axis without interacting with SMPDL3B or PI-PLC pathways.

7.4.1 Mechanistic Fit With ME/CFS Biomarkers

A. Reduction of Hepatocellular Stress (ER stress / oxidative load)

Both UDCA and TUDCA are cytoprotective bile acids that:

• mitigate ER-stress–induced apoptosis
• stabilize mitochondrial membranes
• reduce ROS generation
• improve protein folding and UPR balance

These mechanisms align with metabolic signatures found in ME/CFS:

• impaired β-oxidation
• increased markers of mitochondrial strain
• elevated FGF21 (indicative of hepatocyte stress)

(Hoel et al., 2021; Azimi et al., 2025).

TUDCA has stronger ER-stress reduction effects than UDCA.

B. Improvement of Sinusoidal Microvascular Flow

UDCA improves:

• bile acid hydrophobicity balance
• sinusoidal endothelial stability
• cholangiocyte survival
• portal microvascular resistance

Mechanistically, this complements the documented:

• microvascular dysfunction
• endothelial instability
• hepatic metabolic signatures of hypoxia

These hepatic findings are validated in ME/CFS metabotyping cohorts (Hoel et al., 2021; Beentjes et al., 2025).

C. FXR / TGR5 Modulation & FGF21 Dynamics

UDCA is a weak FXR antagonist and partial agonist of TGR5.

TUDCA indirectly modulates ER stress → FGF21–PPAR pathways.

In ME/CFS:

• FGF21 elevation is strongly associated with metabolic instability and symptom severity (Azimi et al., 2025).

Stabilizing bile-acid profiles may reduce the chronic FGF21 signaling load.

This does not replace AMP-K or mitochondrial-targeting therapies; it may complement them.

D. Gut–Liver Barrier Stabilization (Indirect GLA benefit)

Both UDCA and TUDCA improve:

• intestinal epithelial tight-junction function
• bile-acid detergent toxicity
• endotoxin-induced inflammation
• mucosal mitochondrial stability

This may indirectly reduce the hepatic metabolic strain observed in ME/CFS, which is partly driven by:

• increased intestinal permeability
• portal inflammatory load
• endotoxin flux under microvascular stress

Again, these are consistent with the GLA interpretation of ME hepatic biomarkers.

7.4.2 Phenotype-Specific Considerations (Without Overreach)

✔ Compatible with both SMPDL3B phenotypes

Since UDCA/TUDCA do not modulate:

• PI-PLC
• TLR4 cytokine release
• membrane SMPDL3B
• ceramide pathways

…they do not pose phenotype-specific risk and are not contraindicated in either the SMPDL3B-shedding or SMPDL3B-deficiency subtype.

They act orthogonally to the SMPDL3B axis, reducing hepatic metabolic stress rather than affecting innate immunity or PI-PLC.

7.4.3 Safety and Limitations (Evidence-Aligned)

Strength:

• Mechanistically coherent with GLA
• Compatible with hepatic strain markers validated in ME/CFS
• Broad safety record at low doses (UDCA 125–250 mg/day)

Limitations:

• No ME/CFS clinical trials to date
• Effects on endothelial dysfunction, volume regulation, or autonomic instability remain unproven
• TUDCA may cause mild GI motility changes in hyper-autonomic states

Conclusion: UDCA/TUDCA may serve as a foundational hepatic-stabilizing intervention that complements SMPDL3B-aligned treatments by reducing global metabolic strain and improving hepatocyte resilience. They should be viewed as supportive agents in the hepatic–metabolic limb of the model, not as primary disease-modifying therapies.

This section is exploratory and intended to align existing hepatology and ME/CFS research within the GLA framework. It is not a treatment guideline and does not recommend the use of UDCA or TUDCA without clinician oversight.