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Systematic review and meta-analysis of calculating degree of comorbidity of irritable bowel syndrome with migraine

BioPsychoSocial Medicine volume 17, Article number: 22 (2023) Cite this article

Abstract

Background

Irritable bowel syndrome (IBS) and migraines are often comorbid each other. These disorders are likely to be bidirectionally linked through the gut-brain axis and share several underlying mechanisms including central nervous system sensitization. However, quantitative analysis of comorbidity was not reported enough. The aim of this systematic review and meta-analysis was to calculate the present degree of comorbidity of these two disorders.

Methods

A literature search was performed searching for articles describing IBS or migraine patients with the same inverse comorbidity. Pooled odds ratios (ORs) or hazard ratios (HRs) with 95% confidence intervals (CIs) were then extracted. The total effect estimates were determined and presented by random effect forest plots for the group of articles with IBS patients with migraine and the group of articles on migraine sufferers with comorbid IBS separately. The average results of these plots were compared.

Results

The literature search resulted in initial 358 articles and final 22 articles for the meta-analysis. The total OR values obtained were 2.09 [1.79 – 2.43] in IBS with comorbid migraine or headache, 2.51 [1.76 – 3.58] for migraineurs with comorbid IBS and an overall HR of 1 .62 [1.29 – 2.03] was found for cohort studies of migraine sufferers with comorbid IBS. A similar expression of a selection of other comorbidities was found in IBS and migraine patients, especially for depression and fibromyalgia a strong similarity was found in their expression rate.

Conclusions

This systematic review with meta-analysis was the first to combine data on IBS patients with comorbid migraine and migraineurs with comorbid IBS. The fact that closely related existential rates were observed between these two groups should be used as motivation for future research to further investigate these disorders for why this similarity occurs. Mechanisms involved in central hypersensitivity such as genetic risk factors, mitochondrial dysfunction and microbiota are particularly good candidates. Experimental designs in which therapeutic methods for these conditions can be exchanged or combined may also lead to the discovery of more efficient treatment methods.

Introduction

Chronic pain disorders have a strong impact to impair an individual's quality of life. A large proportion of the global population is experiencing this impact as the prevalence of these disorders ranges from 10% to as much as 50% [1]. Irritable bowel syndrome (IBS) and migraine are conditions recognized under this category. With a worldwide prevalence of 4.1–11%, IBS is one of the most common disorders of gut-brain interaction (DGBI) [2]. Migraine also has a notable impact as it has been confirmed to be the 6th most debilitating condition based on the number of years lost due to disability [3]. In general, IBS and migraine are considered to be two separate clinical disorders due to their anatomically distant locations with associated local symptoms, thus dividing them into the gastrointestinal (GI) disorder or the neurological disorder [4]. This perspective may require change, as previous literature has pointed to similarities between the disorders in several aspects, supporting the idea of classifying them within an overarching disorder group [4,5,6]. Both IBS and migraine show similarity in prevalence, female dominance in patients, psychosomatic dysfunction, somatic pain symptoms, comorbidities and possible underlying biochemical mechanisms related to the development of central hypersensitivity [4, 7]. Numerous studies have reported that it is common for IBS patients to have comorbid migraine and vice versa that migraine patients exhibit IBS symptoms [8,9,10,11,12]. This supports the notion of these clinical manifestations coexisting rather than coincidentally occurring together.

A theoretical foundation that underlies their connection must first be established. The gut-brain axis has been discussed as the bridging link between these seemingly distinct GI and neurological disorders [13]. There exists a bidirectional relationship between the central nervous system (CNS) and the enteric nervous system (ENS) that innervates the GI tract [14]. Influence of communication along brain-gut axis includes not only the ENS and CNS but also the other parts of the autonomic nervous system (ANS), the immune system, the hypothalamic–pituitary–adrenal (HPA) axis, and the gut microbiota [15]. Through these systems, the brain can regulate gut functions related to sensory information processing, motility and secretion, and vice versa, the gut also influences brain functions such as cognition and pain perception [13, 14].

There are some resemblances in neural pathophysiology of IBS and migraine. IBS patients show borderline abnormality in electroencephalography [16]. Migraine also shows abnormal electroencephalogram in 61% of the patients [17]. These dysfunctions may be related to abnormality of some neurotransmitters. Serotonin (5-hydroxytryptamine: 5-HT) is one of candidates of responsible transmitters because 5-HT3 receptor antagonist is effective on patients with IBS with predominant diarrhea [18] and ones with migraine [19]. The other receptors including 5-HT1A, 5-HT1B/D, and 5-HT1F receptors have been shown to have a function leading to the reduction of pain [20, 21]. Several studies also indicated an abnormally increased activation of N-methyl-D-aspartate (NMDA) receptors in individuals suffering from IBS and migraine [22]. This could trigger hyperexcitability of central neurons involved in pain perception, which in turn may lead to the emergence of pain signals in inappropriate situations [7, 22]. These phenomena support rationale of calculating quantitative comorbidity of IBS and migraine.

Recognizing the coexistence of IBS and migraine could lead to considerations of distributing therapy targets across both the gut and brain. This in turn could lead to higher disease management efficiencies in the treatment-resistant patients [23]. To date, however, only unidirectional relationships have been described for these conditions in articles, such as IBS patients with comorbid migraine or migraineurs with comorbid IBS. This systematic review with meta-analysis aims to demonstrate an equal existential magnitude of comorbid migraine in IBS patients as comorbid IBS in migraineurs. We hypothesized that the prevalence, indicated in odds ratio (OR) with a confidence interval (CI) of 95%, of comorbid migraine in IBS patients would be close to equal to that of comorbid IBS in migraine patients. We also hypothesized that IBS and migraine share the resemble mechanism through other comorbidities.

Methods

Sources and search strategies

A literature search of articles reporting the simultaneous presence of both IBS and migraine in participants was conducted using literature databases PubMed, Cochrane Library, and Google Scholar. The search terms were "irritable bowel syndrome" and "migraine" of which MeSH terms and tiab-terms were specifically created for the PubMed search to have a wider reach (Supplementary Fig. 1). Our strategy included three rounds of selection, where firstly the filtering process of literature was based purely on the title, secondly the abstract and finally the articles underwent full review.

Literature selection and data extraction

Based on the inclusion criteria set for this review, English-language articles with cohort, case–control or cross-sectional design were accepted. The desired publication date was after 2003 and the article quality score had to be at least 4, calculated as described by Zia et al., [2]. With regard to the sample characteristics, studies with a sample size of at least 50 per group were included. Participants with IBS and comorbid migraine or headache and migraineurs with comorbid IBS were eligible. Any subtype of IBS was allowed as well as migraine with or without aura. If the study analysed multiple DGBIs, only IBS data was used. For data extraction, it was important that OR or hazard ratio (HR) with 95% CI were reported along with the quantitative or percentage sample sizes of the cases and controls. Exclusion criteria allowed for the rejection of animal studies, studies with participants younger than 18 years of age, and studies that reported migraine by means of a mean somatic symptom score.

Data to be extracted from the literature were author name, date of publication, country of origin, study design, sample size, recruitment method, diagnosis method for IBS and migraine or headache, sample mean age, percentage of women and men, OR or HR with 95% CI and the extent to which other comorbidities occurred in percentages.

Statistical analysis

Review Manager version 5.4 software was used for the current meta-analysis. Effect estimates were determined using generic inverse variance methodology yielding pooled OR with 95% CI and standard error for each study with a case–control or cross-sectional design. A random effect forest plot was selected to represent this data, if the I2 test indicated high heterogeneity between studies with a value greater than 75%. The HR with 95% CI values and standard errors was obtained from the cohort studies. Again, a separate random effect model was plotted in case the I2 test value was higher than 75%. In addition, funnel plots were created for all study groups to see if there was publication bias. Finally, to assess the extent to which the same comorbidities are present, a bar chart was made with the average rates of occurrence of various comorbidities in IBS and migraine patients. For each comorbid disorder, the overall presence was determined by averaging the incidence values of all studies that reported it. The strength of similarity was determined by the difference between the percentages of the IBS and migraine groups for each comorbid condition, with < 5% indicating strong similarity and < 10% indicating moderate similarity.

Results

The current systematic review with meta-analysis assessed the possible coexistence of IBS and migraine by observing an equal presence of comorbid migraine or headache in IBS and IBS comorbidity in migraineurs. A total of 358 articles emerged from the literature search. After the first two selection rounds based on title and abstract, 28 papers remained. These papers then underwent a full review. Subsequently, using the predetermined inclusion and exclusion criteria, the total number of papers ultimately used for analysis amounted 22 (Fig. 1) [9, 12, 24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43].

Fig. 1
figure 1

Flow diagram of literature selection procedure

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Clustering of the studies into different groups took place depending on pathological features and study design. The first group contained 10 articles exclusively with IBS patients who had comorbid migraine or headache [24,25,26,27,28,29,30,31,32,33]. In the second group, there were 9 articles on migraine sufferers with comorbid IBS [34,35,36,37,38,39,40,41,42]. These were all case–control or cross-sectional studies from which OR with 95% CI and standard errors were extracted and pooled (Table 1). Separately, the HR with 95% CI was extracted and pooled from 3 cohort studies of migraine sufferers who developed comorbid IBS [9, 12, 43].

Table 1 Overview of main characteristics and extracted data from articles included in this systematic review
Full size table

Comparison of comorbidity rate in IBS and migraine patients

The total OR with 95% CI resulting from the random effect forest plot analysis of IBS patient group with comorbid migraine or headache was 2.09 [1.79 – 2.43] (Fig. 2). This indicated a higher preference for comorbid migraine or headache in IBS subjects than not having these comorbidities. With the associated value of 78% for the I2 test, it can be confirmed that there was a high heterogeneity between these studies. This supported the choice for the random effect rather than the fixed effect model. However, for these articles within this category, the asymmetric funnel plot did indicate publication bias (Fig. 3) [24,25,26,27,28,29,30,31,32,33].

Fig. 2
figure 2

Forest plot for comorbid migraine or headache in IBS patients. Odds ratio (OR, red small box) and 95% confidence interval (CI, horizontal bar) in 10 case–control and cross-sectional studies were plotted. Black diamond showed calculated value of OR and 95%CI

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Fig. 3
figure 3

Funnel plot presenting association between IBS and migraine or headache comorbidity. Open circle showed 10 case–control and cross-sectional studies

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For the category of migraine sufferers with comorbid IBS, the random effect model resulted in an overall OR value of 2.51 [1.76 – 3.58] (Fig. 4). This showed a stronger presence of comorbid IBS in migraine sufferers. Also for this model, with an I2 test value of 98%, a high heterogeneity between these studies was observed, making the random effect analysis the most optimal method. The respective funnel plot showed an even stronger asymmetry in this migraine with comorbid IBS group, which can be interpreted as strong publication bias (Fig. 5) [34,35,36,37,38,39,40,41,42].

Fig. 4
figure 4

Forest plot for comorbid IBS in migraine patients. Odds ratio (OR, red small box) and 95% confidence interval (CI, horizontal bar) in 9 case–control and cross-sectional studies were plotted. Black diamond showed calculated value of OR and 95%CI

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Fig. 5
figure 5

Funnel plot presenting association between migraine and IBS comorbidity Open circle showed 9 case–control and cross-sectional studies

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Development of comorbid IBS in longitudinal studies

The random-effect forest plot of the cohort studies of migraineurs with comorbid IBS showed an overall HR with 95% CI of 1.62 [1.29 – 2.03] (Fig. 6). It can be argued from this that comorbid IBS is most likely to develop in migraine sufferers over time. High heterogeneity was observed between these cohort studies, as indicated by an I2 test result of 87%. For this reason, a random effect model was chosen. To check for publication bias, a funnel plot was again used and the asymmetry confirmed publication bias for these 3 studies (Fig. 7) [9, 12, 43].

Fig. 6
figure 6

Forest plot for the development of comorbid IBS in migraine patients. Risk ratio (RR, red small box) and 95% confidence interval (CI, horizontal bar) in 3 cohort studies were plotted. Black diamond showed calculated value of RR and 95%CI

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Fig. 7
figure 7

Funnel plot presenting association between migraine and IBS comorbidity development. Open circle showed 3 cohort studies

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Prevalence comparison of other common comorbidities in IBS vs migraine patients

To assess whether IBS and migraine may be part of a spectrum of centrally mediated hypersensitivity disorders, the possible presence of other comorbidities was determined. Depression, panic, anxiety, dyspepsia, peptic ulcer disease (PUD), fibromyalgia, and chronic fatigue syndrome (CFS) were all reported as comorbid in both IBS and migraine patients in multiple studies included in this systematic review (Additional file 2). In particular, depression (migraine – 23.07%, IBS – 25.66%) and fibromyalgia (migraine – 12.90%, IBS – 11.10%) showed strong similarity (< 5% difference) in their comorbid occurrence for both IBS as migraineurs. Also notable were the occurrence of dyspepsia (migraine – 23.99%, IBS – 17.48%) and PUD (migraine – 15.14%, IBS – 6.76%) with moderate similarity (< 10% difference) in their values between the IBS and migraine groups (Fig. 8) [9, 12, 24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43].

Fig. 8
figure 8

Prevalence of similar comorbidities in IBS and migraine patients. Prevalence (%) of comorbidity of depression, panic disorder, anxiety disorder, functional dyspepsia, peptic ulcer disease (PUD), fibromyalgia, and chronic fatigue syndrome (CFS) in migraine (green) and IBS (purple) patients were shown

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Discussion

To our knowledge, this systematic review with meta-analysis was the first to analyze the coexistence of IBS and migraine by combining reciprocal data from IBS patients suffering from comorbid migraine with migraine patients who have comorbid IBS. A total of 22 studies were obtained, of which 10 contained IBS patients with comorbid migraine or headache and for the migraine group with comorbid IBS there were the remaining 12 studies [9, 12, 24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43]. The combined data provided a relatively large sample size of 286,993 IBS patients and 53,520 migraine patients. The results showed closely related OR values for case–control and cross-sectional studies reporting IBS and migraine comorbidity in both directions. These values were 2.09 [1.79 – 2.43] in IBS with comorbid migraine or headache and 2.51 [1.76 – 3.58] for migraineurs with comorbid IBS. The later value is comparable to OR 2.49 (95% CI, 2.22–2.78; I2, 42%) reported by another meta-analysis of prevalence of IBS in migraineurs [5]. With an overall HR of 1.62 [1.29 – 2.03], the cohort studies also showed evidence that migraineurs have a higher tendency to develop comorbid IBS, possibly supporting the claim of their coexistence. Finally, a similar expression of a selection of other comorbidities especially depression and fibromyalgia was found in IBS and migraine patients. Our study suggests that IBS and migraine have strong association with a comparable OR value greater than 2.

Several theories may explain this co-occurrence of IBS and migraines. These include mechanisms involved in central nervous system sensitization. Therefore, previous studies suggested that IBS and migraine could be good candidates for clinical reclassification as 'central hypersensitivity spectrum disorders' (CHSDs) [7, 23].

Genes

The first theory explains this phenomenon through genetic influences. For IBS, genetic effects are expressed as a result of familial aggregation of risk genes [44]. Interesting candidates are genes involved in pain sensitization such as; 5-HT, substance P, nitric oxide (NO), noradrenaline, proteases, dynorphins and opiates [45]. IBS with predominant constipation has been found to have a significant association with alpha 1 and 2 variants of the adrenoceptor [46]. Another example more specific to abdominal pain symptoms is that there is a possible link to mutations in the SCN5A gene, which provide instructions for the construction of Na + channels in neuronal membranes. One study reported that 2% of IBS patients had a missense mutation on the G298S side of this gene [47]. A relationship between IBS and genes involved in the regulation of serotonin is often discussed in the literature. Several gene variants of 5-HT appear to play a role in the type and severity of symptoms [44, 48]. 5-HT3 appears to fulfill a function as a proalgesic, especially in IBS with predominant diarrhea. Another risk factor for IBS is the homozygous presence of the 5-HT2 allele [44]. Connections have also been made with serotonin regulation in migraine. Specifically, migraine with aura was associated with polymorphism in the serotonin transporter-linked promoter region (5-HTTLPR) [46, 48]. On the other hand, migraine without aura appeared to be influenced by the D4 dopamine receptor gene [44]. Lastly, nociceptive receptors such as transient receptor potential cation channel subfamily V member 1 (TrpV1) are also receiving attention as they may play a role in various functional pain disorders, including IBS and migraine [45]. Homozygous allelic variant rs222747 in TrpV1 was associated with higher glutamate activation, which in turn may be translated into increased cortical excitability in migraine sufferers [45]. Also, higher expression of TrpV1 at nerve fiber sites was correlated with visceral pain symptoms in IBS [49]. Shared gene analysis for IBS and migraine should be considered in the future.

Mitochondria

Interestingly, the article by Meeus (2013) reported the influence of mitochondrial dysfunction in conditions such as fibromyalgia and CFS, both of which have been found in this review to be common comorbidities in both IBS and migraine patients [50]. It was described herein that oxidative and nitrosative stress-induced mitochondrial dysfunction could lead to decreased ATP availability in central neurons. As a downstream effect, NMDA receptor hypersensitivity arises in these cells. This results in long-term potentiation of pain signalling and eventual generalized central hypersensitivity to pain [50]. Not surprisingly, this relationship between mitochondrial dysfunction and an increased response to centrally mediated pain has also been reported in articles looking directly at IBS and migraine [51,52,53].

Microbiota

The final theory to discuss regarding hypersensitivity in the central nervous system is due to the gut microbiota. IBS patients are known to have altered gut microbiota and their products [54]. Exacerbation of IBS symptoms is associated with rapid changes in gut microbiota with dynamic changes in the metabolites of neurotransmitters which are related to metabolic activity of gut microbiota [55]. Systematic review on gut microbiota disclosed decreased Faecalibacterium and Bifidobacterium as well as increased Lactobacillaceae, Bacteriodes, and Enterobacteriaceae in IBS patients [56]. Patients with migraine also have altered gut microbiota with increasing Firmicutes, especially the “unfriendly” Clostridium species and reduced Faecalibacterium prausnitzii, Bifidobacterium adolescentis, and Methanobrevibacter smithii with altered metabolites of neurotransmitters [57]. Especially concerning serotonin, fecal microbiome and their metabolome signatures reflect stress and serotonin metabolism in IBS patients [58]. Experiments conducted mainly in rodents have shown that the microbiota is involved in the development of not only IBS model [59] but also migraine model [60]. There was a study that extended nitroglycerin and antibiotics treatment in wild-type mice exacerbated the migraine phenotype through upregulation of tumor necrosis factor- ɑ (TNF- ɑ) [60] as well known in IBS patients [15]. Pain phenotypes in this migraine model were relieved by the administration of probiotic treatment [60] as previously reported in IBS patients [61]. More investigation to clarify underlying mechanisms on gut microbiota in IBS and migraine is warranted.

Concerning to the gut micro-organisms, a scientifically interesting question occurred to us. Infection of Helicobacter pylori (Hp) has strong associations with PUD and dyspepsia. As shown in Fig. 8 of this study, IBS and migraine patients had similar expression rates of PUD and dyspepsia. Does Hp relate to comorbidity of IBS and migraine? The first meta-analysis (2019) failed to establish a link between IBS and Hp infection [62]. The second systematic review and meta-analysis (2021) asserted Hp infection as a risk factor for the development of IBS and that therapeutic elimination of Hp reduces the developmental risk for IBS [63]. The third systematic review and meta-analysis (2022) showed lack of distinct association between IBS and Hp infection but positive association between IBS with diarrhea and Hp infection [64]. A meta-analysis pooling data from 5 case–control studies confirmed a higher frequency of Hp infections in migraine sufferers compared to controls [65]. This increased prevalence was again observed in a case–control study conducted in 2021, although migraine symptoms did not appear to be affected by Hp infections [66]. These studies suggest that the effects of Hp infection go beyond gastroduonenal pathologies. We previously reported that atrophic gastritis patients with positive anti-Hp antibody showed higher risk of depression than atrophic gastritis patients with negative anti-Hp antibody [67]. Interestingly, genome-wide association study of UK biobank revealed positive link between neural cell adhesion molecule (NCAM)-1 gene as a high risk loci for depression and IBS or Hp-relevant PUD/gastroesophageal reflux disease [68]. Large scale analyses including microorganisms, genes, and social environment should be performed in the near future.

This study has several limitations. First, this systematic review mainly included cross-sectional studies. Since these only provide insight into correlations between variables at a specific point in time, no conclusions can be made about any causal relationships between IBS and migraine. Since the mean pooled OR with 95% CI data was used as the main measure for answering the hypothesis, the possible influence of other factors cannot be denied and therefore coincidental co-existence of IBS and migraine cannot be completely rejected. It is therefore strongly recommended that future research should focus on conducting a systematic review with meta-analysis on this topic including cohort studies exclusively. Second, some studies in this review and meta-analysis used old diagnostic criteria. The switch from Rome III to Rome IV criteria has led to a lower prevalence of Rome IV-IBS than that of Rome III-IBS [69]. The newest diagnostic criteria of migraine are the 3rd edition of The International Classification of Headache Disorders [70]. However, headaches were also accepted as a measure of migraine, even though they are not clinically equivalent to migraine. Therefore, it should be considered that the study population was not homogenous. Third, we could not find several cohort studies with identifying migraine in IBS patients. This indicates the need for future research to perform a study design in which IBS patients are observed longitudinally, with the development of migraine being one of the variables of interest. Finally, the comparison of other comorbid disorders in IBS and migraine patients that we performed may be considered to be rough estimation. Although more detailed analysis on this paradigm was reported earlier [2], all studies in the past used independent criteria to identify the comorbid diseases. More accurate estimation is required in the future.

Conclusion

This systematic review with meta-analysis was the first to combine data on IBS patients with comorbid migraine and migraineurs with comorbid IBS. The fact that closely related existential rates were observed between these two groups should be used as motivation for future research to further investigate these disorders for why this similarity occurs. Mechanisms involved in central hypersensitivity such as genetic risk factors, mitochondrial dysfunction and microbiota are particularly good candidates. Experimental designs in which therapeutic methods for these conditions can be exchanged or combined may also lead to the discovery of more efficient treatment methods.

Abbreviations

ANS:

Autonomic nervous system

CHSDs:

Central hypersensitivity spectrum disorders

CNS:

Central nervous system

CFS:

Chronic fatigue syndrome

95% CI:

95% Confidence interval

DGBI:

Disorders of gut-brain interaction

ENS:

Enteric nervous system

GI:

Gastrointestinal

HR:

Hazard ratio

5-HTTLPR:

5-Hydroxytryptamine transporter-linked polymorphic region

HPA:

Hypothalamic–pituitary–adrenal

IBS:

Irritable bowel syndrome

NO:

Nitric oxide

NMDA:

N-methyl-D-aspartate

ORs:

Odds ratios

PUD:

Peptic ulcer disease

5-hydroxytryptamine:

5-HT: serotonin

TrpV1:

Transient receptor potential cation channel subfamily V member 1

TNF-ɑ:

Tumor necrosis factor- ɑ

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Acknowledgements

Authors express sincere gratitude to the double degree program of Tohoku University and Maastricht University.

Funding

This work was supported by JSPS KAKENHI Grant Number 19K22589, SRF, AMED-Moon Shot 20356688. No competing interests declared.

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Authors and Affiliations

  1. Department of Behavioral Medicine, Tohoku University Graduate School of Medicine, 2-1 Seiryo, Aoba, Sendai, 980-8575, Japan

    Tatvan S. Todor & Shin Fukudo

  2. Maastricht University, Maastricht, Netherlands

    Tatvan S. Todor

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Contributions

Tatvan S. Todor and Shin Fukudo designed the study, assessed the data, and wrote the manuscript. Tatvan S. Todor performed analyses of statistics. Shin Fukudo checked the epidemiological rationale of analyses. All authors provided important scientific comments on data analysis and manuscript content. All authors have approved the final version of the article, including the authorship list.

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Correspondence to Shin Fukudo.

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Supplementary Information

Additional file 1: Supplementary Figure 1.

MeSH and tiab terms based on IBS and migraine or headache created for the literature search in PubMed.

Additional file 2: Table S1.

Overview articles reporting other comorbidities in both IBS and AQ migraine patients.

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Todor, T.S., Fukudo, S. Systematic review and meta-analysis of calculating degree of comorbidity of irritable bowel syndrome with migraine. BioPsychoSocial Med 17, 22 (2023). https://doi.org/10.1186/s13030-023-00275-4

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Keywords

BioPsychoSocial Medicine

ISSN: 1751-0759

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