Irritable bowel syndrome and restless legs syndrome: a narrative review of epidemiological and pathophysiological overlap

Abstract

Background:

Irritable bowel syndrome (IBS) and restless legs syndrome (RLS) are chronic, multifactorial disorders that have considerable impact on quality of life and common comorbidity with mood and sleep disorders.

Objectives:

The present narrative review consolidates existing literature to examine the epidemiological connection, shared pathophysiological mechanisms, and clinical implications of IBS–RLS comorbidity.

Methods:

A literature search was conducted using PubMed and Google Scholar (2015–2025). The inclusion criteria were adult population and peer-reviewed, full-text studies on co-occurrence or mechanism between RLS and IBS. There were 48 included articles after independent screening.

Results:

Observational studies report RLS prevalence in IBS patients of about 10–46%, compared with 3–14% in controls, indicating a likely bidirectional association. Both conditions share risk factors like female sex, psychiatric comorbidity, and autonomic dysfunction, and overlap in mechanisms including iron deficiency, neuroinflammation, neurotransmitter imbalance, gut–brain axis disruption, and microbial dysbiosis. This supports a neurogastroenterological link and suggests shared etiologic pathways, highlighting the value of routine reciprocal screening to improve diagnosis and quality of life.

Conclusion:

The co-occurrence of IBS and RLS underscores the necessity of increased clinical vigilance and combined care. Shared mechanisms increase the potential for specific therapy approaches, including dopaminergic drugs, iron supplementation, microbiota modifications, and mast cell stabilizers. Further longitudinal and mechanistic studies are needed to clarify causality and evaluate potential dual-purpose interventions, as current evidence is largely observational and limits causal inference.

Introduction

Irritable bowel syndrome (IBS) is a chronic functional gastrointestinal disease characterized by recurrent abdominal pain and bowel habit changes in the absence of organic pathologic findings. Estimated to affect 3.8% of the population worldwide by Rome IV and 9.2% by the less restrictive Rome III, IBS greatly affects quality of life and contributes a significant healthcare burden^[1^]. The pathophysiology of IBS is complex, with gut–brain axis dysregulation, visceral hypersensitivity, changes in gastrointestinal motility, microbial dysbiosis, and psychosocial stressors all contributing to disease progression^[2,3^]. Restless legs syndrome (RLS), or Willis–Ekbom disease, is a sensorimotor neurological disorder characterized by an irresistible urge to move the legs, typically with uncomfortable sensations. Symptoms are characteristically worse with rest and evening and tend to lead to sleep disturbance and daytime sleepiness^[4^]. The estimated prevalence is 1.5–2.7% for disease involving symptoms that occur at least twice a week and result in moderate or severe distress^[5^]. Both IBS and RLS significantly affects quality of life, increase healthcare utilization, and are strongly correlated with psychiatric comorbidities such as anxiety, depression, and sleep disorders^[2,5,6^]. Their frequent co-occurrence indicates a shared neurobiological basis that remains under-recognized in clinical practice.

HIGHLIGHTS

• IBS and RLS frequently co-occur, suggesting a bidirectional clinical relationship.

• Shared mechanisms include iron deficiency, neurotransmitter imbalance, neuroinflammation, and gut–brain axis dysfunction.

• Female sex, sleep disturbance, and psychiatric comorbidity increase risk in both conditions.

• Overlapping pathways create potential for shared treatment strategies.

• Longitudinal and mechanistic studies are needed to clarify causality.

The etiology of RLS is still unknown, but impaired dopaminergic signaling, iron metabolism disorders, and central nervous system hyperexcitability are central mechanisms that are implicated^[4,7^].

Current literature indicates a significant correlation between IBS and RLS, and various observational studies have indicated greater prevalence of RLS in IBS patients than in the general population, such as Guo et al^[8^], who demonstrated that RLS patients are four times more likely to be affected by IBS compared with healthy individuals, and Acar et al, who also showed that RLS patients with IBS were more anxious and depressive, and suffered from poor sleep quality and more severe autonomic dysfunction than RLS patients without IBS^[9^]. Overlapping pathophysiological mechanisms are observed in both conditions, such as dysregulation of the autonomic nervous system, systemic and neuroinflammation, circadian rhythm abnormalities, and high psychiatric comorbidity such as depression and anxiety^[10^]. Sleep architecture disruption, which is also routinely seen in both RLS and IBS, also supports the hypothesis of central mechanisms shared in the causation of symptomatology^[6,11^].

Knowledge of the connection between IBS and RLS has clinical importance. Despite growing comorbidity evidence and overlapping pathophysiological mechanisms, the summarized relationship between RLS and IBS is unexplored in the literature. This review is unique in its integrative approach, combining recent work from gastroenterology, neurology, and psychiatry to emphasize a neuro-gastroenterological overlap in the two diseases. Identification of common features might contribute to early diagnosis, enhanced symptom control, and therapeutic insights into new mechanisms of action, focusing on common mechanisms. This narrative review aims to determine the epidemiological association between IBS and RLS, explore shared pathophysiological mechanisms including gut–brain axis dysfunction, microbiome alterations, neuroinflammation, and neurotransmitter dysregulation, and assess clinical implications and therapeutic overlap.

Methodology

A comprehensive search of PubMed and Google Scholar was conducted from 2015 to 2025 to identify suitable literature with the keywords “IBS,” “irritable bowel syndrome,” and “restless leg syndrome,” with a detailed search strategy in Table 1. The titles and abstracts of relevant articles were screened independently by 2 authors, and only full-text papers were included in this narrative review. References of identified studies were examined to identify further relevant studies. We found 48 studies published that fulfilled our inclusion criteria up to 2025 (Fig. 1).

Table 1.

Search strategy of included literature.

Items	Specification
Date of search	19 June 2025
Databases	PubMed and Google Scholar (for gray literature)
Search terms used	PubMed: (Irritable bowel syndrome OR IBS OR “Irritable Bowel Syndrome”[Mesh]) AND (restless leg syndrome OR RLS OR Willis-Ekbom disease OR “Restless Legs Syndrome”[Mesh]) AND (Adults OR “Adult”[Mesh])
	Google Scholar: Irritable bowel syndrome, or IBS, and Restless leg syndrome
Timeframe	Jan 2015 to June 2025
Eligibility criteria	Inclusion criteria: (1) adult population, (2) peer-reviewed articles with full text available, (3) available in English language, (4) the stated aim is to evaluate the relationship between restless leg syndrome and irritable bowel syndrome, (5) had clearly stated aim(s) and objectives
	Exclusion criteria: (1) in non-human subjects, (2) exclusively involving children, (3) pregnant women, (4) non-English language, (5) articles not primarily focused on irritable bowel syndrome and restless leg syndrome, (6) conference proceedings, editorials, commentaries, opinions, and modeling studies, (7) articles that did not contain clinical study findings, such as clinical trial protocols with no patient outcomes, (8) articles from the year 2015.

Figure 1.

PRISMA 2020 flow diagram illustrating the literature search and selection process. Following database searches (2015–2025) and screening, 48 studies met the inclusion criteria and were included in the review.

Abstracts, conference proceedings, articles with no patient enrollment and without clinical trial protocols, articles involving pregnant women or children, and articles not focused on IBS and RLS were excluded.

Overview of IBS

IBS, which affects approximately 11% of the global population, is characterized by chronic gastrointestinal (GI) dysfunction and was previously considered a functional disorder of the GI tract, but recent studies have recognized IBS as neurologically based^[12^]. Given the strong association between the gut and brain (the microbiota–brain axis), this bidirectional communication is mediated in part by biogenic amines that affect the CNS through circulation in the blood, and the severity of IBS depends on many factors, including immune and hypersensitivity gut-brain pathways^[13,14^]. The IBS Severity Scoring System (IBS-SSS) was employed to determine the severity of IBS symptoms, and the severity was divided into three categories: mild (75–174), moderate (177–299), and severe (300–500)^[15^]. Table 2 summarizes previous literature on IBS and RLS.

Table 2.

Overview of the existing literature on IBS and RLS.

	Study ID	Study design	Sample size (n)	Study characteristics	Findings	Limitations
	Bjorn et al, 2021	Cross-sectional	2634	IRLSSG Criteria for RLS: adults ≥18 years old (no other inclusion and exclusion criteria)	Significantly higher prevalence of RLS in IBS group (21.8% vs. 13.6%, P = 0.009).	Self-reporting data; no questions about mental health conditions in the questionnaire
	Sanjay et al, 2021	Case report	2	Rome III and Rome IV criteria of IBS	Clinical patterns and treatment overlap; further research is needed	Reported treatment response in just two patients is insufficient to conclude the RLS and IBS association
				IRLSSG criteria for RLS
	Yung Chu et al, 2019	Cohort	82 311	Adults ≥20 years; newly diagnosed IBS; matched controls	Moderate to strong association: IBS increases RLS prevalence by nearly 2-fold (HR 1.91)	The NHIRD dataset lacked clinical details such as IBS subtype classification and RLS severity, neuroimaging, or laboratory confirmation, making it impossible to distinguish between idiopathic and secondary RLS; missing psychological, sleep quality, and behavioral information, which may influence RLS risk.
	Michael et al, 2019	Cross-sectional	1751	61-item questionnaire modified based on patient/general feedback	RLS mentioned as an additional reported symptom; no specific data or analysis on IBS-RLS association provided	The sample is predominantly female, which may cause bias.
	Mustafa et al, 2020	Case–control	206	Inclusion: adults >18 years; diagnosed RLS/WED with digestive complaints; Exclusion: Neurological and rheumatic diseases and sleep disorders	Moderate to strong association: among the GIT disorders, IBS is listed as having high RLS prevalence	Cross-sectional design limits the ability to evaluate endoscopic indications and the impact of post-endoscopy treatments on RLS/WED symptoms
	Akif Acay et al, 2016	Cross-sectional	218	2012 revised IRLSSG criteria for RLS	Clear positive association; IBS is linked to increased RLS risk (8.9% vs. 3.7%); confirms higher likelihood despite slightly lower rates than prior studies.	Small sample size; reliance on self-reported diagnostic tool may cause reporting bias
	Bilgehan Atılgan et al, 2018	Prospective case–control	216	IRLSSG criteria for RLS; Rome III criteria for IBS; Exclusion criteria applied (neurological, systemic, infectious, and cognitive conditions).	Strong positive association: IBS is significantly more prevalent in pRLS patients (46.6% vs. 12.5%), and IBS did not influence RLS severity.	Small sample size; reliance on self-reported questionnaires for autonomic dysfunction and IBS diagnosis rather than objective measures

GIT, gastrointestinal tract; HR, hazard ratio; IBS, irritable bowel syndrome; IRLSSG, International Restless Legs Syndrome Study Group; NHIRD, National Health Insurance Research Database; RLS, restless legs syndrome; WED, Willis–Ekbom disease. A P-value of <0.05 was considered statistically significant where reported. Study characteristics and findings are summarized as reported in the original publications.

Subtypes

IBS is divided into four subtypes based on the prominent stool pattern. These include IBS-D (diarrhea), IBS-C (constipation), IBS-M (mixed), and IBS-U (unclassified) ^[16^]. Subtypes are slightly affected by variations in gut microbiota diversity, except for IBS-D, where there is not much shift in microbiota^[17^]. Different subtypes of IBS are associated with varying levels of comorbidities such as depression and anxiety. Among them, IBS-M has been associated with higher levels of depression, but the prevalence of depression is highest in IBS-C^[18^]. In post-infectious IBS, the risk of occurrence varies among types: IBS-D 46.3%, IBS-C 17.6%, IBS-M 33.3%, and other/unknown 2.8%^[19^].

Diagnostic criteria

The Rome criteria are diagnostic for IBS and categorize the condition according to specific factors.

Clinical features are based on a biophysiological framework. There is a complex relationship.

Interactions exist between components such as the gut microbiota, signaling pathways, and dysregulation of the CNS. Rome III had been in use in previous years; however, it was modified into Rome IV after 10 years^[20^]. The term “abdominal discomfort” (Rome III) was dropped, and one requirement of the Rome IV criteria is the presence of abdominal pain for at least 1 day a week. In comparison with Rome IV-negative participants, the Rome IV-positive population has a greater tendency to be female and younger, and they were also more often recruited from secondary/tertiary care. Additionally, the percentage of anxiety and depression was higher in Rome IV-positive participants.

Participant ^[16^]. If we explore the criteria in greater detail, known as the Rome IV criteria, they state that abdominal pain must have been reported once a week for more than 6 months, and that at least two of the three characteristics stated below are observed^[12^]: defecation-related pain, associated with changes in the frequency of bowel movements and/or stool appearance^[13,14,20^].

Comorbidities

Upon reviewing associated comorbidities, sexual dysfunction serves as one of the most.

Frequently occurring medical and psychological comorbidities in IBS patients.

On the contrary, the quality of life (QOL), which measures subjective well-being, is lower in women with irritable bowel syndrome because of sexual dysfunction. Women that have previously been in, or are presently in, engagements are more likely to have IBS. This finding is in line with a study that demonstrated that married people had a higher prevalence of IBS compared with those who are not married^[20^]. The current study’s result suggests that people with IBS have a significantly higher prevalence of bipolar disorder than patients without IBS^[21^]. On analysis, insomnia is also present as a comorbidity in IBS, as it has been proposed that increased intra-abdominal pressure causes abdominal discomfort while we sleep. Abdominal pain or discomfort can arise from the natural activation of GI motility during rapid eye movement (REM) sleep, which explains its link to insomnia as a comorbidity in IBS^[15^]. Similarly, endometriosis is another comorbidity associated with IBS, characterized by chronic inflammation, abdominal pain, and dyspareunia. These symptoms can be shared with IBS, which overlaps with endometriosis in accordance with the Rome III diagnostic criteria. 59.8% of women with endometriosis have been diagnosed with IBS; however, 28.4% of women without endometriosis have positive findings of IBS, which further supports a connection between the two ^[22,23^].

Pathophysiology of IBS

Genetic susceptibility

Even though the genetic predisposition in IBS is complex, studies offer contradictory findings. Some suggest that genes play an important role in IBS pathogenesis^[24^], and others say that the genetic contribution remains moderate^[25^]. Sequencing of the SCN5A gene in 584 IBS patients in previous research found mutations in 2.2% of diagnosed individuals^[26^]. Polymorphisms in the TNFSF15 and TNFα genes have also been found to be associated in IBS patients^[27^]. Additionally, HTR3A and HTR3E genes are linked to the risk of diarrhea-predominant IBS (IBS-D)^[28^].

Immune system imbalance

Low-grade mucosal inflammation is present in patients with IBS. In one of the prior studies, mast cells and CD3-positive lymphocytes were found to be increased on colonic biopsy, specifically in the recto-sigmoid and descending colon. Intestinal permeability and the stimulation of visceral hypersensitivity are enhanced by mediators such as histamine and tryptase that are released by the aforementioned cells^[29^]. Elevated proinflammatory markers, such as IL-6, IL-8, TNF, and IL-1β, and reduced anti-inflammatory markers like IL-10, are present in the systemic and mucosal cytokine profiles, which show dysregulated immune signaling^[30^]. Polymorphisms in cytokine genes and toll-like receptors link the genetic predisposition to immune imbalance and increased barrier permeability, as evidenced by a meta-analysis^[31^]. Chronic, subtle immune activation contributes to symptom generation through epithelial disruption and gut-brain axis dysfunction, which will be explained later.

Disturbance in the microbiota

One component of the complex pathogenesis of IBS is microbial dysbiosis, which includes reduced diversity and a significant shift in gut bacterial composition. Beneficial bacteria like Bifidobacterium, Lactobacillus, and Faecalibacterium prausnitzii are decreased, while pathogenic groups such as Enterobacteriaceae and Bacteroides are increased^[32^]. Elevated levels of Prevotella and reduced levels of butyrate-producing microbes are observed in diarrhea-predominant IBS, which correlate with visceral hypersensitivity in animal models^[33^]. Loss of butyrate-producing microbes impairs mucosal integrity and modulates gut-brain signaling via short-chain fatty acid production. Furthermore, proinflammatory cytokines such as IL-6 are produced by Enterobacteriaceae and Streptococcus species in these cases^[34^]. These microbial imbalances can disrupt gut function, promote low-grade inflammation, and influence motility and sensation through the gut-brain axis (Fig. 2).

Figure 2.

Illustration of distinct and shared pathophysiological mechanisms of restless legs syndrome (RLS) and irritable-bowel syndrome (IBS), including genetic factors, iron deficiency, immune imbalance, microbiota disturbance, and gut–brain axis disruption.

Role of intestinal infections

Post-infectious IBS (PI-IBS), a form of IBS that develops after an episode of acute infectious gastroenteritis, is triggered by intestinal infections^[35^]. Clinical studies related to prevalence show that 4–36% of individuals develop PI-IBS following bacterial, viral, or protozoal infections, with Campylobacter jejuni, Salmonella, Shigella, and Escherichia coli being the most common microbes^[36,37^]. Approximately 10–20% of cases are caused by Campylobacter jejuni, Salmonella, Escherichia coli, Shigella, Clostridioides difficile, norovirus, and Giardia^[38^]. Following the infection, long-term alterations occur in gut function. There is continuous low-grade inflammation with invasion of lymphocytes and macrophages into the intestinal mucosa. These cells release inflammatory mediators such as IL-1β, IL-6, TNF-α, and IL-8, which excite the enteric nervous system and lead to visceral hypersensitivity, a key point in IBS pathophysiology^[39^]. This persistent inflammatory response can also cause a reduction in beneficial bacteria such as Lactobacillus and Bifidobacterium and an increase in pathobionts like Enterobacteriaceae and Prevotella^[40^]. As a result, both the enteric nervous system and central nervous system (CNS) are affected, causing symptoms like enhanced pain perception, anxiety, and depression^[41^].

Physiological stress

The pathogenesis of IBS is incomplete without the mention of the role of physiological stress in the onset and exacerbation of symptoms. Acting through various pathways of the gut-brain axis, stress activates the hypothalamic-pituitary-adrenal (HPA) axis, which leads to increased cortisol and other stress hormones. These changes affect gastrointestinal motility and intestinal permeability and promote low-grade inflammation ^[42,43^]. Symptoms such as pain, bloating, and altered bowel habits are exacerbated^[44,45^]. Emerging data from neuroimaging studies have shown that brain regions involved in pain perception and emotional regulation, such as the amygdala and anterior cingulate cortex, exhibit altered activity in patients with IBS ^[46^].

Significance of serotonin

A key player in understanding the pathology of IBS is serotonin (5-hydroxytryptamine, or 5-HT), as it plays an important role in regulating gastrointestinal motility, secretion, and sensation. Its significance lies in the fact that 90–95% of the body’s serotonin is produced in the gut. Therefore, abnormalities in serotonin signaling are evident across subtypes of IBS. Patients with IBS-D often show increased postprandial serotonin release, which leads to urgency and accelerated transit, whereas constipation-predominant IBS (IBS-C) may have reduced serotonin availability, causing delayed motility^[47,48^]. Additionally, in IBS, disruptions in the expression of the serotonin reuptake transporter (SERT) have also been observed, contributing to prolonged serotonin signaling and increased visceral hypersensitivity^[49^].

Recent research has provided convincing evidence that blocking mast cells, COX-2, or the prostaglandin E₂ (PGE₂) receptor prevents SERT reduction. These findings indicate that downregulation of SERT is mediated by mast cells, which, upon activation, release PGE₂^[50^].

Overview of RLS

Around 7% of the worldwide population has been estimated to be suffering from RLS, but the clinical presentation of RLS is 2.5% of the population, while the rest are asymptomatic^[51^]. RLS is a prevalent sleep disorder characterized by an urge to move the legs while lying down or at rest, particularly at night, and is relieved by activity, e.g., walking. Irrespective of periodic systemic iron investigations, decreased central iron reserves remain a potential factor associated with RLS, indicating alterations in homeostatic processes. In a similar manner, dopaminergic system modifications caused by RLS lead to elevated circadian dopaminergic variability ^[52,53^]. RLS symptoms are commonly reported by individuals with depression and suicidal ideation^[54^]. From the perspective of comorbidities, these commonly include systemic iron deficiency, renal failure with uremic neuropathy, pregnancy, multiple sclerosis, etc., and ongoing research demonstrates that RLS has a higher mortality rate in women due to sympathetic hyperactivity in association with cardiovascular and cerebrovascular death^[53^]. Additionally, ADH and RLS may correlate with each other due to bidirectional symptomatology, as RLS presents with sleep fragmentation and insomnia, which are shared by ADH, with a reported prevalence of 26% for sleep disorders and 6.7% for RLS^[55^].

Subtypes

Based on etiology, RLS is divided into two types.

Primary

These are mostly idiopathic, commonly affect middle-aged individuals, and their progression is attributed to genetic variations involving genes such as BTBD9, MEIS1, and MAP2K5, which run in families as an autosomal dominant trait, as well as dopaminergic and iron dysregulation^[56^].

Secondary

A variety of conditions, including iron deficiency anemia, pregnancy, and end-stage renal disease, can give rise to secondary RLS without genetic or familial predisposition^[56^].

Diagnostic criteria

The International Restless Legs Syndrome Study Group (IRLSSG) established original diagnostic criteria for RLS in 1995 and updated them in 2002, with the goal of increasing the number of comprehensive studies to be included, which was accomplished by adding three to four questions to the older criteria^[57^]. In 2012, the IRLSSG further modified the criteria by including five additional components, which state: (1) a desire to move the legs, often accompanied by unpleasant sensations in the legs; (2) symptoms that worsen during periods of rest or inactivity; (3) partial or complete relief by movement; (4) symptoms that are worse in the evening or at night than during the day; and (5) the above features are not solely accounted for by another medical or behavioral condition^[55,58,59^]. On the other hand, the IRLSSG criteria are also used as a rating scale that measures disease severity and treatment effectiveness; however, in some cases they do not adequately assess the quantity and quality of symptoms, for which the gold standard is polysomnography^[4^].

Sleep and quality of life

Sleep quality may be severely affected by RLS, as neuroimaging investigations and analyses of cerebrospinal fluid and post-mortem tissue have demonstrated that patients with RLS have dysregulated circadian dynamics due to reduced uptake of fluorine – fluorine-18-L-dihydroxyphenylalanine (¹⁸F-DOPA), which plays a role in dopaminergic dysregulation, leading to effects on the sleep–wake cycle^[60^]. Secondly, children usually complain of daytime sleepiness and nocturnal sleep difficulties due to RLS, which, because of dysesthesias, affects their daily routine. Additionally, patients with RLS have a poor quality of life^[61^]. Moreover, there has consistently been considerable emphasis on how chronic sleep loss affects life; for example, long-term sleep deprivation, especially untreated RLS, can impair memory consolidation and increase the risk of diabetes and hypertension, and is associated with cognitive deficits comparable to those observed after just one night of sleep deprivation^[4^].

Pathophysiology of RLS

Genetic factors

The pathogenesis of RLS involves several complex, interrelated mechanisms. Large genetic studies, called genome-wide association studies (GWAS), were conducted that identified various genetic alterations in five regions of the human genome. These regions include the genes MEIS1, BTBD9, PTPRD, MAP2K/SKOR1, TOX3/BC034767, and one area on chromosome 2 that is located between genes (an intergenic region), marked by the genetic variant called rs6747972^[62^].

Iron deficiency

In RLS, brain iron insufficiency is the key pathological feature. The substantia nigra has been found to have significantly reduced iron levels, given its involvement in primary dopamine production and movement regulation. Additionally, the putamen and caudate, structures that contribute to voluntary motor functions, have been found to show lower iron concentrations. More recent studies have revealed low iron concentrations in the thalamus as well^[63^]. This suggests that RLS is associated with other conditions that show iron deficiency, such as pregnancy and end-stage renal disease^[62^].

Myelin loss

Earlier research used postmortem analysis of brains from RLS patients and voxel-based morphometry (VBM) to test the hypothesis that iron insufficiency in RLS leads to decreased myelin synthesis in the brain. These investigations confirmed the hypothesis by showing impaired myelin integrity. The analysis of myelin proteins revealed a notable 25% reduction in the expression of the three proteins, MBP, PLP, and CNPase, compared to controls^[64^].

Role of dopamine

Studies on RLS suggest altered dopamine transporter (DAT) activity. A study concluded that subjects diagnosed with RLS had a significant decrease in DAT binding activity in certain brain areas (such as the striatum and putamen), leading to reduced dopamine reuptake^[65^]. Consequently, reduced DAT binding causes increased dopamine in the synaptic cleft^[66^]. This imbalance results in an urge to move the legs, discomfort, and sleep disruption in patients.

Shared mechanism of RLS and IBS

RLS and IBS are two distinct, common conditions with characteristic clinical manifestations that affect the nervous system and gastrointestinal tract, respectively. Current literature highlights overlapping pathophysiological mechanisms and shared neuroimmune, biochemical, and microbiota-related pathways.

Genetic susceptibility and environmental influences

Several loci associated with RLS, such as MEIS1, BTBD9, and PTPRD, have been identified in genome-wide studies. This suggests a link between RLS and neurodevelopmental and iron regulatory pathways^[67–69^]. Similarly, evidence of polymorphisms in genes involved in immune regulation, such as TNFSF15, and in neurotransmission has been observed in IBS^[70^].

Environmental factors, including infections, stress, and dietary factors, may trigger or exacerbate symptoms of both conditions^[71^].

Low iron levels

Iron insufficiency is a common part of the pathological mechanism of both IBS and RLS, so similar mechanisms like altered neurotransmission, immune activation, and sensory dysfunction occur in both conditions. In RLS, iron deficiency in the brain impairs dopamine synthesis and receptor regulation, leading to sleep disturbances^[72,73^]. Likewise, IBS patients often show iron deficiency due to factors like malabsorption or gut inflammation, which can exacerbate fatigue, visceral hypersensitivity, and gut–brain axis disruption^[74^]. Moreover, microbial composition and mitochondrial energy metabolism are also affected by iron insufficiency, amplifying the body’s neuroinflammatory and sensory responses in both pathological conditions^[75^]. Therefore, iron deficiency serves as a significant link between central and intestinal manifestations of IBS and RLS.

Neuroinflammation and immune system activation

Chronic stimulation of the immune pathways and the release of proinflammatory cytokines in both disorders have been observed. Studies on IBS have demonstrated increased levels of proinflammatory markers like interleukin (IL)-6, IL-8, tumor necrosis factor-alpha (TNF-α), and mucosal infiltration by mast cells, especially in post-infectious IBS^[37,76,77^]. The results of these alterations are increased sensitivity and dysmotility^[78^]. Furthermore, toll-like receptors (TLRs), present on the intestinal epithelium, are activated and link microbial signals to downstream inflammation, thereby forming the gut-brain axis^[78^]. Similarly, RLS is associated with the increased expression of cytokines like TNF-α and IL-1β, which suggests a pro-inflammatory state. Microglial activation, a hallmark of CNS infection, has been noted in RLS pathogenesis, and it might disturb iron homeostasis in brain regions like the substantia nigra and thalamus ^[39,69–71,76–78^]

Neurotransmitter system dysregulation

Neurotransmitter systems, particularly dopamine, serotonin, GABA, and glutamate, are a major part of the pathophysiological mechanisms in both RLS and IBS. Abnormalities in dopamine signaling lead to motor restlessness and circadian fluctuations, suggesting that the dopaminergic system is a well-established pathway in symptom generation^[79,80^]. Similarly, serotonin and dopamine play a crucial role in IBS pathophysiology. Serotonin is responsible for gut motility, secretion, and visceral sensation^[81^]. Patients with IBS-D show abnormal serotonin reuptake and dysfunctional brain-gut signaling, which lead to hypersensitivity and disturbances in bowel habits^[82^].

Imbalances in GABA and glutamate are also important in both disorders. RLS is linked to reduced GABAergic inhibition because of hyperexcitability of cortical and spinal circuits, whereas increased glutamatergic activity leads to sensory disturbances and sleep discomfort^[83^]. Likewise, glutamate and GABA dysregulation in IBS affects visceral perception and emotional responses to stimuli in the gut, resulting in chronic abdominal pain and anxiety^[84^]. Another shared neurotransmitter is norepinephrine, which regulates both sleep and intestinal motility. Dysregulation of autonomic tone and increased sympathetic activity in both IBS and RLS point toward involvement of noradrenergic pathways^[85^].

Bidirectional gut-brain communication

In IBS, the gut-brain axis is responsible for symptom generation. When visceral hypersensitivity and sensitization are increased, any stimuli from the organs are processed by the brain abnormally^[45^]. Signals coming from the gut affect the corticolimbic circuits, which are responsible for emotional regulation and pain modulation. This explains the simultaneous occurrence of psychiatric symptoms in IBS patients^[86^]. Disruption of the gut–brain axis is also evident in RLS. Earlier research has shown that the gut microbiome can influence dopaminergic function and iron metabolism, both of which are important in RLS pathogenesis^[87^].

Treatment implications

The American College of Gastroenterology has released its first clinical guidelines for managing IBS, built on the GRADE methodology (Grading of Recommendations, Assessment, Development, and Evaluations), which emphasizes evidence-based recommendations. The guidelines suggest starting with a limited trial of a low-FODMAP (Fermentable Oligosaccharides, Disaccharides, Monosaccharides, and Polyols) diet to help improve overall IBS symptoms. For patients experiencing constipation, the use of chloride channel activators and guanylate cyclase activators is recommended. In cases where diarrhea is the main issue, the antibiotic rifaximin is advised to manage symptoms. Additionally, gut-directed psychotherapy is suggested as a beneficial approach to address overall IBS discomfort. These guidelines aim to provide a more personalized and effective treatment strategy for individuals living with IBS^[88^].

Given the complex pathophysiology and multifactorial nature of IBS, there are a variety of pharmacological and non-pharmacological approaches to treating it, such as dietary changes, lifestyle adjustments, sleep hygiene, prebiotics, and probiotics^[89^]. Generally, the first step in treating IBS is making changes to one’s lifestyle and diet – such as trying a low-FODMAP or gluten-free diet. Antispasmodics, peppermint oil, and antidepressants are among the medications used to address motility, sensation, and the gut luminal environment^[90,91^]

On the other hand, RLS still causes significant treatment challenges. According to Phillip et al, treatment choices for RLS are still limited, largely because the biological mechanisms underlying the condition remain incompletely understood. This lack of clarity makes it harder to develop effective and targeted therapies^[92^]. Nevertheless, iron supplements in iron-deficient people or medications like gabapentin, pregabalin, and certain dopamine agonists (such as pramipexole, ropinirole, and rotigotine) are first-line treatments for RLS. If the first-line therapy isn’t tolerated or fails to relieve the symptoms, second-line treatments are considered, which may involve iron through infusion or, in more severe cases, opioids like tramadol, oxycodone, or methadone^[7^]. However, a major drawback of using dopamine agonists over the long term is augmentation – a condition in which the symptoms actually become worse than they were before treatment, even though the medication initially helped – prompting a shift toward newer treatment options^[93,94^].

Weinstock et al stated that the association between IBS and RLS was first discovered in 2008^[95^]. This emerging connection highlights the overlap in their treatment strategies and supports the use of integrated treatment approaches. Shared pathophysiological features, such as small intestinal bacterial overgrowth (SIBO), iron deficiency, vitamin D metabolism, and mast cell activation, are possible targets for dual treatment^[8^] (Fig. 3).

Figure 3.

Treatment approaches for IBS and RLS, highlighting therapies specific to each and overlapping strategies, such as rifaximin, dopamine agonists, iron supplementation, and mast cell stabilizers.

In patients with SIBO, RLS symptoms can be effectively treated with rifamycin, a gut-targeted antibiotic, along with tegaserod and zinc^[96^]. This is especially significant because patients sizable IBS, particularly IBS-D, often have SIBO, which causes systemic inflammation, increased hepcidin levels (reducing iron absorption), and inflammatory mediators that lead to dopaminergic dysfunction in RLS. Moreover, dopamine agonists (pramipexole, levodopa, ropinirole, and rotigotine), which are commonly used in RLS, have also been shown to be effective in treating the symptoms of IBS through their roles in gut motility and pain modulation^[97,98^]. Additionally, iron supplements treat symptoms of fatigue and mood in IBS while also managing iron deficiency in patients with RLS, serving a dual purpose. Another important factor is mast cell activation, which induces inflammatory alterations that cause abdominal discomfort in IBS and sensory hypersensitivity in RLS. A cross-sectional study conducted by Leonard et al found that targeting this pathway with mediator blockers and mast cell stabilizers could help effectively treat both disorders^[99^].

In conclusion, greater awareness of the link between IBS and RLS may lead to integrated multidisciplinary care involving psychiatrists, neurologists, and gastroenterologists, ultimately aiming to provide more holistic and effective patient care.

Discussion

This review is on the possible correlation between RLS and IBS, and the findings were derived from a detailed analysis of observational studies, cohort data, and narrative reviews. A consistent trend is present between RLS and IBS: when one condition is diagnosed, the prevalence of the other is higher. A bidirectional relationship is present between the two chronic disorders, though the strength and type of evidence vary ^[8^]. Across included studies, the prevalence of RLS in IBS patients ranged from 8.9% to 46.6%, compared to 3–14% in control populations, with cohort studies demonstrating nearly a two-fold increased risk (HR ≈ 1.9) (101, 108, and 109). Several studies report co-prevalence rates as high as 46.6%, suggesting a substantial overlap between IBS and RLS. This overlap suggests that IBS and RLS may represent manifestations of a shared neuroimmune disorder rather than independent conditions^[100^]. National health insurance databases and disease registries, including NHIRD and IQVIA, were used to support the findings. These databases offer access to a broad population, reduce selection bias, and enhance external validity.

Co-occurrence between RLS and IBS can be explained by many overlapping mechanisms. The gut-brain axis is a bidirectional communication network between the CNS and the GI tract, and it is impaired in both disorders.

Neurological mechanisms

RLS is also known as a dopaminergic disorder. There is neuroinflammation and dysregulation of the serotonin and dopamine pathways^[101^]. Mood disorders such as depression and anxiety are common in both disorders, which suggests the involvement of central neurotransmitters in their pathogenesis^[102^].

Gastrointestinal mechanisms

In IBS, altered gut motility, immune activation, and hypersensitivity are mediated through this axis. The co-occurrence of RLS and IBS can be explained by many overlapping mechanisms. These alterations in gut motility and hypersensitivity contribute to the persistence of symptoms and reflect dysfunction within the GI tract.

Immunological mechanisms

In RLS, the problem involves central neurotransmitters and systemic inflammation. Neuroinflammation and dysregulation of serotonin and dopamine pathways are also involved. Systemic inflammation further supports the association between the two disorders and contributes to their chronic nature.

Microbiome and the gut–brain axis

The gut-brain axis is a bidirectional communication network between the CNS and GI tract, and it is disrupted in both disorders. In IBS, altered gut motility, immune activation, and hypersensitivity are mediated through this axis, while in RLS, the problem lies in central neurotransmission and systemic inflammation. This bidirectional communication reflects the involvement of both central and gastrointestinal pathways in their pathogenesis.

Strengths and limitations

Although there are limitations, the consistency with which both symptoms occur is a strength. The study includes a diverse population, ranging from outpatient clinics to nationwide health system cohorts. The observed relationship is consistent across all regions and demographics. However, subgroup analyses by age and gender remain limited in the current literature. Another strength is the inclusion of cross-sectional and longitudinal analyses. Depending on the temporal relationship, the onset of IBS may precede and predict the development of RLS.

Over-reliance on cross-sectional designs Cross-sectional study design is the most commonly adopted method, which assesses participants at a particular point in time^[103^]. This study design not only exaggerates and misinterprets trends or reverse causality but also interferes with the relationship, identifying it as associative rather than indicating cause and effect. Scarcity of large-scale randomized controlled trials (RCTs). RCTs that are high quality and large enough to generate generalizable conclusions remain limited. Observational cross-sectional work is more abundant, yet this design does not substitute for RCTs in establishing the efficacy of mechanistic pathways.

Cultural and sex-based reporting bias. A clear gender bias is present in the clinical research landscape. Females are not only under-represented but are analyzed separately in studies across all designs, including clinical trials, systematic reviews, and pharmacovigilance data^[104^]. For example, Cochrane reviews frequently fail to conduct gender-disaggregated analyses, and male subjects are the default research group^[105^]. Likewise, the cultural or geographical bias persists and is poorly represented^[106^].

There is a need for mechanistic studies. The existing literature fails to delve into the underlying biological and physiological mechanisms. Unexplained associations persist, and there is a lack of functional exploration.

Research gaps

There are several important gaps in the literature. The direction of the association is still unclear. We know that IBS predisposes patients to RLS through mechanisms of chronic inflammation or altered serotonin metabolism, but the reverse may also be true, in that RLS-related sleep disturbances or dopaminergic dysfunction could contribute to GI dysregulation. Without proper prospective studies and interventional trials, the causative pathway remains undetermined. Few studies have examined the impact of treating one condition on the course of the other. This is a crucial area for future research, given the high burden of both disorders and their impact on quality of life.

Future directions

Emerging advances in nanotechnology and precision medicine are opening new directions for understanding and managing the complex overlap between IBS and RLS. Nanocarrier-based drug delivery systems have been shown to effectively improve the bioavailability, stability, and targeted delivery of therapeutics, specifically in conditions involving the central nervous system and the gut–brain axis. In this regard, nanoparticle-assisted iron delivery may be a more effective approach to correcting both central and peripheral iron deficiency, a mechanism that plays an important role in the pathophysiology of both disorders. Moreover, microbiome-focused nanoformulations are being explored for their capacity to modulate gut microbial composition and influence metabolic signaling, which in turn may regulate neuroinflammatory responses and neurotransmitter balance. Such strategies can be a path to the simultaneous targeting of gastrointestinal, neurological, and immune components involved in disease progression. Additionally, incorporating nanomedicine with personalized therapeutic approaches may support the development of tailored, disease-modifying interventions based on individual patient profiles. However, despite these promising developments, their clinical application remains limited, and further studies are required to establish safety, efficacy, and long-term outcomes, particularly in the context of IBS–RLS comorbidity.

Conclusion

IBS and RLS frequently co-occur and appear to share overlapping mechanisms, including iron deficiency, neurotransmitter dysregulation, neuroinflammation, and gut-brain axis disruption. Current evidence suggests a possible bidirectional relationship; however, it is derived largely from observational studies, and causality remains uncertain. Recognizing this comorbidity may facilitate earlier diagnosis and more integrated patient management, although the clinical benefits of targeted therapeutic strategies require further validation. Future longitudinal and mechanistic studies are needed to clarify the shared biological pathways, establish causal relationships, and determine whether these findings can be translated into effective precision medicine approaches.

Ethical approval

Not applicable.

Consent

Not applicable.

Sources of funding

None.

Author contributions

J.F. contributed to conceptualization, writing of the original draft, and review and editing of the manuscript. R.M.U.K., F.J., A.I., and M.G. contributed to writing of the original draft. H.A., T.M., F.F., and A.S. contributed to review and editing of the manuscript. All authors read and approved the final manuscript.

Conflicts of interest disclosure

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Research registration unique identifying number (UIN)

Not applicable.

Guarantor

The corresponding author (Aalaa Saleh) accepts full responsibility for the work and the conduct of the study.

Provenance and peer review

Not commissioned, externally peer reviewed.

Data availability statement

Data available from corresponding author on appropriate request.

Acknowledgements

Not applicable.