Multidimensional iron dysmetabolism and gut-brain axis interactions in restless legs syndrome: from peripheral deficiency to central dysregulation
This narrative review proposes a multilevel iron metabolism dysfunction in RLS — from intestinal absorption to BBB transport — with an adjuvant role for gut microbiota, but presents no original data and quantifies no clinical effects.
| Population | Adults with primary RLS, including subgroups with normal ferritin and central iron deficit |
|---|---|
| Intervention | Theoretical model integrating the hepcidin-ferroportin axis, BBB transport, and gut microbiota as regulators of brain iron supply |
| Comparator | null |
| Outcome | Serum hepcidin levels in RLS with normal ferritin; Iron markers in neuron-derived extracellular vesicles; Peripheral-central iron discordance in RLS; Gut microbiota role in cerebral iron availability; Efficacy of iron supplementation in RLS |
Summary of findings
| Outcome | Effect | 95% CI | Certainty | Clinical relevance | Notes |
|---|---|---|---|---|---|
| Serum hepcidin levels in RLS with normal ferritin | positive correlation with PLMS; in the effect size or 95% CI reported in this review (data from Dauvilliers et al., 2018) | — | Low | — | 1 studies |
| Iron markers in neuron-derived extracellular vesicles | elevated ferritin + reduced TfR in NDEVs; in the quantitative effect size reported | — | Low | — | 1 studies |
| Peripheral-central iron discordance in RLS | narrative synthesis only; in the pooled statistic | — | Low | — | |
| Gut microbiota role in cerebral iron availability | hypothetical mechanism only; in the clinical trial data | — | Very low | — | |
| Efficacy of iron supplementation in RLS | narrative reference to symptom relief; in the pooled RR, OR, or MD reported | — | Low | — |
Context
RLS affects 5–15% of the Western adult population and iron dysregulation is a central pathophysiological axis. The frequent discordance between normal serum ferritin and CNS iron deficit justifies broader explanatory models. Mechanistic reviews influence iron screening and supplementation protocols, making their critical appraisal clinically relevant.
What the study showed
The text synthesizes evidence from cited primary studies (no original meta-analysis) to argue that: (1) hepcidin levels are elevated in RLS patients with normal ferritin >50 ng/mL, positively correlating with periodic limb movements during sleep (Dauvilliers et al., 2018); (2) neuron-derived extracellular vesicles show elevated ferritin and reduced transferrin receptors, suggesting impaired neuronal iron uptake; (3) gut microbiota may compete for luminal iron and induce low-grade inflammation, systemically elevating hepcidin. No original effect sizes, 95% CIs, or absolute case numbers are reported by this article.
How it was done
Narrative review without a registered protocol, explicit systematic search strategy, or inclusion/exclusion criteria. No risk-of-bias tool applied (AMSTAR-2 not applicable given the absence of systematic methods). No original sample; quantitative data derive from cited primary studies.
Effect magnitude
No pooled effect size is calculated. The only recurring numerical datum is the positive correlation between hepcidin and periodic limb movements reported by Dauvilliers et al. (2018), with no 95% CI provided by this review.
Risk of bias
Narrative review without systematization: study selection is potentially biased toward confirmation of the mechanistic hypothesis. No formal quality assessment of primary studies. Several references dated 2025–2026 cannot be verified for existence or quality. The gut-brain model for RLS remains hypothetical, lacking direct validation from controlled clinical trials.
What this study does NOT prove
This article does not prove causality between gut dysbiosis and RLS, nor between hepcidin elevation and clinical RLS severity. Findings are not generalizable to secondary RLS or patients with significant inflammatory comorbidities.
In clinical practice
Clinicians should assess serum iron, ferritin, TIBC, and TSAT together in RLS patients rather than relying on ferritin alone, consistent with existing IRLSSG recommendations. The hypothesis of hepcidin-mediated functional iron deficiency may guide investigation in refractory RLS patients with normal ferritin, but does not change grade A or B evidence-based practice until clinical trials confirm interventions targeting this axis.
Limitations
Narrative review without systematization: study selection is potentially biased toward confirmation of the mechanistic hypothesis. No formal quality assessment of primary studies. Several references dated 2025–2026 cannot be verified for existence or quality. The gut-brain model for RLS remains hypothetical, lacking direct validation from controlled clinical trials.
What is still missing
Randomized controlled trials testing interventions on the hepcidin-ferroportin axis or gut microbiota in RLS patients with normal ferritin, using validated clinical outcomes (IRLS score, PLMS index, sleep quality).
Technical appendix
Version history
- 1.0 · 2026-10-21 — Auto-generated under Evidence Standard v1.0