Metabolic mediators of the causal relationship between inflammatory bowel disease and allergic rhinitis: insights from Mendelian randomization

Abstract

Inflammatory bowel disease, including Crohn’s disease and ulcerative colitis, is associated with various comorbidities, such as allergic diseases like allergic rhinitis. However, the causal relationship and potential metabolic mechanisms remain unclear. This study investigates the association between inflammatory bowel disease and allergic rhinitis, focusing on potential metabolic mediation through Mendelian randomization analysis. A two-sample Mendelian randomization analysis was conducted using datasets from European populations to evaluate the relationships between inflammatory bowel disease, Crohn’s disease, ulcerative colitis, and allergic rhinitis. Additionally, 212 potential mediating metabolites were analyzed to explore metabolic mechanisms. Horizontal pleiotropy was excluded, and mediation analysis identified specific metabolites mediating these effects. Results revealed a significant association between inflammatory bowel disease, Crohn’s disease, and allergic rhinitis, while ulcerative colitis showed no significant impact. Further analysis confirmed a unidirectional causal relationship from inflammatory bowel disease and Crohn’s disease to allergic rhinitis. Metabolite analysis identified 91 significant metabolites, with 67 showing consistent effects. Notably, erythritol, 1-myristoyl-2-arachidonoyl-GPC, and the 3-methyl-2-oxovalerate to 4-methyl-2-oxopentanoate ratio exhibited significant mediation effects. These findings highlight a significant causal link between inflammatory bowel disease, particularly Crohn’s disease, and allergic rhinitis, mediated by specific metabolites, offering new insights and potential targets for clinical interventions.

Introduction

Allergic rhinitis is a common chronic immune disorder primarily triggered by inhaled allergens, manifesting as symptoms such as nasal itching, sneezing, runny nose, and nasal congestion.^(1,2) Globally, the incidence of allergic rhinitis has been steadily rising, particularly in urbanized areas. This condition not only significantly reduces patients’ quality of life but is also closely associated with other respiratory diseases, such as asthma and sinusitis, leading to increased use of healthcare resources.⁽³⁾ Additionally, allergic rhinitis negatively affects children’s learning abilities and adults’ work efficiency, contributing to a considerable burden on society and the economy.^(4,5) As a result, allergic rhinitis has become a key focus of attention in global public health, extending beyond being merely a health issue.

Inflammatory bowel disease (IBD) refers to a group of serious chronic gastrointestinal disorders,⁽⁶⁾ primarily comprising Crohn’s disease^(7,8) and ulcerative colitis.^(9,10) These conditions are characterized by recurrent inflammation of the gastrointestinal tract, leading to symptoms such as abdominal pain, diarrhea, weight loss, and fatigue. IBD profoundly affects patients’ quality of life, increasing the need for hospitalization and surgery,^(11,12) and is associated with elevated psychological stress and a higher risk of depression. Due to its complex pathogenesis and treatment challenges, IBD imposes a significant economic burden on both patients and society.^(13,14) Although Crohn’s disease and ulcerative colitis are both classified as IBD, they differ in the affected regions and pathological features. Crohn’s disease can affect any part of the gastrointestinal tract, from the mouth to the anus, and often presents with segmental lesions, where affected areas alternate with healthy tissue. The inflammation typically involves the entire thickness of the intestinal wall, potentially leading to complications such as fistulas, strictures, and perforations. In contrast, ulcerative colitis mainly affects the colon and rectum, with inflammation usually confined to the mucosal layer and presenting in a continuous pattern. Despite similarities in clinical manifestations and treatment strategies, the pathogenesis, disease progression, and risk of complications differ significantly between the two conditions.^(15,16)

Existing research has begun to explore the potential link between IBD and allergic rhinitis.^(17,18) These studies suggest that the incidence of allergic rhinitis is significantly higher among IBD patients compared to the general population, indicating a possible underlying connection between the two conditions. However, IBD consists of two main types: Crohn’s disease and ulcerative colitis. While they share many clinical similarities, their pathogenic mechanisms differ considerably. It remains unclear which type of IBD is more closely associated with allergic rhinitis. Gaining clarity on this issue is crucial for accurately identifying and understanding the relationship between these diseases.

In addition to identifying the relationship between IBD and allergic rhinitis, the causal relationship and potential metabolic mechanisms linking the two conditions warrant further investigation. Most existing studies are observational, making it difficult to eliminate confounding factors, thus preventing the establishment of a clear causal relationship. More importantly, even if an association exists, the specific metabolic pathways remain unclear. Given the distinct pathogenic mechanisms of Crohn’s disease and ulcerative colitis, each may influence the onset and progression of allergic rhinitis through different metabolic pathways. Therefore, exploring the causal relationship between IBD and allergic rhinitis, along with the potential metabolic mechanisms involved, could not only shed light on the interaction between these diseases but also provide crucial scientific insights for future therapeutic strategies.

Mendelian randomization (MR) is a research method that uses genetic variations as instrumental variables to assess the causal relationship between exposure factors and disease outcomes.⁽¹⁹⁾ Since genetic variations are determined at conception and are not influenced by many confounding factors, the MR method offers high reliability in causal inference, particularly in complex biomedical research, providing clearer evidence of causality. In this study, we applied the MR approach to investigate the causal relationship between IBD, including Crohn’s disease and ulcerative colitis, and allergic rhinitis. Additionally, we analyzed the potential metabolic links between these diseases. Through this method, our study aims to offer new insights into the complex relationships between IBD-related diseases and allergic rhinitis, uncover their potential biological mechanisms, and provide a scientific foundation for future clinical interventions.

Methods

Bidirectional MR

MR is an epidemiological method used to assess the causal relationship between exposure factors and disease or health outcomes. This study is based on the four core assumptions of MR: 1) the genetic variants are significantly associated with the exposure (relevance assumption); 2) the genetic variants are independent of potential confounders (independence assumption); 3) the genetic variants affect the outcome only through the exposure (exclusivity assumption); and 4) the instrumental variables are sufficiently strong to avoid bias from weak instruments (instrument strength assumption).⁽²⁰⁾

This study aims to evaluate the causal relationship between the two main types of IBD—Crohn’s disease and ulcerative colitis—and allergic rhinitis using a bidirectional two-sample MR approach. First, we analyze the causal relationship between IBD, Crohn’s disease, and ulcerative colitis as exposures and allergic rhinitis as the outcome using relevant genetic variants as instrumental variables. In the reverse analysis, we treat allergic rhinitis as the exposure and IBD and its subtypes as the outcomes, further exploring the causal associations between the two conditions (Fig. 1).

Fig. 1.

Causal pathways between IBD-related diseases and allergic rhinitis explored through Mendelian randomization. The image elements are provided by Figdraw.

Metabolite-mediated MR

To investigate potential metabolic mechanisms, this study applied a two-step MR approach to identify relevant metabolites and evaluate their mediating effects.⁽²¹⁾ In the first step, genetic variants (single nucleotide polymorphisms, SNPs) associated with IBD were used as instrumental variables to identify metabolites that have a significant influence on IBD. In the second step, genetic variants linked to these metabolite levels were used as instrumental variables to assess their impact on allergic rhinitis. By analyzing the relationship between these genetic variants and the risk of allergic rhinitis, we aimed to determine whether these metabolites act as mediators between IBD and allergic rhinitis.

The primary estimation method used in this analysis was the inverse variance weighted (IVW) method.⁽²²⁾ To ensure the robustness and reliability of the results, additional methods were employed, including MR Egger,⁽²³⁾ the weighted median method,⁽²⁴⁾ the simple mode, and the weighted mode. Furthermore, to assess the potential influence of pleiotropy on the findings,⁽²⁵⁾ we conducted tests for horizontal pleiotropy, which helped confirm the validity of the instrumental variables and the robustness of the overall analysis.

Data sources for IBD-related diseases

All data used in this study were obtained from the integrative epidemiology unit (IEU) Open GWAS database (https://gwas.mrcieu.ac.uk/).⁽²⁶⁾ Among the 55 datasets related to IBD, Crohn’s disease, and ulcerative colitis, incomplete or redundant datasets were excluded. After screening for data specific to European populations, 37 IBD-related datasets were ultimately included. These consist of 10 datasets related to IBD, 9 datasets on Crohn’s disease, and 18 datasets on ulcerative colitis.

Allergic rhinitis

We initially selected the largest GWAS dataset available for use as the exposure variable. If any of the following conditions arose, alternative large-scale GWAS datasets were considered: (1) insufficient number of instrumental variables; (2) presence of population stratification or incomplete data; or (3) failure to pass horizontal pleiotropy tests. After applying these screening criteria, the dataset for allergic rhinitis that met all the necessary requirements (ebi-a-GCST90013920)⁽²⁷⁾ was ultimately chosen.

Results

Causal relationship between IBD-related diseases and allergic rhinitis

In this study, a total of 55 datasets related to IBD, including Crohn’s disease and ulcerative colitis, were collected. After screening, 37 datasets from European populations were included for MR analysis. Using allergic rhinitis as the outcome, two-sample MR analyses were conducted for each dataset. The results showed significant effects of IBD and Crohn’s disease on allergic rhinitis (Fig. 2), while no significant effect was found for ulcerative colitis. Further odds ratio (OR) analyses indicated that both IBD and Crohn’s disease are risk factors for allergic rhinitis, suggesting that these conditions may contribute to the development of allergic rhinitis (Table 1).

Fig. 2.

Scatterplot of Mendelian randomization analysis on the causal effects of IBD-related diseases on allergic rhinitis risk. This graph illustrates the relationship between the impacts of SNPs on IBD, Crohn’s disease, and their effects on allergic rhinitis risk. Each point represents an SNP, with the various lines indicating causal effect estimates derived from different MR methods.

Table 1.

Causal effects of IBD-related diseases on allergic rhinitis estimated using MR-IVW, MR-weighted median, and MR-Egger

Exposure	Sample size	Outcome	MR-IVW			MR-weighted median			MR-Egger		MR-Egger intercept	Intercept p value
			OR (95% CI)	p		OR (95% CI)	p		OR (95% CI)	p
Inflammatory bowel disease	65,642	Allergic rhinitis	1.05 (1.01–1.08)	0.01		1.04 (1.02–1.06)	0.001		1.05 (0.97–1.14)	0.192	−0.0009	0.84
Inflammatory bowel disease	34,652	Allergic rhinitis	1.04 (1.01–1.08)	0.012		1.04 (1.02–1.06)	0.001		1.05 (0.98–1.14)	0.188	−0.0011	0.785
Inflammatory owel disease	75,000	Allergic rhinitis	1.04 (1.00–1.07)	0.033		1.03 (1.00–1.05)	0.027		1.00 (0.93–1.09)	0.921	0.0041	0.384
Crohn’s disease	20,883	Allergic rhinitis	1.04 (1.00–1.07)	0.039		1.03 (1.01–1.04)	0.001		1.02 (0.94–1.10)	0.689	0.0049	0.576
Crohn’s disease	20,883	Allergic rhinitis	1.06 (1.02–1.09)	0.001		1.04 (1.02–1.06)	<0.001		1.04 (0.96–1.13)	0.357	0.0021	0.716
Crohn’s disease	30,740	Allergic rhinitis	1.05 (1.02–1.08)	0.001		1.03 (1.01–1.05)	<0.001		1.02 (0.96–1.08)	0.594	0.0046	0.309
Crohn’s disease	51,874	Allergic rhinitis	1.06 (1.03–1.10)	<0.001		1.04 (1.03–1.06)	<0.001		1.05 (0.97–1.15)	0.247	0.0015	0.794
Ulcerative colitis	417,932	Allergic rhinitis	1.02 (0.98–1.06)	0.373		1.03 (1.00–1.06)	0.036		1.02 (0.94–1.12)	0.602	−0.0008	0.921
Ulcerative colitis	27,432	Allergic rhinitis	1.01 (0.97–1.06)	0.523		0.99 (0.97–1.01)	0.284		0.92 (0.82–1.04)	0.191	0.0192	0.101
Ulcerative colitis	26,405	Allergic rhinitis	1.00 (0.99–1.02)	0.552		1.00 (0.99–1.01)	0.924		0.98 (0.95–1.02)	0.342	0.0054	0.158

Additionally, reverse MR analysis revealed that allergic rhinitis has no significant effect on IBD or Crohn’s disease, indicating a unidirectional causal relationship where IBD and Crohn’s disease act as causal factors for allergic rhinitis. All results were free from the influence of horizontal pleiotropy (Fig. 3). It is noteworthy that, although Crohn’s disease and ulcerative colitis are both major forms of IBD, only Crohn’s disease was associated with allergic rhinitis, warranting further investigation into the underlying reasons for this difference.

Fig. 3.

Funnel plot from Mendelian randomization analysis of the impact of IBD-related diseases on allergic rhinitis. The plot displays the estimated effects of various SNPs on allergic rhinitis under different obesity indicators (IBD and Crohn’s disease). The lines represent effect estimates from the IVW and MR Egger methods, used to assess heterogeneity and pleiotropy. The symmetry around the central line indicates the robustness of the results.

Exploration of metabolic mechanisms linking IBD and Crohn’s disease to allergic rhinitis

Based on metabolite information from Chen et al.,⁽²⁸⁾ combined with literature review and statistical analysis strategies, we identified 212 potential mediating metabolites, forming a candidate metabolite pool. Using MR analysis, we assessed the association between all metabolites in the pool and allergic rhinitis. The results indicated that 91 of these metabolites had a significant effect on allergic rhinitis (Fig. 4). Further OR analysis and horizontal pleiotropy tests showed that 67 of these 91 metabolites demonstrated consistent effects across multiple analytical methods.

Fig. 4.

Forest plot of the effects of 67 metabolites with significant impact on allergic rhinitis. Each metabolite’s effect is represented by a dot, with the horizontal axis showing the OR, indicating the magnitude and direction of the metabolite’s impact on allergic rhinitis. The color of the dots represents the direction of the association, with blue indicating a negative correlation and red indicating a positive correlation. The size of the dots reflects the significance of the p values, with larger dots denoting higher significance.

Next, we conducted mediation MR analyses on the IBD and Crohn’s disease datasets to evaluate their relationship with allergic rhinitis-related metabolites. The results showed that IBD significantly influenced the levels of metabolites such as Erythritol, 1-myristoyl-2-arachidonoyl-GPC (14:0/20:4), X-18921, and 2'-O-methylcytidine. In addition, Crohn’s disease significantly affected the ratios of 3-methyl-2-oxovalerate and 4-methyl-2-oxopentanoate. These findings suggest that these metabolites may serve as intermediaries in the metabolic mechanisms linking IBD-related diseases and allergic rhinitis, thereby facilitating the interplay between these two conditions.

Metabolite mediation analysis of IBD and Crohn’s disease in triggering allergic rhinitis

This study employed mediation MR to verify the mediating effects of certain metabolites between IBD-related diseases and allergic rhinitis (Fig. 5). The results demonstrated consistent mediation effects of metabolites such as Erythritol, 1-myristoyl-2-arachidonoyl-GPC (14:0/20:4), and X-18921 across various IBD datasets, with a high degree of robustness. Further OR analyses revealed that levels of Erythritol and 1-myristoyl-2-arachidonoyl-GPC (14:0/20:4) were negatively associated with IBD, while positively associated with the severity of allergic rhinitis. Conversely, X-18921 showed a positive association with IBD and a negative association with allergic rhinitis severity, indicating a contrasting metabolic pathway compared to the other two metabolites.

Fig. 5.

Sankey diagram of the metabolite mediation pathways between IBD, Crohn’s disease, and allergic rhinitis. This diagram illustrates the mediating effects of key metabolites on the relationship between IBD, Crohn’s disease, and allergic rhinitis. The left side represents the disease categories (IBD and Crohn’s disease), the middle displays the metabolite, and the right side represents allergic rhinitis. The thickness of the flows indicates the magnitude of the OR, with thicker flows representing stronger effects. Red flows indicate positive correlations, while blue flows indicate negative correlations.

In the analysis of Crohn’s disease, the ratio of 3-methyl-2-oxovalerate to 4-methyl-2-oxopentanoate exhibited a significant mediation effect between Crohn’s disease and allergic rhinitis (p<0.05), with a mediation proportion of 2.63% (0.00535%, 5.25%). 3-Methyl-2-oxovalerate has been reported to be significantly elevated in the serum of IBD patients, particularly those with Crohn’s disease.⁽²⁹⁾ OR analyses indicated that this metabolite ratio was positively correlated with both Crohn’s disease and allergic rhinitis, suggesting that as Crohn’s disease worsens, the 3-methyl-2-oxovalerate to 4-methyl-2-oxopentanoate ratio increases, and the severity of allergic rhinitis also escalates (Table 2).

Table 2.

Mediation effects of the metabolite between IBD-related diseases and allergic rhinitis

Exposure	Metabolite	Outcome	Mediated proportion	p
Inflammatory bowel disease	Erythritol levels in elite athletes	Allergic rhinitis	−2.63% (−5.65%, 0.382%)	0.087
Inflammatory bowel disease	1-myristoyl-2-arachidonoyl-GPC (14:0/20:4) levels	Allergic rhinitis	−2.88% (−6.67%, 0.922%)	0.1377
Inflammatory bowel disease	X-18921 levels	Allergic rhinitis	−2.96% (−6.94%, 1.02%)	0.1452
Inflammatory bowel disease	2'-o-methylcytidine levels	Allergic rhinitis	−1.38% (−3.76%, 1%)	0.257
Crohn’s disease	3-methyl-2-oxovalerate to 4-methyl-2-oxopentanoate ratio	Allergic rhinitis	2.63% (0.00535%, 5.25%)	0.0495

Discussion

This study conducted a comprehensive MR analysis to investigate the causal relationship between IBD-related diseases and allergic rhinitis, further exploring the mediating role of metabolites in this association. Our findings indicate a significant causal relationship between IBD, particularly Crohn’s disease, and allergic rhinitis, while ulcerative colitis did not show a significant association with allergic rhinitis. These results provide new evidence for understanding the role of IBD, especially Crohn’s disease, in the development of allergic rhinitis, contributing to a deeper understanding of the complex pathological mechanisms underlying allergic diseases.

Firstly, the results of this study clearly demonstrate that IBD, particularly Crohn’s disease, is a significant risk factor for allergic rhinitis. In the 37 European population datasets included, two-sample MR analyses revealed that both IBD and Crohn’s disease have a significant impact on allergic rhinitis, whereas ulcerative colitis did not exhibit such an effect. This finding partially aligns with previous clinical observations that highlight the common comorbidity of allergic diseases among IBD patients. However, the lack of a significant association between ulcerative colitis and allergic rhinitis suggests potential biological differences between IBD subtypes in their role in triggering allergic conditions. Although both ulcerative colitis and Crohn’s disease are major forms of IBD, their underlying pathogenesis may differ significantly, warranting further investigation in future studies.

Secondly, this study further explored the metabolic mechanisms underlying the relationship between IBD-related diseases and allergic rhinitis. By screening 212 potential mediating metabolites, we established a candidate metabolite pool and evaluated the association between these metabolites and allergic rhinitis using MR analysis. The results showed that metabolites such as Erythritol, 1-myristoyl-2-arachidonoyl-GPC (14:0/20:4), and X-18921 exhibited consistent mediating effects in IBD. These findings suggest that these metabolites may serve as crucial intermediaries linking the immune response triggered by IBD to the development of allergic rhinitis.

Specifically, the levels of Erythritol and 1-myristoyl-2-arachidonoyl-GPC (14:0/20:4) were negatively associated with IBD, while positively correlated with the severity of allergic rhinitis. This finding may reflect the impact of IBD-induced inflammation on metabolite levels, which in turn exacerbates the pathological progression of allergic rhinitis. In contrast, the levels of X-18921 were positively associated with IBD but negatively correlated with the severity of allergic rhinitis, indicating an opposite pathway compared to Erythritol and 1-myristoyl-2-arachidonoyl-GPC (14:0/20:4). This complex metabolic mechanism suggests the possibility of multiple interacting biological pathways between IBD and allergic rhinitis, the specific regulatory mechanisms of which require further elucidation in future studies.

In the metabolite mediation analysis of Crohn’s disease, the ratio of 3-methyl-2-oxovalerate to 4-methyl-2-oxopentanoate exhibited a significant mediating effect. The ratio analysis indicated that as Crohn’s disease severity increased, the 3-methyl-2-oxovalerate to 4-methyl-2-oxopentanoate ratio also increased, correlating with greater severity of allergic rhinitis. This finding supports the hypothesis that Crohn’s disease may influence allergic rhinitis through specific metabolic pathways. Although the mediating effect of the 3-methyl-2-oxovalerate to 4-methyl-2-oxopentanoate ratio was relatively small (2.63%), this modest effect may still have a notable impact on disease progression, particularly in the context of long-term disease development. Isoleucine is a degradation product of 3-methyl-2-oxovalerate. In enzymology, valine-3-methyl-2-oxovalerate transaminase catalyzes the reaction between valine and 3-methyl-2-oxopentanoate.⁽³⁰⁾ This enzyme belongs to the transferase family, which is responsible for transferring nitrogenous groups. According to the literature, transaminase levels are elevated in 40–50% of Crohn’s disease patients.⁽³¹⁾ Furthermore, isoleucine has been identified as a specific biomarker for both ulcerative colitis and Crohn’s disease.⁽³²⁾

The findings of this study hold significant clinical and theoretical implications. First, given the causal and metabolic links between IBD and allergic rhinitis, clinical strategies could focus on targeting these metabolites to develop new treatments that may reduce the risk of allergic rhinitis in IBD patients. Second, the mediating effects of metabolites such as Erythritol, 1-myristoyl-2-arachidonoyl-GPC (14:0/20:4), X-18921, and the ratio of 3-methyl-2-oxovalerate to 4-methyl-2-oxopentanoate offer potential targets for future biomarker research. These metabolites not only contribute to a better understanding of the pathological mechanisms linking IBD and allergic rhinitis but may also provide new avenues for diagnosis and treatment of both conditions.

However, this study has some limitations. Although horizontal pleiotropy was ruled out, other confounding factors may still be present. Moreover, the metabolite analyses were based primarily on data from European populations, and the applicability of these findings to other ethnic groups or populations remains uncertain. Future research should incorporate data from diverse ethnicities and regions to comprehensively evaluate the causal relationship and metabolic mechanisms between IBD and allergic rhinitis.

In conclusion, this study systematically explored the causal relationship between IBD-related diseases and allergic rhinitis, as well as their potential metabolic mechanisms, using Mendelian randomization analysis. The findings indicate that IBD, particularly Crohn’s disease, is a significant risk factor for allergic rhinitis, and this relationship may be mediated through specific metabolic pathways. Although the study has identified key metabolites and their mechanisms, further research is needed to gain a deeper understanding of the specific roles these metabolites play in the context of IBD and allergic rhinitis. Future studies will contribute to a better understanding and treatment of these complex immune-related diseases, offering new insights for clinical practice.

Author Contributions

Y-YH and J-YZ conceptualized and designed the study; H-CX, J-YZ, and Y-YH acquired and vali-dated the data; Y-YH and J-YZ curated the datasets; H-CX, J-YZ, and Y-YH drafted and revised the manuscript. All authors have read and approved the final version of the manuscript.

Funding

This research was funded by National Natural Science Foundation of China, grant number 82100025.

Data Availability Statement

Data are available in a public, open-access repository. Data URLs: https://gwas.mrcieu.ac.uk; https://www.ebi.ac.uk/gwas/down-loads/summary-statistics.

Conflict of Interest

No potential conflicts of interest were disclosed.