Causal Relationship Between Inflammatory Bowel Disease and Neuropsychiatric Disorders: A Bidirectional Mendelian Randomization Study

Inflammatory bowel disease (IBD) encompasses a range of chronic, recurrent conditions characterized by inflammation of the gastrointestinal tract, affecting more than 2.5 million individuals across Europe (Molodecky et al. 2012). The two main types of IBD are ulcerative colitis (UC) and Crohn's disease (CD). IBD is believed to arise from a combination of genetic susceptibility and an abnormal immune response, leading to a persistent pro‐inflammatory state in the gut (Liu et al. 2015, Hedin et al. 2019). While the inflammation is most prominent within the gastrointestinal tract, there is increasing recognition of the extraintestinal manifestations of IBD, particularly its connection to neuropsychiatric symptoms (Ferro and Oliveira Santos 2021). A growing body of evidence highlights the importance of the gut‐brain axis, a complex bidirectional communication network that links the gastrointestinal system with the central nervous system (CNS). This pathway is increasingly regarded as a crucial mediator connecting gastrointestinal inflammation with CNS function and dysfunction (Gracie et al. 2019).

Neuropsychiatric symptoms, including mood disturbances, anxiety, and cognitive impairments, are notably more common in individuals with IBD compared to the general population. Reported prevalence rates of these symptoms in IBD patients range from 0.25% to 47.5%, with considerable variability depending on the study population and diagnostic methods (Ferro and Oliveira Santos 2021). Notably, studies have explored the bidirectional relationship between IBD and various neuropsychiatric conditions. For instance, research by Bisgaard has suggested a potential two‐way interaction between IBD and depression, where both the presence of IBD and depressive symptoms may influence each other (Bisgaard et al. 2022). Similarly, evidence supports a bidirectional association between IBD and multiple sclerosis (MS), suggesting that inflammatory processes in the gut may contribute to the development or exacerbation of MS, and vice versa (Kosmidou et al. 2017). There is also some indication that IBD may increase the risk of developing Parkinson's disease (PD), though the mechanisms behind this association remain unclear (Zhu et al. 2019).

Despite these findings, the degree of association between IBD and neuropsychiatric disorders remains inconsistent across studies, with significant variations in the reported strength and direction of these relationships (Fairbrass et al. 2022, Barberio et al. 2021). One of the key challenges in understanding this complex interaction is the unclear directionality of the association. While it is plausible that active IBD could lead to or exacerbate neuropsychiatric symptoms, it is equally possible that pre‐existing neuropsychiatric conditions may trigger or worsen IBD symptoms. This bidirectional relationship underscores the need for further research to unravel the complex interplay between IBD and neuropsychiatric health, potentially leading to more targeted treatment strategies that address both the gastrointestinal and psychological aspects of these diseases (Bonaz and Bernstein 2013).

Mendelian randomization (MR) is an epidemiological approach that utilizes genome‐wide association study (GWAS) data to infer causal relationships between exposure factors and outcomes (Skrivankova et al. 2021). MR is becoming a significant driving force in the field of neuropsychiatric diseases (Wang et al. 2022, Sun et al. 2023, Sun et al. 2024, Sun et al. 2024, Ma et al. 2024). Since genetic variants are randomly assigned at birth and do not change with disease occurrence and progression, the MR approach effectively overcomes the inherent limitations of observational studies (reverse causation, confounding factors) (Yuan and Larsson 2022).

Here, we aim to employ MR analysis to comprehensively assess the potential causal relationships between IBD (including UC and CD) and seven major neuropsychiatric disorders: major depressive disorder (MDD), bipolar disorder (BD), schizophrenia (SCZ), Alzheimer's disease (AD), PD, MS, and amyotrophic lateral sclerosis (ALS), thereby enhancing our understanding of the pathophysiology of the gut‐brain axis and informing related therapeutic strategies.

In this study, we utilized MR methods to investigate the causal relationships between IBD and seven major neuropsychiatric disorders. Our analysis revealed that IBD and CD have positive causal effects on MDD and SCZ, and similarly, SCZ is positively correlated with an increased risk of IBD and UC. There is a bidirectional positive association between IBD, UC, and MS, while CD has a positive causal effect on MS. In contrast, we found no evidence supporting the causal effects of MDD, BD, AD, PD, or ALS on IBD or UC. Sensitivity analyses further reinforced the robustness of the MR estimates. These results provide novel insights into the complex interplay between gastrointestinal and neuropsychiatric conditions, highlighting the potential role of inflammatory processes in the pathogenesis of both. The association between IBD and depression has been extensively documented (Bisgaard et al. 2022). The prevalence of depressive symptoms in individuals with IBD ranges from 21% to 25.2% (Barberio et al. 2021, Mikocka‐Walus et al. 2016). Studies have shown that depression is a significant comorbidity of IBD, with a cohort study revealing an increased risk of new‐onset depression, particularly around ten years following an IBD diagnosis (Bisgaard et al. 2023). This highlights the chronic and long‐term impact that IBD can have on mental health. Our analysis further supports this relationship, indicating that both IBD and CD may elevate the risk of developing depression. However, no evidence was found to support a causal relationship in the reverse direction, suggesting that depression may not significantly contribute to the onset of IBD. These findings underscore the need for clinicians to monitor and address mental health in IBD patients, especially those with a long history of the disease.

In the current MR estimates, IBD is associated with an increased risk of SCZ, and vice versa; however, the association between CD, UC, and SCZ is inconsistent. Previous cohort studies have demonstrated a significant association between SCZ and an increased risk of subsequent IBD, although this was conducted in an East Asian population (Sung et al. 2022). A European cohort study involving 7,704 participants found that individuals with a history of any autoimmune disease had a 45% increased risk of developing SCZ, with a higher prevalence of SCZ among patients compared to controls (Eaton et al. 2006). This suggests a bidirectional risk between SCZ and autoimmune diseases, which was not observed in our study. Additionally, the relationship between BD and IBD remains perplexing. Research by Kao et al. indicated that patients with IBD are more likely to develop BD (Kao et al. 2019). However, a large cohort study based on a Danish population confirmed no association between IBD and BD, either before or after the diagnosis (Bisgaard et al. 2023), which is consistent with the findings of our MR analysis.

Neurological disorders demonstrate significantly higher prevalence among IBD patients. Accumulating evidence substantiates elevated rates of headache disorders, migraine, and myasthenia gravis in this population (Leitão et al. 2021, Leitão et al. 2025, Gondim Fde et al. 2014, Rocha et al. 2017). A prior comparative study revealed substantially greater incidence of neuromuscular disorders in both CD and UC patients relative to those with gastritis or dyspepsia (Gondim Fde et al. 2015). Furthermore, emerging data implicate peripheral neuropathy as a clinically relevant extraintestinal manifestation of IBD (Gondim Fde et al. 2015, Gondim et al. 2005). Regarding neurological disorders, we identified a bidirectional association between IBD and MS. Notably, causal relationships were also confirmed between UC, CD, and MS. A meta‐analysis by Kosmidou et al. investigated the correlation between MS and IBD (Kosmidou et al. 2017). The study found that individuals with either IBD or MS exhibited a 50% increased risk of developing comorbidities associated with MS or IBD, respectively. However, this finding was not replicated in patients with CD or UC (Kosmidou et al. 2017). Additionally, several previous studies suggested that IBD may increase the risk of PD (Weimers et al. 2019, Villumsen et al. 2019), while others found IBD, CD, and UC to be associated with a lower risk of PD (Camacho‐Soto et al. 2018). Growing evidence highlights the significant role of inflammation in AD (Chen and Holtzman 2022). Research by Aggarwal et al. supports the notion that IBD could be an independent risk factor for AD (Aggarwal et al. 2023). Another study found that IBD patients have a higher risk of developing dementia within 15 years compared to non‐IBD patients (Zingel et al. 2021). However, similar to previous MR analyses (Zeng et al. 2023), we did not observe an association between IBD and PD or AD. Unlike earlier MR analyses (Li et al. 2021), our study does not support a positive association between IBD and ALS. Currently, there is a lack of observational evidence regarding the association between IBD and ALS, and further research is warranted. Notably, our study utilized larger summary datasets, providing new genetic‐level evidence for the causal relationships between IBD and neurodegenerative diseases.

Overall, our study underscores the association between IBD and its clinical subtypes with neuropsychiatric disorders. The current findings diverge from some observational evidence, potentially due to design flaws such as confounding factors in previous studies. Our MR analysis typically reflects lifetime effects, which may result in discrepancies compared to the short‐term follow‐up periods of cohort studies.

This study has several advantages. Firstly, we systematically assessed the potential causal associations between IBD and its subtypes with seven major neuropsychiatric disorders, enhancing the understanding of both extra‐intestinal manifestations of IBD and the intestinal manifestations of neuropsychiatric disorders. Notably, the use of MR methods effectively reduced confounding factors and reverse causation interference. Additionally, sensitivity analyses reinforced the robustness of our MR analysis. However, our study has some limitations. Firstly, our results are limited to European populations, and the findings may not apply to other populations. Second, since the GWAS summary statistics utilized in this study lacked individual‐level sex‐stratified data (which were not disclosed in the original studies), we were unable to conduct sex‐specific stratification analyses or investigate potential nonlinear causal relationships. Third, current evidence remains insufficient to comprehensively elucidate the genetic effects on both IBD subtypes and neuropsychiatric disorders, necessitating further investigation to unravel this complex interplay. Thus, further research is needed to validate our results.

In summary, our results support the potential causal effects between IBD and its subtypes and neuropsychiatric disorders. These findings provide genetic evidence further highlighting the interaction between the gut‐brain axis. Clinicians should take this into account to develop appropriate clinical management strategies. Further research is needed to validate our findings.

Jiawei Lei: writing – original draft, writing – review and editing, methodology, formal analysis, validation, visualization, data curation, software, and investigation. Liping Gong: writing – review and editing, visualization, and methodology. Shan Wei: methodology, visualization, writing – review and editing. Junshan Deng: conceptualization, writing – original draft, writing – review and editing, supervision, and resources.

The authors have nothing to report.

All data used in this study were made publicly available in the original GWAS study, and appropriate patient consent and ethical approval were obtained.

The authors declare no conflicts of interest.