Gut, microbiome and inflammation in RLS

This synthesis covers small intestinal bacterial overgrowth (SIBO), irritable bowel syndrome (IBS), celiac disease, inflammatory bowel disease (Crohn's disease and ulcerative colitis), Helicobacter pylori, the gut microbiome, and systemic inflammatory/cytokine and hepcidin biomarkers in RLS — together with the "inflammatory hypothesis" (Weinstock 2012) that ties them into a single candidate mechanism: gut dysbiosis or infection → systemic/local inflammation → hepcidin upregulation → functional iron sequestration and/or direct autoimmune injury to nerve tissue → RLS. Every claim below cites a study note (filename) or PMID from this knowledge base.

What is established (grade A/B)

• Inflammatory bowel disease carries a substantially and consistently elevated RLS burden. A 2025 systematic review and meta-analysis pooled the available literature and estimated RLS prevalence at 15% in IBD overall (17% in Crohn's disease, 18% in ulcerative colitis) — several-fold above general-population estimates in most regions — though pooled heterogeneity was extremely high (I²=98.8%), which is why this is graded B rather than A (2025-banihashemian-ibd-rls-meta-analysis.md, PMID 41280137).
• A large, decade-long, propensity-matched German primary-care registry (n=35,988) independently confirmed that an IBD diagnosis precedes and predicts significantly higher subsequent RLS incidence: Crohn's disease HR 1.60 (95% CI 1.23-2.09), ulcerative colitis HR 1.26 (95% CI 1.02-1.55) (2023-loosen-ibd-rls-parkinsons-cohort-germany.md, PMID 37109426). This temporal design strengthens the case that gut inflammation precedes, rather than merely coexists with, RLS in many patients.
• A large multicenter prospective cohort (n=272) similarly showed Crohn's disease increases RLS prevalence 3-fold over spouse controls (30.2% vs 9%), with 92% of comorbid cases developing RLS during or after CD onset (2010-weinstock-crohns-disease-association.md, PMID 19575360).
• A nationwide Taiwanese registry (n=46,965) found Helicobacter pylori infection more than doubles the hazard of subsequently developing a sleep-related movement disorder (adjusted HR 2.18, 95% CI 1.26-3.82), with risk rising with age and with time since infection (HR 3.33 at ≥5 years) — a dose/latency pattern consistent with a slow, cumulative inflammatory mechanism rather than a coincidental association (2022-sung-h-pylori-nationwide-cohort-taiwan.md, PMID 36299273).
• At proteome-wide scale in the largest RLS biomarker study to date (combined n=2,107), hepcidin and ferritin were the top signals associated with periodic limb movements, and interleukin-17A — a cytokine central to gut-associated Th17 immunity — was independently elevated in RLS (2023-cederberg-proteomics-stages-hepcidin-il17.md, PMID 37563071). A separate large general-population cohort (n=3,564) found systemic CRP and anti-interferon-alpha autoantibodies significantly associated with RLS even in healthy blood donors (2022-dowsett-crp-supar-cytokine-autoantibodies.md, PMID 35102231), showing the inflammation-RLS link is not an artifact of studying only sick, clinically-referred patients.
• Countervailing this, an equally large, equally rigorous cohort of the same Danish Blood Donor population found no association between plasma hepcidin specifically and RLS (2021-dowsett-hepcidin-danish-blood-donors-negative.md, PMID 34736065, n=9,708). Taken together, the honest grade-B summary is: systemic inflammation and IBD/H. pylori exposure are robustly associated with RLS risk at large scale, but hepcidin elevation specifically is not a universal finding — it appears concentrated in more severe, secondary, or dialysis-associated RLS rather than in RLS drawn from the general population (see Contested, below).

Emerging C

• The foundational observation, from the same investigator (Leonard Weinstock) who later authored the field's synthesizing hypothesis, is that RLS patients recruited without any GI-symptom bias have markedly higher rates of SIBO (69% vs 28% general-population controls, vs 10% completely healthy controls) and IBS (28% vs 4%) (2011-weinstock-ibs-sibo-association.md, PMID 21570907). A separate community-recruited IBS cohort (n=90) found 29% had RLS, confirmed by polysomnography in 92% of screened cases, concentrated in diarrhea-predominant IBS (2011-basu-ibs-rls-prevalence-rifaximin.md, PMID 22110266).
• Treating SIBO appears to relieve RLS: rifaximin (± tegaserod/zinc/probiotic) produced ≥80% RLS improvement in 10/13 patients in an open-label case series (2007-weinstock-sibo-rifaximin-case-series.md, PMID 17934858), and a separate open-label pilot of rifaximin alone reported RLS improvement, though the confirmed record lacks a structured abstract with numeric detail (2009-weinstock-rifaximin-pilot-antibiotic.md, PMID 20042368).
• Celiac disease is repeatedly (though not universally — see Contested) linked to RLS: prevalence 25-35% in celiac cohorts vs about 10% in matched non-celiac controls (2010-weinstock-celiac-disease-association.md, PMID 19731029; 2010-moccia-celiac-rls-prevalence.md, PMID 20461805), with a small case series showing all 4 patients with unexplained severe low ferritin and undiagnosed celiac disease improved on a gluten-free diet, 2 discontinuing RLS medication entirely (2009-manchanda-celiac-ferritin-case-series.md, PMID 19138881). In children, celiac-associated RLS tracks with lower vitamin D, ferritin, and folate, and with disease-activity antibody titers, but not clearly with gluten-free diet adherence itself (2026-tok-pediatric-celiac-vitamind-iron-gfd.md, PMID 41851650).
• H. pylori shows converging, if heterogeneous, clinical signals beyond the large Taiwanese registry above: seropositivity is significantly more common in RLS patients in a Tehran case-control study (2018-rezvani-h-pylori-seroprevalence.md, PMID 29623817), and RLS patients with dyspepsia show significantly more gastric mucosal intestinal metaplasia and atrophy on biopsy (independent of active H. pylori status), alongside lower ferritin (2020-cam-endoscopic-gastric-mucosa-findings.md, PMID 32294750).
• The first dedicated gut-microbiome sequencing study in RLS (16S rRNA, n=101) found a specific, RLS-distinctive (not merely sleep-disruption-related) reduction in the SCFA-producing genera Lachnoclostridium and Flavonifractor compared with both insomnia patients and healthy controls, worsening with longer disease duration — directly linking dysbiosis to loss of anti-inflammatory short-chain fatty acid production and, mechanistically, to hepcidin-mediated iron restriction (2026-montini-gut-microbiota-metagenomic-signature.md, PMID 41378921).
• Hepcidin dysregulation recurs across multiple idiopathic and secondary-RLS populations at grade C: elevated in drug-free idiopathic RLS regardless of ferritin or dopaminergic treatment status (2020-chenini-hepcidin-ferritin-case-control.md, PMID 32681031), elevated and severity-correlated in hemodialysis (2020-tufekci-hemodialysis-hepcidin-rls.md, PMID 33029690) and peritoneal dialysis patients (2021-guo-peritoneal-dialysis-hepcidin-rls.md, PMID 34966748), and tracking dopaminergic-treatment response even though not elevated at baseline in a small drug-naive, non-anemic cohort (2020-im-hepcidin-treatment-response.md, PMID 33419264).
• Direct GI-disease interventions improve RLS in uncontrolled or small studies: iron/folate/B12 supplementation in IBD patients with documented deficiency produced significant RLS improvement at 4 weeks (7/8 patients, p=0.029) (2018-becker-ibd-iron-supplementation-improves-rls.md, PMID 29610943); IBD prevalence and severity of RLS was elevated in a large Saudi cohort, with obesity, TSH, and hemoglobin as risk factors (2021-alharbi-ibd-rls-prevalence-risk-factors.md, PMID 34596594).
• General systemic-inflammation markers correlate with RLS presence and severity outside the gut specifically: CRP/albumin ratio (2019-olgun-yazar-crp-albumin-ratio-rls.md, PMID 31129525), psoriasis severity and CRP (2022-solak-psoriasis-rls-inflammation.md, PMID 36468846), and IL-6/CRP/oxidative stress in hemodialysis (2015-higuchi-hemodialysis-oxidative-stress-inflammation.md, PMID 26070856) — consistent with gut inflammation being one major, but not the only, contributor to the systemic inflammatory burden implicated in RLS.
• A 2025 JAMA review anchors the mainstream-medicine view that gut malabsorptive/inflammatory disease (atrophic gastritis, celiac disease, bariatric surgery, IBD — 13-90% iron-deficient depending on activity) is a leading cause of the iron deficiency that produces RLS in 32-40% of iron-deficient patients, and that IV (not oral) iron is preferred when gut absorption or inflammation is impaired (2025-auerbach-jama-iron-deficiency-review.md, PMID 40159291); a smaller French review makes the same hepcidin-ferroportin-microbiota point (2014-cozon-iron-deficiency-digestive-disorders-review.md, PMID 25282486), and a general gut-brain-axis review names RLS explicitly among the conditions plausibly linked to endotoxin/LPS-driven inflammation and dysbiosis (2014-galland-gut-microbiome-brain-review.md, PMID 25402818).
• Mast cell activation syndrome (MCAS) — an inflammatory/allergic disorder driven by dysregulated mast cells, which are concentrated in the gut mucosa — is associated with markedly higher RLS prevalence than spouse controls (40.8% vs 12.9%, p<.0001; male OR 3.4-7.7, female OR 6.1-6.7 vs published population rates), extending the inflammatory hypothesis to a distinct mast-cell-mediated pathway (2020-weinstock-mast-cell-activation-syndrome.md, PMID 31994488). A separate case-control cytokine panel found plasma IL-1β, IL-6, and TNF-α (though not CRP) significantly elevated in primary RLS versus controls, with IL-6 tracking severity, providing direct evidence of low-grade systemic inflammation even without a diagnosed GI disease (2020-uslu-circulating-cytokines-elevated.md, PMID 33083922). A viral (non-gut) trigger can produce the same pattern: women with long-COVID showed RLS prevalence rising from a recalled 5.7% pre-infection baseline to 14.8% post-infection (never-infected controls stable at 6.7%), showing the postinfectious/inflammatory mechanism generalizes beyond gut-specific triggers (2022-weinstock-long-covid-rls.md, PMID 35484639). At the tissue level, postmortem RLS brain specimens showed significantly more gliosis and CD3+ T-cell infiltration co-localized with microvascular lesions than controls — direct, if very small-sample, histological evidence that immune cells physically infiltrate RLS-affected brain tissue (2021-walters-postmortem-tcell-microvascular.md, PMID 33998250).

Contested or negative findings

• Hepcidin is not universally elevated in RLS. The largest general-population study of hepcidin and RLS (Danish blood donors, n=9,708) found no association at all (median hepcidin identical between cases and controls, adjusted OR 1.00, p=0.429) (2021-dowsett-hepcidin-danish-blood-donors-negative.md, PMID 34736065), directly contrasting with positive findings in idiopathic, dialysis, and treatment-response cohorts above. The most likely explanation is that blood donors are a pre-screened "healthy" population unlikely to include the more severe, secondary, or inflammation-driven RLS phenotypes where hepcidin elevation has been observed — meaning hepcidin may be a marker of a specific inflammatory RLS subtype, not of RLS in general.
• Celiac disease does not always increase RLS prevalence, and gluten-free diet adherence does not always track with RLS severity. A pediatric case-control study (n=494) found essentially identical overall RLS prevalence in children with celiac disease versus controls (3.5% vs 3.0%, p=0.98), although RLS was earlier-onset and more severe within the celiac group (2018-isikay-pediatric-celiac-rls-negative.md, PMID 30102482). A separate serology study (n=193) found celiac/gluten-sensitive-enteropathy antibody positivity was not increased in RLS patients versus controls, arguing that any celiac-RLS link runs through iron deficiency rather than direct gluten-immune injury (2011-cikrikcioglu-gluten-antibodies-negative.md, PMID 22368967). And in the 2026 pediatric cohort above, gluten-free diet adherence itself was not significantly associated with RLS severity even though celiac status was (2026-tok-pediatric-celiac-vitamind-iron-gfd.md, PMID 41851650).
• IBD does not always increase RLS prevalence. A well-powered Saudi case-control study (n=429) found no significant difference in RLS prevalence between IBD patients and controls (7.34% vs 8.06%, OR=0.90, p=0.78) — the only significant IBD-specific predictor of RLS was vitamin B12 deficiency, not IBD status itself (2020-mosli-ibd-rls-no-difference.md, PMID 33130811). This sits in real tension with the meta-analysis and German registry findings above and is best read as evidence that population, IBD activity/phenotype, and RLS ascertainment method (self-report questionnaire vs polysomnography-confirmed) substantially affect whether an IBD-RLS association is detected.
• The most recent, most rigorous microbiome study found dysbiosis largely independent of diagnosed GI comorbidity. In the 2026 16S study, only 8% of RLS patients had comorbid IBS (versus 28% in the original Weinstock SIBO cohort) and none had Crohn's disease or celiac disease, yet the RLS-specific microbial signature (reduced Lachnoclostridium/Flavonifractor) was still present — suggesting dysbiosis may be a general RLS feature that does not require a diagnosed gut disease to manifest, which complicates the simple "treat the gut disease and RLS resolves" narrative (2026-montini-gut-microbiota-metagenomic-signature.md, PMID 41378921).
• Directly testing the "leaky gut" mechanism found no overall difference. Plasma zonulin (a specific biomarker of intestinal permeability) did not differ significantly between RLS patients and controls in a dedicated case-control study, though more RLS patients fell in the "high zonulin" category and levels were higher in overweight/obese RLS patients specifically; the authors concluded this indirectly favors central over gut-permeability mechanisms as the dominant driver of RLS (2025-darol-zonulin-intestinal-permeability.md, PMID 40802396). This is a genuine tension with the dysbiosis and SIBO findings above and suggests that if gut-derived inflammation matters, it may act through bacterial translocation/immune signaling other than simple barrier leakiness, or only in specific subgroups (obesity, diagnosed GI disease) rather than as a general RLS mechanism.

Mechanistic picture in 5 bullet points

1. Dysbiosis/SIBO/infection as the upstream trigger: SIBO, IBS, IBD, celiac disease, and H. pylori infection are all independently associated with RLS at rates well above matched controls, and in the case of SIBO and iron/B12 deficiency in IBD, correcting the gut condition has been shown to relieve RLS symptoms (2011-weinstock-ibs-sibo-association.md; 2007-weinstock-sibo-rifaximin-case-series.md; 2018-becker-ibd-iron-supplementation-improves-rls.md).
2. Loss of anti-inflammatory microbial output: the RLS-specific reduction in SCFA-producing genera (Lachnoclostridium, Flavonifractor) means less short-chain-fatty-acid production, which normally strengthens the gut epithelial barrier and dampens inflammation; less SCFA lets bacterial lipopolysaccharide leak into the bloodstream, raising systemic inflammation (2026-montini-gut-microbiota-metagenomic-signature.md; 2014-galland-gut-microbiome-brain-review.md).
3. Inflammation converges on hepcidin: systemic inflammation (from gut or other sources) upregulates hepcidin, which degrades the iron exporter ferroportin, trapping iron in enterocytes/macrophages and restricting the iron available for absorption and for delivery to the brain — functionally reproducing brain iron deficiency even when peripheral ferritin looks adequate (2012-weinstock-inflammatory-immune-hypothesis.md; 2020-chenini-hepcidin-ferritin-case-control.md; 2006-clardy-hepcidin-ferroportin-signaling.md, pre-existing note; 2018-dauvilliers-hepcidin-severity-rls.md, pre-existing note).
4. A parallel, iron-independent immune/molecular-mimicry pathway may exist: elevated IL-17A, IL-1β, IL-6, and TNF-α, plus the specific hypothesis that gliadin peptides structurally mimic and disrupt the NMDA-glutamate-receptor component GRINA, suggest immune activation (gut-triggered or otherwise, per the MCAS and long-COVID findings) could injure central or peripheral nervous tissue directly, or amplify the independently-established glutamatergic hyperarousal mechanism, rather than acting solely through iron. Direct histological support comes from postmortem RLS brain tissue showing CD3+ T-cell infiltration co-localized with microvascular lesions (2023-cederberg-proteomics-stages-hepcidin-il17.md; 2016-garcia-quintanilla-gliadin-grina-hypothesis.md; 2020-uslu-circulating-cytokines-elevated.md; 2021-walters-postmortem-tcell-microvascular.md).
5. The inflammatory contribution is graded and population-dependent, not universal: hepcidin and celiac-antibody associations are strong and reproducible in severe/secondary/dialysis-associated RLS but essentially absent in healthy general-population cohorts, and dysbiosis appears present even without diagnosed GI comorbidity — implying gut/inflammatory mechanisms likely explain a meaningful subset, not all, of RLS, layered on top of (and probably interacting with) the primary brain-iron-deficiency and genetic mechanisms described elsewhere in this knowledge base (2021-dowsett-hepcidin-danish-blood-donors-negative.md; 2020-mosli-ibd-rls-no-difference.md).

Implications for a non-drug long-term plan for people currently on dopamine agonists or alpha-2-delta ligands

• Screen the gut when iron repletion alone is not working. For patients on a dopamine agonist or alpha-2-delta ligand whose ferritin remains stubbornly low, or whose symptoms persist despite adequate iron therapy, this evidence supports asking about GI symptoms and considering celiac serology, H. pylori testing, and (where available) SIBO breath testing, since treating an underlying gut condition has produced RLS improvement independent of dopaminergic dose changes in multiple studies (2011-weinstock-ibs-sibo-association.md; 2007-weinstock-sibo-rifaximin-case-series.md; 2010-weinstock-celiac-disease-association.md; 2018-rezvani-h-pylori-seroprevalence.md). This should always be physician-supervised, alongside — never as a substitute for — the medically-supervised, gradual approach to any dopamine-agonist dose change; per this project's non-negotiable rules, tapering must never be abrupt.
• Use hepcidin thoughtfully, not as a universal test. Because hepcidin elevation tracks with more severe, secondary, or dialysis/inflammation-associated RLS but was entirely absent in a large healthy-population sample, it is most useful as an adjunct marker in patients with plausible inflammatory drivers (known IBD, dialysis, elevated CRP) rather than as a routine screen in every RLS patient (2020-chenini-hepcidin-ferritin-case-control.md; 2021-dowsett-hepcidin-danish-blood-donors-negative.md).
• Favor IV over oral iron when gut absorption or inflammation is a factor. Because inflammation-driven hepcidin blocks intestinal iron absorption, and because oral iron itself transiently raises hepcidin for about 24 hours (blocking absorption from a same/next-day dose — a pre-existing, non-gut-specific but directly relevant finding), patients with celiac disease, IBD, or confirmed elevated inflammatory markers may need IV iron or carefully spaced alternate-day oral dosing rather than daily oral iron to achieve repletion (2025-auerbach-jama-iron-deficiency-review.md; 2017-stoffel-alternate-day-iron-absorption.md, pre-existing note).
• A gluten-free diet is a reasonable, low-risk trial only when celiac disease (or strong suspicion) is present — not a blanket recommendation. Evidence supports gluten-free diet improving RLS specifically in biopsy/serology-confirmed celiac disease with iron deficiency, but negative and mixed findings (no increased celiac-antibody prevalence in RLS generally; no association between diet adherence and RLS severity in one pediatric cohort) argue against recommending gluten elimination to RLS patients without a celiac work-up (2010-weinstock-celiac-disease-association.md; 2011-cikrikcioglu-gluten-antibodies-negative.md; 2026-tok-pediatric-celiac-vitamind-iron-gfd.md).
• Consider non-gut inflammatory triggers when RLS worsens or appears without a clear iron/dose explanation. New-onset or worsening RLS after a viral illness, or in a patient with unexplained allergic/mast-cell-type symptoms (flushing, food/medication reactions, GI upset without a clear diagnosis), fits a documented pattern of infection- or MCAS-triggered RLS; flagging this to a physician can prompt appropriate allergy/immunology referral rather than an unnecessary dopaminergic dose increase, though this remains an emerging C observation, not a validated screening pathway (2020-weinstock-mast-cell-activation-syndrome.md; 2022-weinstock-long-covid-rls.md; 2020-uslu-circulating-cytokines-elevated.md).
• Do not assume "leaky gut" as the mechanism, or intestinal-permeability supplements as a fix, without a specific diagnosis. A direct test of plasma zonulin found no general RLS-control difference, so marketed "gut healing" or permeability-targeted supplements lack evidentiary support as a stand-alone RLS treatment; the evidence base instead supports specific, diagnosable conditions (SIBO, celiac disease, IBD, H. pylori) as the actionable targets (2025-darol-zonulin-intestinal-permeability.md).
• General anti-inflammatory and gut-supportive lifestyle measures (fiber/SCFA-supporting diet, treating dysbiosis, weight and metabolic management) are reasonable adjuncts with a plausible mechanism (SCFA/hepcidin/cytokine axis) but currently only case-series or cross-sectional support — they should be framed to patients as biologically plausible and low-risk, not as proven substitutes for guideline-recommended iron therapy or alpha-2-delta ligands (2026-montini-gut-microbiota-metagenomic-signature.md; 2022-solak-psoriasis-rls-inflammation.md).

Open questions

• Is gut dysbiosis in RLS a cause, a consequence (e.g., of reduced mobility, altered diet, or medication effects), or a shared downstream effect of a common upstream driver? The 2026 microbiome study is cross-sectional and cannot resolve this (2026-montini-gut-microbiota-metagenomic-signature.md).
• Why does hepcidin elevation appear in some RLS populations (idiopathic clinical cohorts, dialysis patients) but not others (general-population blood donors)? Is this a true subtype distinction, a severity threshold effect, or a measurement/assay difference (2020-chenini-hepcidin-ferritin-case-control.md vs 2021-dowsett-hepcidin-danish-blood-donors-negative.md)?
• Does eradicating H. pylori, or treating SIBO with rifaximin under controlled (randomized, blinded) conditions, produce durable RLS improvement independent of iron status changes? All current supportive evidence is uncontrolled or open-label (2007-weinstock-sibo-rifaximin-case-series.md; 2009-weinstock-rifaximin-pilot-antibiotic.md; 2018-rezvani-h-pylori-seroprevalence.md).
• Is the gliadin-GRINA/NMDA-receptor mechanism real in vivo, and if so, does it explain cases of RLS improvement on a gluten-free diet that occur without measurable iron or antibody changes (2016-garcia-quintanilla-gliadin-grina-hypothesis.md)?
• Could a targeted probiotic or prebiotic (e.g., one that restores Lachnoclostridium/SCFA production) be tested as a standalone RLS intervention, and would benefit require pre-existing dysbiosis or GI comorbidity to be present? No such trial currently exists in this literature.
• What explains the discordant IBD-RLS prevalence findings (elevated in the meta-analysis, German registry, and Saudi AlHarbi cohort; null in the Saudi Mosli cohort) — is it IBD activity/phenotype, RLS ascertainment method, or population-specific confounders (2025-banihashemian-ibd-rls-meta-analysis.md vs 2020-mosli-ibd-rls-no-difference.md vs 2021-alharbi-ibd-rls-prevalence-risk-factors.md)?
• Is intestinal permeability (zonulin) genuinely uninvolved in RLS generally, or only in the unselected patients studied so far — would a zonulin study restricted to RLS patients with confirmed SIBO, celiac disease, or IBD show a different result than the general RLS population tested to date (2025-darol-zonulin-intestinal-permeability.md)?
• Do MCAS and long-COVID-associated RLS share the same hepcidin/iron-sequestration mechanism as gut-disease-associated RLS, or a distinct cytokine-driven pathway (e.g., IL-6/TNF-α acting on dopaminergic or glutamatergic systems directly) — no study has measured hepcidin and cytokines together in the same MCAS or post-viral RLS cohort (2020-weinstock-mast-cell-activation-syndrome.md; 2022-weinstock-long-covid-rls.md; 2020-uslu-circulating-cytokines-elevated.md).

Notes in this topic

New notes written for this sweep (all tagged gut-microbiome-inflammation):

• 2011-weinstock-ibs-sibo-association.md — Foundational study: SIBO in 69% and IBS in 28% of unbiased-recruitment RLS patients vs controls (PMID 21570907).
• 2012-weinstock-inflammatory-immune-hypothesis.md — The field-defining review proposing gut/immune inflammation and hepcidin as an RLS mechanism (PMID 22258033).
• 2007-weinstock-sibo-rifaximin-case-series.md — Rifaximin-based SIBO treatment produced ≥80% RLS improvement in 10/13 patients (PMID 17934858).
• 2009-weinstock-rifaximin-pilot-antibiotic.md — Early open-label rifaximin pilot in idiopathic RLS; numeric details not retrievable (PMID 20042368).
• 2011-basu-ibs-rls-prevalence-rifaximin.md — 29% RLS prevalence in IBS, concentrated in diarrhea-predominant subtype (PMID 22110266).
• 2010-weinstock-crohns-disease-association.md — Crohn's disease triples RLS prevalence (30.2% vs 9%) in a 272-patient multicenter cohort (PMID 19575360).
• 2010-weinstock-celiac-disease-association.md — Celiac disease raises RLS prevalence to 25%; gluten-free diet improved symptoms in 50% of a subset (PMID 19731029).
• 2009-manchanda-celiac-ferritin-case-series.md — 4/4 RLS patients with unexplained severe low ferritin had celiac disease and improved on gluten-free diet (PMID 19138881).
• 2010-moccia-celiac-rls-prevalence.md — 31% RLS prevalence in adult celiac disease, not explained by iron metabolism alone (PMID 20461805).
• 2011-cikrikcioglu-gluten-antibodies-negative.md — Negative finding: celiac/GSE antibody positivity not increased in RLS overall (PMID 22368967).
• 2018-isikay-pediatric-celiac-rls-negative.md — Negative finding: no overall RLS prevalence increase in pediatric celiac disease, but earlier onset/greater severity when present (PMID 30102482).
• 2026-tok-pediatric-celiac-vitamind-iron-gfd.md — Pediatric celiac RLS severity tracks with vitamin D/iron/folate, not gluten-free diet adherence (PMID 41851650).
• 2016-garcia-quintanilla-gliadin-grina-hypothesis.md — Hypothesis: gliadin peptide mimics and disrupts the NMDA-receptor component GRINA (PMID 26990286).
• 2018-rezvani-h-pylori-seroprevalence.md — H. pylori seropositivity significantly more common in RLS (PMID 29623817).
• 2020-cam-endoscopic-gastric-mucosa-findings.md — Gastric mucosal atrophy/metaplasia (not H. pylori itself) elevated in RLS with dyspepsia (PMID 32294750).
• 2022-sung-h-pylori-nationwide-cohort-taiwan.md — Nationwide cohort: H. pylori infection more than doubles later sleep-related movement disorder risk (PMID 36299273).
• 2014-galland-gut-microbiome-brain-review.md — General gut-brain-axis mechanistic review naming RLS among linked conditions (PMID 25402818).
• 2026-montini-gut-microbiota-metagenomic-signature.md — First RLS-specific 16S microbiome signature: reduced SCFA-producing Lachnoclostridium/Flavonifractor (PMID 41378921).
• 2020-mosli-ibd-rls-no-difference.md — Negative finding: no RLS prevalence increase in Saudi IBD cohort; vitamin B12 deficiency was the real predictor (PMID 33130811).
• 2025-banihashemian-ibd-rls-meta-analysis.md — Meta-analysis: pooled 15% RLS prevalence in IBD, high heterogeneity (PMID 41280137).
• 2023-loosen-ibd-rls-parkinsons-cohort-germany.md — Large 10-year registry: IBD significantly predicts subsequent RLS (HR 1.26-1.60) (PMID 37109426).
• 2018-becker-ibd-iron-supplementation-improves-rls.md — Iron/B12/folate supplementation improved RLS in IBD patients with documented deficiency (PMID 29610943).
• 2021-alharbi-ibd-rls-prevalence-risk-factors.md — RLS more prevalent and severe in IBD (21.5% vs 9.7%); obesity/TSH/hemoglobin as risk factors (PMID 34596594).
• 2025-auerbach-jama-iron-deficiency-review.md — Anchor review: gut malabsorptive/inflammatory disease as leading cause of RLS-associated iron deficiency (PMID 40159291).
• 2014-cozon-iron-deficiency-digestive-disorders-review.md — French review linking hepcidin/ferroportin/microbiota to iron-deficiency symptoms including RLS (PMID 25282486).
• 2020-chenini-hepcidin-ferritin-case-control.md — Hepcidin (not ferritin) elevated in drug-free RLS regardless of treatment/augmentation history (PMID 32681031).
• 2021-dowsett-hepcidin-danish-blood-donors-negative.md — Negative finding: no hepcidin-RLS association in a large healthy general-population cohort (PMID 34736065).
• 2023-cederberg-proteomics-stages-hepcidin-il17.md — Largest RLS proteomic study: hepcidin/ferritin dominate PLM signal; IL-17A elevated in RLS (PMID 37563071).
• 2020-tufekci-hemodialysis-hepcidin-rls.md — Hepcidin and HbA1c independently associated with RLS in hemodialysis patients (PMID 33029690).
• 2021-guo-peritoneal-dialysis-hepcidin-rls.md — Hepcidin an independent determinant of RLS in peritoneal dialysis patients (PMID 34966748).
• 2020-im-hepcidin-treatment-response.md — Hepcidin not elevated at baseline in drug-naive non-anemic RLS, but its decrease tracks treatment response (PMID 33419264).
• 2022-solak-psoriasis-rls-inflammation.md — RLS more common and more severe with worse psoriasis/CRP, showing systemic (non-gut) inflammation also matters (PMID 36468846).
• 2022-dowsett-crp-supar-cytokine-autoantibodies.md — CRP and anti-interferon-alpha autoantibodies associated with RLS in a large healthy cohort (PMID 35102231).
• 2019-olgun-yazar-crp-albumin-ratio-rls.md — CRP/albumin ratio elevated and tracking severity in RLS (PMID 31129525).
• 2015-higuchi-hemodialysis-oxidative-stress-inflammation.md — IL-6, CRP, and oxidative stress marker 8-OHdG elevated in hemodialysis RLS (PMID 26070856).

New notes added in this update (2026-09-11 verification/gap-fill pass):

• 2020-weinstock-mast-cell-activation-syndrome.md — RLS far more common in mast cell activation syndrome (40.8% vs 12.9% controls) (PMID 31994488).
• 2020-uslu-circulating-cytokines-elevated.md — IL-1β, IL-6, TNF-α elevated in primary RLS vs controls; IL-6 tracks severity (PMID 33083922).
• 2022-weinstock-long-covid-rls.md — RLS prevalence in women rose from 5.7% pre- to 14.8% post-long-COVID, a postinfectious/non-gut inflammatory trigger (PMID 35484639).
• 2021-walters-postmortem-tcell-microvascular.md — Postmortem RLS brain tissue shows more gliosis and CD3+ T-cell infiltration than controls (PMID 33998250).
• 2025-darol-zonulin-intestinal-permeability.md — Negative/mixed finding: plasma zonulin (intestinal permeability marker) not significantly different in RLS overall (PMID 40802396).

Pre-existing notes from other topic sweeps, also directly relevant here:

• 2006-clardy-hepcidin-ferroportin-signaling.md — Site-specific hepcidin/ferroportin dysregulation (CSF vs brain tissue) in RLS (PMID 16759669).
• 2018-dauvilliers-hepcidin-severity-rls.md — Hepcidin (not ferritin) elevated and non-linearly tied to severity in drug-free normal-ferritin RLS (PMID 29418021).
• 2020-lyu-mu-opioid-receptor-knockout-mouse.md — Mu-opioid-receptor knockout mice show an RLS-like phenotype with "anemia of inflammation," mechanistically linking endogenous opioid, inflammatory, and iron pathways (PMID 32424971).
• 2017-stoffel-alternate-day-iron-absorption.md — Oral iron transiently raises hepcidin for ~24h, blocking absorption from a same/next-day dose — directly relevant to dosing iron in inflamed/gut-disease patients (PMID 29032957).