Exploring the causal relationship between inflammatory bowel disease and Bell's palsy based on inflammatory proteins: a Mendelian randomization study

Exploring the causal relationship between inflammatory bowel disease and Bell's palsy based on inflammatory proteins: a Mendelian randomization study | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Exploring the causal relationship between inflammatory bowel disease and Bell's palsy based on inflammatory proteins: a Mendelian randomization study Daofeng Fan, Wenbao Wu, Yinjuan Chen, Qingqing Lian, Jiaqian Dai, and 3 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6043269/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background: The relationship between Inflammatory Bowel Disease (IBD) and Bell’s palsy remains unsubstantiated. This study aims to investigate the causal relationship between IBD and Bell’s palsy. Methods: Using two-sample Mendelian randomization (MR) method to explore the relationship between IBD and Bell’s palsy. We applied Bell’s palsy summary statistics from GWAS statistics for 91 inflammatory proteins and FinnGen R10 and IBD summary statistics from the International Inflammatory Bowel Disease Genetics Consortium. Results: The two-sample MR study indicates a significant positive association between IBD and Bell’s palsy (OR: 1.13, 95% CI [1.03 to 1.23], P = 0.0065) and between Crohn’s disease and Bell’s palsy (OR: 1.10, 95% CI [1.02 to 1.18], P = 0.0088). After applying Bonferroni correction, IBD remained significantly correlated with Bell’s palsy. Subsequently, the causal relationship between circulating inflammatory proteins in Bell's palsy and inflammatory bowel disease samples was reevaluated. The results of MR study between inflammatory proteins among these two diseases suggests that the C-X-C Motif Chemokine Ligand 5 (CXCL5) is a potential protective factor and interleukin_17C (IL_17C) is a risk factor for these two diseases. Conversely, Signaling Lymphocytic Activation Molecule Family Member 1 (SLAMF1) is a protective factor for Bell's palsy and a risk factor for inflammatory bowel disease. Conclusions: The findings indicate that IBD may be a risk factor for Bell’s palsy at the genetic level. CXCL5, IL_17C, SLAMF1 are possible co-acting pathways between Bell's palsy and inflammatory bowel disease. These findings may provide new targets for the treatment of both diseases. Two-sample Mendelian randomization Inflammatory bowel disease Bell’s palsy inflammatory proteins Figures Figure 1 Figure 2 Figure 3 Figure 4 1 Introduction Inflammatory bowel disease (IBD) includes a group of inflammatory disorders that affect the gastrointestinal tract, mainly Crohn’s disease (CD) and ulcerative colitis (UC) [1] . These conditions cause various symptoms linked to inflammation in the intestines, like abdominal pain, fever, vomiting, diarrhea, rectal bleeding, anemia, and weight loss [2] . The prevalence of IBD is higher in developed countries, with Europe and North America [3] . The highest incidence rates in Europe are observed, with UC affecting 505 per 100,000 people and CD affecting 322 per 100,000 people. In North America, the rates are 249 per 100,000 people for UC and 319 per 100,000 people for CD [4] . The number of IBD cases worldwide is increasing yearly, significantly burdening healthcare systems worldwide [5] . Although the exact etiology of IBD is not fully understood, its pathogenesis involves a complex interaction of genetic, immunologic, and environmental factors. In recent years, more and more studies have focused on the impact of IBD on general health, especially its potential association with various neurological disorders. Bell’s palsy (BP), also known as idiopathic facial paralysis, is characterized by paralysis of the facial muscles due to inflammation of the facial nerve [6, 7] . Most cases resolve within a month, but about 30% of patients recover within six months, and some may have incomplete recoveries, leading to ongoing facial weakness and spasms [8] . Bell’s palsy can impact individuals of all ages, with an annual incidence ranging from 20 to 30 cases per 100,000 people in different populations [9, 10] . Facial spasms and exposure keratitis linked to Bell’s palsy can significantly affect patients’ quality of life, potentially impacting their work and productivity [11] . Visible facial asymmetry and limited facial movements can cause social issues, depression, and avoidance behaviors [12] . Previous studies have suggested that systemic inflammation and immune system abnormalities may play an important role in the pathogenesis of Bell's palsy [6] . As a result, more attention is being given to studying ways to prevent Bell’s palsy effectively. Although IBD and BP differ in clinical manifestations and organs involved, there is growing evidence of a possible association between the two. Epidemiologic studies have shown that the prevalence of BP is higher in patients with IBD than in the general population, suggesting that the two diseases may share certain pathophysiologic mechanisms [ 7 ]. However, since most of these studies were based on observational data, a causal relationship could not be established. Therefore, it has become particularly important to explore the causal relationship between IBD and BP using genetic epidemiology. Mendelian randomization is a statistical method that employs single nucleotide polymorphisms (SNPs) as instrumental variables to assess causal relationships, thereby mitigating confounding and reverse causation biases commonly encountered in traditional observational studies[ 13 ][ 14 ]. By analyzing the associations between genetic variants and both IBD and BP, we can provide a more accurate evaluation of the causal relationship between these two diseases. This study aims to utilize Mendelian randomization to assess the causal relationship between IBD and BP through genetic instrumental variables, with a particular focus on the role of inflammatory proteins in this association. 2 Methods 2.1 Study Design In this study, we used two-sample Mendelian randomization (MR) approach, a causal inference method based on genetic variation, to assess the causal relationship between inflammatory bowel disease (IBD) and Bell's palsy (BP). We utilized summary statistics data for IBD from the International Inflammatory Bowel Disease Genetics Consortium (IIBDGC) for IBD and from the FinnGen R10 for BP. The use of these datasets complied with appropriate patient consent and ethical approvals. The specific process is illustrated in Figure 1. 2.2 Data Sources Summary-level data for IBD, including CD and UC, were obtained from the IIBDGC consortium, including 12,882 IBD cases, 5,956 Crohn’s disease cases, and 6,968 UC cases [15] . Additionally, summary-level data for Bell’s palsy were sourced from the FinnGen Consortium (consisting of 3781 Bell’s palsy cases and 360538 controls). GWAS statistics for 91 inflammatory proteins were summarized from 14,824 Europeans [16].The sources and detailed information of these datasets are presented in Table 1 . Table 1. Data Sources. Data Sample size (cases/controls) Ancestry Significance level Data Sources Inflammatory bowel disease 12882/21770 European 5e−8 IIBDGC (ieu-a-31) Crohn’s disease 5956/14927 European 5e−8 IIBDGC (ieu-a-30) Ulcerative colitis 6968/20464 European 5e−8 IIBDGC (ieu-a-32) Bell’s palsy 3781 /360538 European 5e−8 FinnGen R10 2.3 Instrumental Variable Selection Single nucleotide polymorphisms (SNPs), representing variations at a single nucleotide position in the DNA sequence, constitute the most prevalent form of genetic variation among humans. For SNPs to serve as instrumental variables in Mendelian randomization studies, they must fulfil three critical criteria[17, 18]. First, the SNP must exhibit an association with the exposure under investigation. The SNP should not be associated with confounders that might influence the relationship between the exposure and the outcome. The SNP’s influence on the outcome must be mediated exclusively through its effect on the exposure, ensuring no direct impact on the outcome beyond this pathway. Our research examined IBD, CD, and UC as exposure variables. We utilized the International Inflammatory Bowel Disease Genetics Consortium, which comprises data on 12,882 individuals diagnosed with IBD, including 5,956 cases of Crohn’s disease and 6,968 cases of UC, all of European descent[15]. A rigorous control series was implemented to identify eligible instrumental variables (IVs). Specifically, IVs for IBD were chosen from SNPs associated with the disease at a genome-wide significance level (p<5×10-8)[19]. In order to incorporate more SNPs associated with 91 inflammatory proteins, we adjusted the threshold for inflammatory proteins by raising it to p < 1×10-5, allowing more SNPs as IVs. To ensure the independence of the instrumental variables for IBD, we applied a clumping strategy with an r 2 threshold of <0.001 and a clump window of 10,000 kb, based on the 1000 Genomes Project linkage disequilibrium (LD) reference panel for European populations[20]. Applying the standard quality control measures outlined above, 65 SNPs, 53 SNPs, and 39 SNPs were selected as instrumental variables for the exposure. We then calculated the F-statistics for all these SNPs to assess the strength of the genetic instruments, finding that all exhibited F-statistics greater than 10. The IVs utilized in this study are detailed in Supplementary Tables S1-3 . 2.4 Protein-protein interaction network construction (PPI) We constructed the protein-protein interactions using STRING (https://string-db.org/) s' with a confidence score threshold of 0.4 as the minimum interaction score required, while all other parameters were kept at their default settings. The resulting PPI network was used to visualize potentially meaningful protein-protein interactions. 2.5 Statistical Analysis To investigate the potential causal relationship between IBD—encompassing Crohn’s disease (CD) and UC and BP, we employed several statistical methodologies to identify potential causal relationships. These methods included inverse variance weighting (IVW), MR-Egger regression, and the weighted median approach. Each technique was utilized to rigorously analyze the data for evidence of causality, thereby ensuring the robustness of our findings. IVW was used as the primary method for MR analysis. MR-Egger and weighted median were added as sensitivity analysis methods. In addition, we used MR-PRESSO and leave-one-out analyses to assess horizontal multiplicity and identify outliers. Statistical analyses were performed using the TwoSampleMR (version 0.6.1) and MR-PRESSO (version 1.0) packages in R (version 4.2.3), and plots were created using the ggplot2 package. A p-value < 0.05/3 (with Bonferroni corrections) was considered statistically significant, with p-values between 0.05 and 0.0167 considered suggestively significant. We interpreted the results not solely based on p-values but also considered the strengths of the associations and the consistency across sensitivity analyses. 3 Results 3.1 Causal effect of IBD and its subtypes on BP Figure 2. clearly illustrates the causal relationship between IBD and BP. This study definitively indicates that IBD, including CD, is a risk factor for BP ( Supplementary Tables S4-S 12 ). The Inverse Variance Weighted (IVW) method identified significant causal relationships. Data from the FinnGen consortium demonstrated a significant positive association between IBD and BP (OR: 1.13, 95% CI [1.03-1.23], P = 0.0065). CD was also observed to be positively correlated with BP (OR: 1.10, 95% CI [1.02-1.18], P = 0.0088 < 0.0167). After applying the Bonferroni correction, IBD remained positively correlated with BP. The heterogeneity test showed no heterogeneity between the included exposure tools (IBD, CD, and UC) and BP. The horizontal pleiotropy test also revealed no horizontal pleiotropy. The scatterplot suggests a positive causal relationship between IBD, CD, and BP ( Supplementary Figure 1 ). Furthermore, the funnel plot shows no heterogeneity between the three conditions ( Supplementary Figure 2 ). The leave-one-out plot also indicates the stability of this study model ( Supplementary Figure 3 ). 3.2 Exploration of the causal relationship between 91 inflammatory proteins and IBD Causal relationship between 91 inflammatory proteins and IBD from a two-sample Mendelian randomization study suggests that 18 inflammatory proteins, including FGF21, CD40, CXCL5, IL18, IL17C and SLAMF1, are potentially causally associated with IBD. After FDR correction, there was a significant causal relationship between FGF21, CD40, CXCL5, IL18 and IBD, as detailed in Figure 3( Supplementary Tables S 13-S 14 ). PPI network indicated that CXCL5, CXCL9, CXCL11, CCL4, CD40, IL18 and HGF were the core of these 18 proteins( Supplementary Figure 4 ). 3.3 Exploration of the causal relationship between 91 inflammatory proteins and BP Causal relationship between 91 inflammatory proteins and BP from a two-sample Mendelian randomization study showed that seven inflammatory proteins, including TGFA, IL17A, IL17C, CXCL5, and SLAMF1, were potentially causally related to IBD. After FDR correction, there was a significant causal relationship between TGFA and BP (OR: 1.33, 95% CI [1.15-1.53], pFDR = 0.012 < 0.05), as detailed in Figure 3( Supplementary Tables S 15-S 16 ). PPI network indicated that CSF1 and IL17A were the core of these 7 proteins( Supplementary Figure 5 ). 3.4 Exploring the relationship between all inflammatory proteins that have a potential relationship with IBD and BP There are 23 inflammatory proteins that are potentially causally related to either IBD and BP, with CXCL5 and SLAMF1 potentially causally related to both diseases. We loaded 23 inflammatory proteins into the STRING database to create a PPI network. The results are shown in Figure 4, including a protein interaction pathway consisting of 23 nodes and 42 edges. Among them, CXCL5, CXCL9, CXCL11, CCL4, IL17A and IL18 as the core of this network have significant interactions with other inflammatory proteins. CXCL5 and SLAMF1, which are both associated with these two diseases, also interact. However, while CXCL5 is protective against BP and IBD, IL_17C appears to be a risk factor for the two diseases. SLAMF1, on the other hand, is protective for BP and a risk factor for IBD (detailed in Figure 4 and Supplementary Tables S 17 ). 4 Discussion This two-sample Mendelian randomization study investigates the relationship between IBD and BP using summary statistics from the International Inflammatory Bowel Disease Genetics Consortium and Bell’s palsy data from FinnGen R10. These insights could be crucial in managing BP risk factors. The results of this study showed a significant positive causal relationship IBD and BP. Our findings indicate that IBD, including CD, is a risk factor for BP. This finding is consistent with the higher prevalence of BP among IBD patients observed in previous epidemiologic studies. The results of a Mendelian randomization study of 91 inflammatory proteins across IBD and BP patients suggest that the CXCL5 is protective against both while IL_17C is a risk factor for the two diseases. Alternatively, SLAMF1 is a protective factor for BP and a risk factor for IBD. The finding that genetic variants associated with IBD were also linked to the risk of BP further supports a possible common mechanism of inflammation in both diseases. Few observational studies have reported an association between IBD and BP, with only a few cases of IBD complicating BP. This two-sample Mendelian randomization study suggests that genetic predisposition to IBD may contribute to the pathogenesis of BP. Several potential mechanisms could explain this relationship. On the one hand, there are systemic inflammatory mechanisms[ 21 ]. IBD involves chronic inflammation of the gastrointestinal tract, which can lead to systemic inflammation. This chronic inflammatory state may impact various organs and systems, including the peripheral nervous system. Previous studies have documented that IBD can mediate diseases such as myasthenia gravis and polymyositis dermatomyositis[ 22 ]. Moreover, systemic inflammation indices have been identified as markers and prognostic indicators for BP[ 23 ]. The Mendelian randomization study exploring the relationship between 91 inflammatory proteins and IBD suggests interleukin-18 (IL-18) as a potential risk factor for IBD. IL-18 is a pro-inflammatory cytokine that regulates inflammatory and immune responses. Studies have indicated that IL-18 mediates neuroinflammation under pathological conditions, which supports the notion that IL-18, among IBD risk factors, may increase the risk of BP. However, another Mendelian randomization study between 91 inflammatory proteins and BP suggests that CXCL5 and SLAMF1 may be protective against BP. CXC chemokine ligand 5 (CXCL5) is an important neutrophil chemokine, and neutrophils act as immunomodulators both to promote inflammatory responses and, in some cases, to protect against them [ 24 ]. CXCL5 serves as a biomarker of prognosis in neurodegenerative diseases, neuropathic pain, peripheral nerve injury diseases and tumors [ 25 ], whereas it is rarely mentioned in BP. The mechanism of BP is widely recognized to involve damage to the facial nerve due to the inflammatory response triggered by HSV infection [ 26 – 28 ]. HSV infection contributes to the massive expression of CXCL5 through Toll-like receptor 2 signaling [ 29 ]. SLAMF1 (SLAM family member 1) is an immunoregulatory molecule located on the surface of immune cells and belongs to the SLAM (Signal-Linking Regulatory Molecules of the Immune System) family. SLAMF1 is expressed in a wide range of immune cells such as T-cells, B-cells, natural killer cells, and macrophages, and plays a key role in regulating the immune response[ 30 ]. It is involved in the regulation of adaptive and innate immune responses by promoting cell-cell interactions and signaling, and enhancing the activation and proliferation of immune cells. Studies have shown that SLAMF1 plays an important role in a variety of immune-related diseases, such as autoimmune diseases, infections, and tumors [ 31 ]. Activation of SLAMF1 inhibits excessive inflammatory responses and protects tissues from damage[ 32 ]. Several studies have suggested that polymorphisms in SLAMF1 may be associated with susceptibility to IBD[ 33 ]. In addition, SLAMF1 may influence the immune environment in the gut by regulating immune cell activity and cell-cell interactions[ 34 ]. Based on the previously published evidence, SLAMF1 is a risk factor for IBD, in line with the finings of the present study. The results of a study on the relationship between cerebrospinal fluid proteomics and BP additionally suggest that SLAMF1 may help to reduce neuroinflammation and protect the integrity of the facial nerve[ 35 ], further corroborating the results of this Mendelian randomization study. This study suggests that IL_17C is a potential risk factor for inflammatory bowel disease. The findings of the current study support previously reported positive correlation between IL-17C levels and IBD[ 36 ], and previous studies indicating that each isoform of IL-17 increases the risk of IBD[ 37 ]. In addition, IL-17 is involved in the pathogenesis of many other inflammatory diseases, including neurological disorders. The results of this Mendelian randomization study suggest that IL_17C is also a potential risk factor for BP. Previous studies have shown that IL-17 contributes to the neuroinflammatory response after neurological injury[ 38 ]. Another study indicated that IL-17c is a neurotrophic cytokine[ 39 , 40 ]. Thus, IL_17C may be involved in the inflammatory response of the facial nerve in BP. The mechanism by which inflammatory bowel disease may increase the risk of BP may be due to the release of inflammatory proteins CXCL5, IL_17C and SLAMF1, which are induced by IL-18. IL-18 induces the expression of CXCL5, which further contributes to the release of IL_17C and enhances the migration and activation of neutrophils. This upregulation of chemokines not only exacerbates local inflammation, but may also lead to a systemic inflammatory response, which in turn affects the expression and function of SLAMF1 and modulates the immune cell response. During neuroinflammation, SLAMF1 may inhibit IL-18 and CXCL5 mediated hyperinflammatory responses to some extent by regulating immune cell interactions. By regulating immune cell activity, SLAMF1 may help to reduce neuroinflammation and protect facial nerve integrity. In addition, the regulation of SLAMF1 may also result in milder activation of immune cells, thus avoiding excessive damage to nerve tissue and reducing the incidence of BP. This study is the first to examine the relationship between IBD and BP using Mendelian randomization. Our results show that IBD increases the risk of BP, emphasizing the importance of preventing IBD to avert major neurological disorders. This study also suggests that CXCL5 and SLAMF1 may act as common pathways of action between facial paralysis and inflammatory bowel disease etiology, possibly through mechanisms that regulate immune responses, promote tissue repair and maintain immune homeostasis. Further studies will contribute to a deeper understanding of the specific roles of CXCL5, SLAMF1 in these two diseases and explore their potential as therapeutic targets. Although the present study provides genetic evidence for a causal relationship between IBD and BP, several limitations remain. First, our study relied on existing genetic and phenotypic data, which may be subject to selection bias and information bias. Second, although we adjusted for multiple potential confounders, there may still be unidentified or unadjusted confounders. In addition, our study sample was primarily derived from a European population, which may limit the generalizability of the results to broader populations. 5 Conclusion Our study provides compelling evidence that IBD may be a risk factor for BP at the genetic level. These findings underscore the importance of considering neurological complications in the management of IBD. CXCL5, IL_17C, SLAMF1 as possible co-acting channels between BP and IBD may provide new potential targets for the treatment of both diseases. Abbreviations CXCL5,C-X-C Motif Chemokine Ligand 5; SLAMF1,Signaling Lymphocytic Activation Molecule Family Member 1; IL_17C,Interleukin-17C; IL_18,Interleukin-18; FGF21,Fibroblast Growth Factor 21; TGFA,Transforming Growth Factor Alpha; CD40,Cluster of Differentiation 40; Declarations Conflict of interest: The authors declare no conflicts of interest. Institutional Review Board statement This research did not increase the risk or economic burden of patients. The patients’ rights were fully protected. The project design was conducted in line with scientific and ethical principles. All data used in this study were retrieved from previously published GWAS. Each institutional review board in this research obtained written informed consent from all the participants in their respective studies. Funding: This project was funded by the Fujian Province Natural Science Foundation (No. 2024J011629), and Longyan Science and Technology Bureau projects (No. 2023LYF17043). Author Contribution W.W. D.F. and Y.C. conceived the idea for the study. The genetic data was obtained by W.W, D.F., B.Q., C.Z., and R.Q., W.W, D.F, and J.D. performed the data analyses. Q.L., D.F..,W.W. and J.D. interpreted the results of the data analyses. All authors wrote the manuscript. All authors read and approved the final manuscript. Acknowledgement Thanks to all the staff of the IEU Open GWAS, FinnGen, and the International Inflammatory Bowel Disease Genetics Consortium for their efforts in this study. Availability of data and materials: The GWAS summary statistics for Bell’s palsy are available on the IEU Open GWAS project consortium website ( https://gwas.mrcieu.ac.uk/ ) and FinnGen R9 website ( https://www.finngen.fi/en ). The GWAS summary statistics for inflammatory bowel disease are available on the International Inflammatory Bowel Disease Genetics Consortium ( https://www.ibdgc.org/ ). The data generated or analyzed in this study are available in this published article and its Supplementary Information document. References Gilliland A, Chan JJ, De Wolfe TJ, Yang H, Vallance BA. Pathobionts in Inflammatory Bowel Disease: Origins, Underlying Mechanisms, and Implications for Clinical Care. Gastroenterology. 2024. 166(1): 44-58. de Lange KM, Barrett JC. Understanding inflammatory bowel disease via immunogenetics. J Autoimmun. 2015. 64: 91-100. Morshedzadeh N, Rahimlou M, Shahrokh S, Mirmiran P, Zali MR. Nutritional management of inflammatory bowel disease; an overview of the evidences. Diabetes Metab Syndr. 2022. 16(3): 102440. Ashton JJ, Beattie RM. Inflammatory bowel disease: recent developments. Arch Dis Child. 2024. 109(5): 370-376. Yadav V, Varum F, Bravo R, Furrer E, Bojic D, Basit AW. Inflammatory bowel disease: exploring gut pathophysiology for novel therapeutic targets. Transl Res. 2016. 176: 38-68. Zhang W, Xu L, Luo T, Wu F, Zhao B, Li X. The etiology of Bell's palsy: a review. J Neurol. 2020. 267(7): 1896-1905. Heckmann JG, Urban PP, Pitz S, Guntinas-Lichius O, Gágyor I. The Diagnosis and Treatment of Idiopathic Facial Paresis (Bell's Palsy). Dtsch Arztebl Int. 2019. 116(41): 692-702. Sandell A. Recent developments in Bell's palsy: who should provide the care. BMJ. 2004. 329(7474): 1103; author reply 1104; discussion 1104. Atan D, İkincioğulları A, Köseoğlu S, et al. New Predictive Parameters of Bell's Palsy: Neutrophil to Lymphocyte Ratio and Platelet to Lymphocyte Ratio. Balkan Med J. 2015. 32(2): 167-70. Luu NN, Chorath KT, May BR, Bhuiyan N, Moreira AG, Rajasekaran K. Clinical practice guidelines in idiopathic facial paralysis: systematic review using the appraisal of guidelines for research and evaluation (AGREE II) instrument. J Neurol. 2021. 268(5): 1847-1856. Eviston TJ, Croxson GR, Kennedy PG, Hadlock T, Krishnan AV. Bell's palsy: aetiology, clinical features and multidisciplinary care. J Neurol Neurosurg Psychiatry. 2015. 86(12): 1356-61. Skuladottir AT, Bjornsdottir G, Thorleifsson G, et al. A meta-analysis uncovers the first sequence variant conferring risk of Bell's palsy. Sci Rep. 2021. 11(1): 4188. Skrivankova VW, Richmond RC, Woolf B, et al. Strengthening the Reporting of Observational Studies in Epidemiology Using Mendelian Randomization: The STROBE-MR Statement. JAMA. 2021. 326(16): 1614-1621. Davies NM, Holmes MV, Davey Smith G. Reading Mendelian randomisation studies: a guide, glossary, and checklist for clinicians. BMJ. 2018. 362: k601. Liu JZ, van Sommeren S, Huang H, et al. Association analyses identify 38 susceptibility loci for inflammatory bowel disease and highlight shared genetic risk across populations. Nat Genet. 2015. 47(9): 979-986. Zhao JH, Stacey D, Eriksson N, et al. Genetics of circulating inflammatory proteins identifies drivers of immune-mediated disease risk and therapeutic targets. Nat Immunol. 2023. 24(9): 1540-1551. Birney E. Mendelian Randomization. Cold Spring Harb Perspect Med. 2022. 12(4): a041302. Carter AR, Sanderson E, Hammerton G, et al. Mendelian randomisation for mediation analysis: current methods and challenges for implementation. Eur J Epidemiol. 2021. 36(5): 465-478. Zeng R, Wang J, Jiang R, et al. Investigating Causality and Shared Genetic Architecture between Neurodegenerative Disorders and Inflammatory Bowel Disease. Aging Dis. 2023. 14(4): 1349-1359. Lu C, Chen Q, Tao H, et al. The causal effect of inflammatory bowel disease on diffuse large B-cell lymphoma: two-sample Mendelian randomization study. Front Immunol. 2023. 14: 1171446. Orrù V, Steri M, Sidore C, et al. Complex genetic signatures in immune cells underlie autoimmunity and inform therapy. Nat Genet. 2020. 52(10): 1036-1045. Ferro JM, Oliveira Santos M. Neurology of inflammatory bowel disease. J Neurol Sci. 2021. 424: 117426. Kınar A, Ulu Ş, Bucak A, Kazan E. Can Systemic Immune-Inflammation Index (SII) be a prognostic factor of Bell's palsy patients. Neurol Sci. 2021. 42(8): 3197-3201. Balog BM, Sonti A, Zigmond RE. Neutrophil biology in injuries and diseases of the central and peripheral nervous systems. Prog Neurobiol. 2023. 228: 102488. Zhang W, Wang H, Sun M, et al. CXCL5/CXCR2 axis in tumor microenvironment as potential diagnostic biomarker and therapeutic target. Cancer Commun (Lond). 2020. 40(2-3): 69-80. Morgan M, Moffat M, Ritchie L, Collacott I, Brown T. Is Bell’s palsy a reactivation of varicella zoster virus. J Infect. 1995. 30(1): 29-36. McCormick DP. Herpes-simplex virus as a cause of Bell’s palsy. Lancet. 1972. 1(7757): 937-9. Zimmermann J, Jesse S, Kassubek J, Pinkhardt E, Ludolph AC. Differential diagnosis of peripheral facial nerve palsy: a retrospective clinical, MRI and CSF-based study. J Neurol. 2019. 266(10): 2488-2494. Aravalli RN, Hu S, Rowen TN, Palmquist JM, Lokensgard JR. Cutting edge: TLR2-mediated proinflammatory cytokine and chemokine production by microglial cells in response to herpes simplex virus. J Immunol. 2005. 175(7): 4189-93. Dragovich MA, Mor A. The SLAM family receptors: Potential therapeutic targets for inflammatory and autoimmune diseases. Autoimmun Rev. 2018. 17(7): 674-682. Gordiienko I, Shlapatska L, Kovalevska L, Sidorenko SP. SLAMF1/CD150 in hematologic malignancies: Silent marker or active player. Clin Immunol. 2019. 204: 14-22. Wei Q, Li J, Zhao C, et al. Blood-based inflammatory protein biomarker panel for the prediction of relapse and severity in patients with neuromyelitis optica spectrum disorder: A prospective cohort study. CNS Neurosci Ther. 2024. 30(6): e14811. Zhang P, Amarasinghe HE, Whalley JP, et al. Epigenomic analysis reveals a dynamic and context-specific macrophage enhancer landscape associated with innate immune activation and tolerance. Genome Biol. 2022. 23(1): 136. Monini S, Lazzarino AI, Iacolucci C, Buffoni A, Barbara M. Epidemiology of Bell's palsy in an Italian Health District: incidence and case-control study. Acta Otorhinolaryngol Ital. 2010. 30(4): 198.. Masouris I, Klein M, Angele B, et al. Quantitative proteomic analysis of cerebrospinal fluid from patients with idiopathic facial nerve palsy. Eur J Neurol. 2023. 30(4): 1048-1058. Friedrich M, Diegelmann J, Schauber J, Auernhammer CJ, Brand S. Intestinal neuroendocrine cells and goblet cells are mediators of IL-17A-amplified epithelial IL-17C production in human inflammatory bowel disease. Mucosal Immunol. 2015. 8(4): 943-58. Cai Y, Jia X, Xu L, Chen H, Xie S, Cai J. Interleukin-17 and inflammatory bowel disease: a 2-sample Mendelian randomization study. Front Immunol. 2023. 14: 1238457. Kim CF, Moalem-Taylor G. Interleukin-17 contributes to neuroinflammation and neuropathic pain following peripheral nerve injury in mice. J Pain. 2011. 12(3): 370-83. Peng T, Chanthaphavong RS, Sun S, et al. Keratinocytes produce IL-17c to protect peripheral nervous systems during human HSV-2 reactivation. J Exp Med. 2017. 214(8): 2315-2329. Iliev ID, Lin WY, Gaffen SL. When IL-17 gets on your nerves. Cell. 2023. 186(3): 466-468. Additional Declarations No competing interests reported. Supplementary Files SupplementaryTable.20241215203239232.xls supplementaryfig.pdf Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-6043269","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":418433581,"identity":"69d986aa-b993-47b9-9d25-807d8b64ef4b","order_by":0,"name":"Daofeng Fan","email":"","orcid":"","institution":"Longyan First Hospital Affiliated to Fujian Medical University","correspondingAuthor":false,"prefix":"","firstName":"Daofeng","middleName":"","lastName":"Fan","suffix":""},{"id":418433582,"identity":"e60a818f-739d-4fa0-af6f-e876ddd34ba0","order_by":1,"name":"Wenbao Wu","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA20lEQVRIiWNgGAWjYLACxgYGBjb25sMPPhjY2BGvhY/nWJrhjIK0ZOK1yEnkGEjzfDgEYuMHBjdyDB8X7rCTY5NISzC2MTjAzMB++OgGAlqMjWeeSTZm43l84HGOwR0+Bp60tBv4tJjdyN0mzdvGnNjGDrQlx+AZM4MEjxkhLdt/87bVJ7YxAP1iYXCYsYEILduYedsOJ7ZxALUwEKPF/sz7z9K8Z44D/QIM5B6DtGQ2Qn6RbE9L/My7o1pOvh0YlT/+2Njxsx8+hlcLJmAjTfkoGAWjYBSMAmwAAJ0vSv8Wh+DxAAAAAElFTkSuQmCC","orcid":"","institution":"Longyan First Hospital Affiliated to Fujian Medical University","correspondingAuthor":true,"prefix":"","firstName":"Wenbao","middleName":"","lastName":"Wu","suffix":""},{"id":418433583,"identity":"79e01c43-35e6-4f80-bce8-74254ee2d0d5","order_by":2,"name":"Yinjuan Chen","email":"","orcid":"","institution":"Longyan First Hospital Affiliated to Fujian Medical University","correspondingAuthor":false,"prefix":"","firstName":"Yinjuan","middleName":"","lastName":"Chen","suffix":""},{"id":418433584,"identity":"6dc84696-e4fa-4b87-af4f-ba171e1c82a7","order_by":3,"name":"Qingqing Lian","email":"","orcid":"","institution":"Longyan First Hospital Affiliated to Fujian Medical University","correspondingAuthor":false,"prefix":"","firstName":"Qingqing","middleName":"","lastName":"Lian","suffix":""},{"id":418433585,"identity":"73b626a2-e92e-4685-a60f-8eb519e863af","order_by":4,"name":"Jiaqian Dai","email":"","orcid":"","institution":"Longyan First Hospital Affiliated to Fujian Medical University","correspondingAuthor":false,"prefix":"","firstName":"Jiaqian","middleName":"","lastName":"Dai","suffix":""},{"id":418433586,"identity":"351e68e1-199b-4ad6-9c30-95b30d052339","order_by":5,"name":"Changbo Zhao","email":"","orcid":"","institution":"Xingwen County Hospital of Traditional Chinese Medicine","correspondingAuthor":false,"prefix":"","firstName":"Changbo","middleName":"","lastName":"Zhao","suffix":""},{"id":418433587,"identity":"8f1f09fc-b6d5-4dcc-9e46-4f71e93d0c09","order_by":6,"name":"Binfu Que","email":"","orcid":"","institution":"Longyan First Hospital Affiliated to Fujian Medical University","correspondingAuthor":false,"prefix":"","firstName":"Binfu","middleName":"","lastName":"Que","suffix":""},{"id":418433588,"identity":"06029e46-9138-4c73-b2c0-1341eaea5ec6","order_by":7,"name":"Rui Qiu","email":"","orcid":"","institution":"Longyan First Hospital Affiliated to Fujian Medical University","correspondingAuthor":false,"prefix":"","firstName":"Rui","middleName":"","lastName":"Qiu","suffix":""}],"badges":[],"createdAt":"2025-02-16 23:08:10","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6043269/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6043269/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":77107812,"identity":"923ed4bc-3c97-414b-a081-065baa6156ee","added_by":"auto","created_at":"2025-02-25 08:29:49","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":1312350,"visible":true,"origin":"","legend":"\u003cp\u003eThe study flowchart.\u003c/p\u003e","description":"","filename":"Figure1.png","url":"https://assets-eu.researchsquare.com/files/rs-6043269/v1/ae03f98017ab22b227f16fcb.png"},{"id":77108251,"identity":"b9646128-59c0-473b-9c4c-1026ebc0612d","added_by":"auto","created_at":"2025-02-25 08:37:49","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":454926,"visible":true,"origin":"","legend":"\u003cp\u003eThe forest plot of all the result.\u003c/p\u003e","description":"","filename":"Figure2.png","url":"https://assets-eu.researchsquare.com/files/rs-6043269/v1/33e71223810f15ae47796c90.png"},{"id":77108252,"identity":"89244e1a-2e9f-42a7-9782-087164e245e9","added_by":"auto","created_at":"2025-02-25 08:37:49","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":1433576,"visible":true,"origin":"","legend":"\u003cp\u003eThe forest plot of 91 inflammatory proteins results.\u003c/p\u003e\n\u003cp\u003eNote: CXCL5, IL17_C and SLAMF1 are inflammatory proteins with common potential causality across IBD and BP.\u003c/p\u003e","description":"","filename":"Figure31.png","url":"https://assets-eu.researchsquare.com/files/rs-6043269/v1/f3725ca6f620fb7cc0860c88.png"},{"id":77107816,"identity":"b3efa4ba-b150-4fa5-bcdd-65c2be9ca306","added_by":"auto","created_at":"2025-02-25 08:29:49","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":2538797,"visible":true,"origin":"","legend":"\u003cp\u003ePPI network diagram of inflammatory factors potentially associated with IBD and BP\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eNote:\u003c/strong\u003eCXCL5 plays an important role in the regulation of IL_17C and SLAMF1.\u003c/p\u003e","description":"","filename":"Figure4.png","url":"https://assets-eu.researchsquare.com/files/rs-6043269/v1/aa890c67c142069b4c826323.png"},{"id":77109712,"identity":"74d156d3-ec7c-4051-9b8c-f3924f486b3f","added_by":"auto","created_at":"2025-02-25 08:45:53","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":5982861,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6043269/v1/e64da3b4-454e-474b-94e0-95fd42dd02d0.pdf"},{"id":77107818,"identity":"0c16787d-69c2-4742-b750-8407b61e53fa","added_by":"auto","created_at":"2025-02-25 08:29:49","extension":"xls","order_by":0,"title":"","display":"","copyAsset":false,"role":"supplement","size":3563520,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementaryTable.20241215203239232.xls","url":"https://assets-eu.researchsquare.com/files/rs-6043269/v1/8124e7595997a8bf06a900b0.xls"},{"id":77107814,"identity":"e18864fe-8eaf-4183-9129-ad573bca45dd","added_by":"auto","created_at":"2025-02-25 08:29:49","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":1314247,"visible":true,"origin":"","legend":"","description":"","filename":"supplementaryfig.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6043269/v1/ce48abc38416e209be87829e.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Exploring the causal relationship between inflammatory bowel disease and Bell's palsy based on inflammatory proteins: a Mendelian randomization study","fulltext":[{"header":"1 Introduction","content":"\u003cp\u003eInflammatory bowel disease (IBD) includes a group of inflammatory disorders that affect the gastrointestinal tract, mainly Crohn\u0026rsquo;s disease (CD) and ulcerative colitis (UC)\u003csup\u003e[1]\u003c/sup\u003e. These conditions cause various symptoms linked to inflammation in the intestines, like abdominal pain, fever, vomiting, diarrhea, rectal bleeding, anemia, and weight loss\u003csup\u003e[2]\u003c/sup\u003e. The prevalence of IBD is higher in developed countries, with Europe and North America \u003csup\u003e[3]\u003c/sup\u003e. The highest incidence rates in Europe are observed, with UC affecting 505 per 100,000 people and CD affecting 322 per 100,000 people. In North America, the rates are 249 per 100,000 people for UC and 319 per 100,000 people for CD\u003csup\u003e[4]\u003c/sup\u003e. The number of IBD cases worldwide is increasing yearly, significantly burdening healthcare systems worldwide\u003csup\u003e[5]\u003c/sup\u003e. Although the exact etiology of IBD is not fully understood, its pathogenesis involves a complex interaction of genetic, immunologic, and environmental factors. In recent years, more and more studies have focused on the impact of IBD on general health, especially its potential association with various neurological disorders.\u003c/p\u003e \u003cp\u003eBell\u0026rsquo;s palsy (BP), also known as idiopathic facial paralysis, is characterized by paralysis of the facial muscles due to inflammation of the facial nerve\u003csup\u003e[6, 7]\u003c/sup\u003e. Most cases resolve within a month, but about 30% of patients recover within six months, and some may have incomplete recoveries, leading to ongoing facial weakness and spasms\u003csup\u003e[8]\u003c/sup\u003e. Bell\u0026rsquo;s palsy can impact individuals of all ages, with an annual incidence ranging from 20 to 30 cases per 100,000 people in different populations\u003csup\u003e[9, 10]\u003c/sup\u003e. Facial spasms and exposure keratitis linked to Bell\u0026rsquo;s palsy can significantly affect patients\u0026rsquo; quality of life, potentially impacting their work and productivity\u003csup\u003e[11]\u003c/sup\u003e. Visible facial asymmetry and limited facial movements can cause social issues, depression, and avoidance behaviors\u003csup\u003e[12]\u003c/sup\u003e. Previous studies have suggested that systemic inflammation and immune system abnormalities may play an important role in the pathogenesis of Bell's palsy\u003csup\u003e[6]\u003c/sup\u003e. As a result, more attention is being given to studying ways to prevent Bell\u0026rsquo;s palsy effectively.\u003c/p\u003e \u003cp\u003eAlthough IBD and BP differ in clinical manifestations and organs involved, there is growing evidence of a possible association between the two. Epidemiologic studies have shown that the prevalence of BP is higher in patients with IBD than in the general population, suggesting that the two diseases may share certain pathophysiologic mechanisms [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. However, since most of these studies were based on observational data, a causal relationship could not be established. Therefore, it has become particularly important to explore the causal relationship between IBD and BP using genetic epidemiology.\u003c/p\u003e \u003cp\u003eMendelian randomization is a statistical method that employs single nucleotide polymorphisms (SNPs) as instrumental variables to assess causal relationships, thereby mitigating confounding and reverse causation biases commonly encountered in traditional observational studies[\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e][\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. By analyzing the associations between genetic variants and both IBD and BP, we can provide a more accurate evaluation of the causal relationship between these two diseases. This study aims to utilize Mendelian randomization to assess the causal relationship between IBD and BP through genetic instrumental variables, with a particular focus on the role of inflammatory proteins in this association.\u003c/p\u003e"},{"header":"2 Methods","content":"\u003ch2\u003e2.1 Study Design\u003c/h2\u003e\n\u003cp\u003eIn this study, we used two-sample Mendelian randomization (MR)\u0026nbsp;approach, a causal inference method based on genetic variation, to assess the causal relationship between inflammatory bowel disease (IBD) and Bell\u0026apos;s palsy (BP). We utilized summary statistics data for\u0026nbsp;IBD\u0026nbsp;from the International Inflammatory Bowel Disease Genetics Consortium (IIBDGC) for IBD and from the FinnGen R10 for BP. The use of these datasets complied with appropriate patient consent and ethical approvals. The specific process is illustrated in \u003cstrong\u003eFigure 1.\u003c/strong\u003e\u003c/p\u003e\n\u003ch2\u003e2.2 Data Sources\u003c/h2\u003e\n\u003cp\u003eSummary-level data for IBD, including CD and UC, were obtained from the IIBDGC consortium, including 12,882 IBD cases, 5,956 Crohn\u0026rsquo;s disease cases, and 6,968 UC cases\u003csup\u003e[15]\u003c/sup\u003e. Additionally, summary-level data for Bell\u0026rsquo;s palsy were sourced from the FinnGen Consortium (consisting of 3781 Bell\u0026rsquo;s palsy cases and 360538 controls). GWAS statistics for 91 inflammatory proteins were summarized from 14,824 Europeans [16].The sources and detailed information of these datasets are presented in \u003cstrong\u003eTable 1\u003c/strong\u003e.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 1.\u0026nbsp;\u003c/strong\u003eData Sources.\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"699\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 186px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eData\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 119px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eSample size (cases/controls)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 112px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eAncestry\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 113px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eSignificance level\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 169px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eData Sources\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 186px;\"\u003e\n \u003cp\u003eInflammatory bowel disease\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 119px;\"\u003e\n \u003cp\u003e12882/21770\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 112px;\"\u003e\n \u003cp\u003eEuropean\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 113px;\"\u003e\n \u003cp\u003e5e\u0026minus;8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 169px;\"\u003e\n \u003cp\u003eIIBDGC (ieu-a-31)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 186px;\"\u003e\n \u003cp\u003eCrohn\u0026rsquo;s disease\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 119px;\"\u003e\n \u003cp\u003e5956/14927\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 112px;\"\u003e\n \u003cp\u003eEuropean\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 113px;\"\u003e\n \u003cp\u003e5e\u0026minus;8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 169px;\"\u003e\n \u003cp\u003eIIBDGC (ieu-a-30)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 186px;\"\u003e\n \u003cp\u003eUlcerative colitis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 119px;\"\u003e\n \u003cp\u003e6968/20464\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 112px;\"\u003e\n \u003cp\u003eEuropean\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 113px;\"\u003e\n \u003cp\u003e5e\u0026minus;8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 169px;\"\u003e\n \u003cp\u003eIIBDGC (ieu-a-32)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 186px;\"\u003e\n \u003cp\u003eBell\u0026rsquo;s palsy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 119px;\"\u003e\n \u003cp\u003e3781\u0026nbsp;/360538\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 112px;\"\u003e\n \u003cp\u003eEuropean\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 113px;\"\u003e\n \u003cp\u003e5e\u0026minus;8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 169px;\"\u003e\n \u003cp\u003eFinnGen R10\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003ch2\u003e2.3 Instrumental Variable Selection\u003c/h2\u003e\n\u003cp\u003eSingle nucleotide polymorphisms (SNPs), representing variations at a single nucleotide position in the DNA sequence, constitute the most prevalent form of genetic variation among humans. For SNPs to serve as instrumental variables in Mendelian randomization studies, they must fulfil three critical criteria[17, 18]. First, the SNP must exhibit an association with the exposure under investigation. The SNP should not be associated with confounders that might influence the relationship between the exposure and the outcome. The SNP\u0026rsquo;s influence on the outcome must be mediated exclusively through its effect on the exposure, ensuring no direct impact on the outcome beyond this pathway.\u003c/p\u003e\n\u003cp\u003eOur research examined IBD, CD, and UC as exposure variables. We utilized the International Inflammatory Bowel Disease Genetics Consortium, which comprises data on 12,882 individuals diagnosed with IBD, including 5,956 cases of Crohn\u0026rsquo;s disease and 6,968 cases of UC, all of European descent[15]. A rigorous control series was implemented to identify eligible instrumental variables (IVs). Specifically, IVs for IBD were chosen from SNPs associated with the disease at a genome-wide significance level (p\u0026lt;5\u0026times;10-8)[19]. In order to incorporate more SNPs associated with 91 inflammatory proteins, we adjusted the threshold for inflammatory proteins by raising it to p \u0026lt; 1\u0026times;10-5, allowing more SNPs as IVs. To ensure the independence of the instrumental variables for IBD, we applied a clumping strategy with an r\u003csup\u003e2\u003c/sup\u003e threshold of \u0026lt;0.001 and a clump window of 10,000 kb, based on the 1000 Genomes Project linkage disequilibrium (LD) reference panel for European populations[20]. Applying the standard quality control measures outlined above, 65 SNPs, 53 SNPs, and 39 SNPs were selected as instrumental variables for the exposure. We then calculated the F-statistics for all these SNPs to assess the strength of the genetic instruments, finding that all exhibited F-statistics greater than 10. The IVs utilized in this study are detailed in \u003cstrong\u003eSupplementary\u003c/strong\u003e\u003cstrong\u003eTables S1-3\u003c/strong\u003e.\u003c/p\u003e\n\u003ch2\u003e2.4 Protein-protein interaction network construction (PPI)\u003c/h2\u003e\n\u003cp\u003eWe constructed the protein-protein interactions using STRING (https://string-db.org/) s\u0026apos; with a confidence score threshold of 0.4 as the minimum interaction score required, while all other parameters were kept at their default settings. The resulting PPI network was used to visualize potentially meaningful protein-protein interactions.\u003c/p\u003e\n\u003ch2\u003e2.5 Statistical Analysis\u003c/h2\u003e\n\u003cp\u003eTo investigate the potential causal relationship between IBD\u0026mdash;encompassing Crohn\u0026rsquo;s disease (CD) and UC and BP, we employed several statistical methodologies to identify potential causal relationships. These methods included inverse variance weighting (IVW), MR-Egger regression, and the weighted median approach. Each technique was utilized to rigorously analyze the data for evidence of causality, thereby ensuring the robustness of our findings. IVW was used as the primary method for MR analysis. MR-Egger and weighted median were added as sensitivity analysis methods. In addition, we used MR-PRESSO and leave-one-out analyses to assess horizontal multiplicity and identify outliers. Statistical analyses were performed using the TwoSampleMR (version 0.6.1) and MR-PRESSO (version 1.0) packages in R (version 4.2.3), and plots were created using the ggplot2 package. A p-value \u0026lt; 0.05/3 (with Bonferroni corrections) was considered statistically significant, with p-values between 0.05 and 0.0167 considered suggestively significant. We interpreted the results not solely based on p-values but also considered the strengths of the associations and the consistency across sensitivity analyses.\u003c/p\u003e"},{"header":"3 Results","content":"\u003ch3\u003e3.1 Causal effect of IBD and its subtypes on BP\u003c/h3\u003e\n\u003cp\u003e\u003cstrong\u003eFigure 2.\u003c/strong\u003e clearly illustrates the causal relationship between IBD and BP. This study definitively indicates that IBD, including CD, is a risk factor for BP (\u003cstrong\u003eSupplementary Tables S4-S\u003c/strong\u003e\u003cstrong\u003e12\u003c/strong\u003e). The Inverse Variance Weighted (IVW) method identified significant causal relationships. \u0026nbsp;Data from the FinnGen consortium demonstrated a significant positive association between IBD and BP (OR: 1.13, 95% CI [1.03-1.23], \u003cem\u003eP =\u003c/em\u003e 0.0065). CD was also observed to be positively correlated with BP (OR: 1.10, 95% CI [1.02-1.18], \u003cem\u003eP =\u003c/em\u003e 0.0088 \u0026lt; 0.0167). After applying the Bonferroni correction, IBD remained positively correlated with BP. The heterogeneity test showed no heterogeneity between the included exposure tools (IBD, CD, and UC) and BP. The horizontal pleiotropy test also revealed no horizontal pleiotropy. The scatterplot suggests a positive causal relationship between IBD, CD, and BP (\u003cstrong\u003eSupplementary Figure 1\u003c/strong\u003e). Furthermore, the funnel plot shows no heterogeneity between the three conditions (\u003cstrong\u003eSupplementary Figure 2\u003c/strong\u003e). The leave-one-out plot also indicates the stability of this study model (\u003cstrong\u003eSupplementary Figure 3\u003c/strong\u003e).\u003c/p\u003e\n\u003ch3\u003e3.2\u0026nbsp;Exploration of the causal relationship between 91 inflammatory proteins and IBD\u003c/h3\u003e\n\u003cp\u003eCausal relationship between 91 inflammatory proteins and IBD from a two-sample Mendelian randomization study suggests that 18 inflammatory proteins, including FGF21, CD40, CXCL5, IL18, IL17C\u0026nbsp;and SLAMF1, are potentially causally associated with IBD. After FDR correction, there was a significant causal relationship between FGF21, CD40, CXCL5, IL18 and IBD, as detailed in Figure 3(\u003cstrong\u003eSupplementary Tables S\u003c/strong\u003e\u003cstrong\u003e13-S\u003c/strong\u003e\u003cstrong\u003e14\u003c/strong\u003e).\u0026nbsp;PPI network indicated that CXCL5, CXCL9, CXCL11,\u0026nbsp;CCL4, CD40, IL18 and HGF were the core of these 18 proteins(\u003cstrong\u003eSupplementary Figure\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;4\u003c/strong\u003e).\u003c/p\u003e\n\u003ch3\u003e3.3\u0026nbsp;Exploration of the causal relationship between 91 inflammatory proteins and\u0026nbsp;BP\u003c/h3\u003e\n\u003cp\u003eCausal relationship between 91 inflammatory proteins and BP from a two-sample Mendelian randomization study showed that seven inflammatory proteins, including TGFA, IL17A, IL17C, CXCL5, and SLAMF1, were potentially causally related to IBD. After FDR correction, there was a significant causal relationship between TGFA and BP (OR: 1.33, 95% CI [1.15-1.53], pFDR = 0.012 \u0026lt; 0.05), as detailed in Figure 3(\u003cstrong\u003eSupplementary Tables S\u003c/strong\u003e\u003cstrong\u003e15-S\u003c/strong\u003e\u003cstrong\u003e16\u003c/strong\u003e).\u0026nbsp;PPI network indicated that CSF1 and IL17A were the core of these 7 proteins(\u003cstrong\u003eSupplementary Figure\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003e5\u003c/strong\u003e).\u003c/p\u003e\n\u003ch3\u003e3.4\u0026nbsp;Exploring the relationship between all inflammatory proteins that have a potential\u003c/h3\u003e\n\u003ch3\u003erelationship with IBD and BP\u003c/h3\u003e\n\u003cp\u003eThere are 23 inflammatory proteins that are potentially causally related to either IBD and BP, with CXCL5 and SLAMF1 potentially causally related to both diseases. We loaded 23 inflammatory proteins into the STRING database to create a PPI network. The results are shown in Figure 4, including a protein interaction pathway consisting of 23 nodes and 42 edges. Among them, CXCL5, CXCL9, CXCL11,\u0026nbsp;CCL4, IL17A and IL18 as the core of this network have significant interactions with other inflammatory proteins. CXCL5 and SLAMF1, which are both associated with these two diseases, also interact. However, while CXCL5 is protective against BP and IBD, IL_17C appears to be a risk factor for the two diseases. SLAMF1, on the other hand, is protective for BP and a risk factor for IBD (detailed in\u0026nbsp;Figure 4 and\u0026nbsp;\u003cstrong\u003eSupplementary Tables S\u003c/strong\u003e\u003cstrong\u003e17\u003c/strong\u003e).\u003c/p\u003e"},{"header":"4 Discussion","content":"\u003cp\u003eThis two-sample Mendelian randomization study investigates the relationship between IBD and BP using summary statistics from the International Inflammatory Bowel Disease Genetics Consortium and Bell\u0026rsquo;s palsy data from FinnGen R10. These insights could be crucial in managing BP risk factors. The results of this study showed a significant positive causal relationship IBD and BP. Our findings indicate that IBD, including CD, is a risk factor for BP. This finding is consistent with the higher prevalence of BP among IBD patients observed in previous epidemiologic studies. The results of a Mendelian randomization study of 91 inflammatory proteins across IBD and BP patients suggest that the CXCL5 is protective against both while IL_17C is a risk factor for the two diseases. Alternatively, SLAMF1 is a protective factor for BP and a risk factor for IBD. The finding that genetic variants associated with IBD were also linked to the risk of BP further supports a possible common mechanism of inflammation in both diseases.\u003c/p\u003e \u003cp\u003eFew observational studies have reported an association between IBD and BP, with only a few cases of IBD complicating BP. This two-sample Mendelian randomization study suggests that genetic predisposition to IBD may contribute to the pathogenesis of BP. Several potential mechanisms could explain this relationship. On the one hand, there are systemic inflammatory mechanisms[\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. IBD involves chronic inflammation of the gastrointestinal tract, which can lead to systemic inflammation. This chronic inflammatory state may impact various organs and systems, including the peripheral nervous system. Previous studies have documented that IBD can mediate diseases such as myasthenia gravis and polymyositis dermatomyositis[\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. Moreover, systemic inflammation indices have been identified as markers and prognostic indicators for BP[\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. The Mendelian randomization study exploring the relationship between 91 inflammatory proteins and IBD suggests interleukin-18 (IL-18) as a potential risk factor for IBD. IL-18 is a pro-inflammatory cytokine that regulates inflammatory and immune responses. Studies have indicated that IL-18 mediates neuroinflammation under pathological conditions, which supports the notion that IL-18, among IBD risk factors, may increase the risk of BP. However, another Mendelian randomization study between 91 inflammatory proteins and BP suggests that CXCL5 and SLAMF1 may be protective against BP.\u003c/p\u003e \u003cp\u003eCXC chemokine ligand 5 (CXCL5) is an important neutrophil chemokine, and neutrophils act as immunomodulators both to promote inflammatory responses and, in some cases, to protect against them [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. CXCL5 serves as a biomarker of prognosis in neurodegenerative diseases, neuropathic pain, peripheral nerve injury diseases and tumors [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e], whereas it is rarely mentioned in BP. The mechanism of BP is widely recognized to involve damage to the facial nerve due to the inflammatory response triggered by HSV infection [\u003cspan additionalcitationids=\"CR27\" citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]. HSV infection contributes to the massive expression of CXCL5 through Toll-like receptor 2 signaling [\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eSLAMF1 (SLAM family member 1) is an immunoregulatory molecule located on the surface of immune cells and belongs to the SLAM (Signal-Linking Regulatory Molecules of the Immune System) family. SLAMF1 is expressed in a wide range of immune cells such as T-cells, B-cells, natural killer cells, and macrophages, and plays a key role in regulating the immune response[\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e]. It is involved in the regulation of adaptive and innate immune responses by promoting cell-cell interactions and signaling, and enhancing the activation and proliferation of immune cells. Studies have shown that SLAMF1 plays an important role in a variety of immune-related diseases, such as autoimmune diseases, infections, and tumors [\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e]. Activation of SLAMF1 inhibits excessive inflammatory responses and protects tissues from damage[\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e]. Several studies have suggested that polymorphisms in SLAMF1 may be associated with susceptibility to IBD[\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e]. In addition, SLAMF1 may influence the immune environment in the gut by regulating immune cell activity and cell-cell interactions[\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e]. Based on the previously published evidence, SLAMF1 is a risk factor for IBD, in line with the finings of the present study. The results of a study on the relationship between cerebrospinal fluid proteomics and BP additionally suggest that SLAMF1 may help to reduce neuroinflammation and protect the integrity of the facial nerve[\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e], further corroborating the results of this Mendelian randomization study.\u003c/p\u003e \u003cp\u003eThis study suggests that IL_17C is a potential risk factor for inflammatory bowel disease. The findings of the current study support previously reported positive correlation between IL-17C levels and IBD[\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e], and previous studies indicating that each isoform of IL-17 increases the risk of IBD[\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e]. In addition, IL-17 is involved in the pathogenesis of many other inflammatory diseases, including neurological disorders. The results of this Mendelian randomization study suggest that IL_17C is also a potential risk factor for BP. Previous studies have shown that IL-17 contributes to the neuroinflammatory response after neurological injury[\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e]. Another study indicated that IL-17c is a neurotrophic cytokine[\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e, \u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e]. Thus, IL_17C may be involved in the inflammatory response of the facial nerve in BP.\u003c/p\u003e \u003cp\u003eThe mechanism by which inflammatory bowel disease may increase the risk of BP may be due to the release of inflammatory proteins CXCL5, IL_17C and SLAMF1, which are induced by IL-18. IL-18 induces the expression of CXCL5, which further contributes to the release of IL_17C and enhances the migration and activation of neutrophils. This upregulation of chemokines not only exacerbates local inflammation, but may also lead to a systemic inflammatory response, which in turn affects the expression and function of SLAMF1 and modulates the immune cell response. During neuroinflammation, SLAMF1 may inhibit IL-18 and CXCL5 mediated hyperinflammatory responses to some extent by regulating immune cell interactions. By regulating immune cell activity, SLAMF1 may help to reduce neuroinflammation and protect facial nerve integrity. In addition, the regulation of SLAMF1 may also result in milder activation of immune cells, thus avoiding excessive damage to nerve tissue and reducing the incidence of BP.\u003c/p\u003e \u003cp\u003eThis study is the first to examine the relationship between IBD and BP using Mendelian randomization. Our results show that IBD increases the risk of BP, emphasizing the importance of preventing IBD to avert major neurological disorders. This study also suggests that CXCL5 and SLAMF1 may act as common pathways of action between facial paralysis and inflammatory bowel disease etiology, possibly through mechanisms that regulate immune responses, promote tissue repair and maintain immune homeostasis. Further studies will contribute to a deeper understanding of the specific roles of CXCL5, SLAMF1 in these two diseases and explore their potential as therapeutic targets. Although the present study provides genetic evidence for a causal relationship between IBD and BP, several limitations remain. First, our study relied on existing genetic and phenotypic data, which may be subject to selection bias and information bias. Second, although we adjusted for multiple potential confounders, there may still be unidentified or unadjusted confounders. In addition, our study sample was primarily derived from a European population, which may limit the generalizability of the results to broader populations.\u003c/p\u003e"},{"header":"5 Conclusion","content":"\u003cp\u003eOur study provides compelling evidence that IBD may be a risk factor for BP at the genetic level. These findings underscore the importance of considering neurological complications in the management of IBD. CXCL5, IL_17C, SLAMF1 as possible co-acting channels between BP and IBD may provide new potential targets for the treatment of both diseases.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eCXCL5,C-X-C Motif Chemokine Ligand 5;\u003c/p\u003e\n\u003cp\u003eSLAMF1,Signaling Lymphocytic Activation Molecule Family Member 1;\u003c/p\u003e\n\u003cp\u003eIL_17C,Interleukin-17C;\u003c/p\u003e\n\u003cp\u003eIL_18,Interleukin-18;\u003c/p\u003e\n\u003cp\u003eFGF21,Fibroblast Growth Factor 21;\u003c/p\u003e\n\u003cp\u003eTGFA,Transforming Growth Factor Alpha;\u003c/p\u003e\n\u003cp\u003eCD40,Cluster of Differentiation 40;\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e \u003ch2\u003eConflict of interest:\u003c/h2\u003e \u003cp\u003eThe authors declare no conflicts of interest.\u003c/p\u003e \u003c/p\u003e\u003cp\u003e \u003ch2\u003eInstitutional Review Board statement\u003c/h2\u003e \u003cp\u003eThis research did not increase the risk or economic burden of patients. The patients\u0026rsquo; rights were fully protected. The project design was conducted in line with scientific and ethical principles. All data used in this study were retrieved from previously published GWAS. Each institutional review board in this research obtained written informed consent from all the participants in their respective studies.\u003c/p\u003e \u003c/p\u003e\u003ch2\u003eFunding:\u003c/h2\u003e \u003cp\u003eThis project was funded by the Fujian Province Natural Science Foundation (No. 2024J011629), and Longyan Science and Technology Bureau projects (No. 2023LYF17043).\u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eW.W. D.F. and Y.C. conceived the idea for the study. The genetic data was obtained by W.W, D.F., B.Q., C.Z., and R.Q., W.W, D.F, and J.D. performed the data analyses. Q.L., D.F..,W.W. and J.D. interpreted the results of the data analyses. All authors wrote the manuscript. All authors read and approved the final manuscript.\u003c/p\u003e\u003ch2\u003eAcknowledgement\u003c/h2\u003e\u003cp\u003eThanks to all the staff of the IEU Open GWAS, FinnGen, and the International Inflammatory Bowel Disease Genetics Consortium for their efforts in this study.\u003c/p\u003e\u003ch2\u003eAvailability of data and materials:\u003c/h2\u003e \u003cp\u003eThe GWAS summary statistics for Bell\u0026rsquo;s palsy are available on the IEU Open GWAS project consortium website (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://gwas.mrcieu.ac.uk/\u003c/span\u003e\u003cspan address=\"https://gwas.mrcieu.ac.uk/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e) and FinnGen R9 website (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.finngen.fi/en\u003c/span\u003e\u003cspan address=\"https://www.finngen.fi/en\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e). The GWAS summary statistics for inflammatory bowel disease are available on the International Inflammatory Bowel Disease Genetics Consortium (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.ibdgc.org/\u003c/span\u003e\u003cspan address=\"https://www.ibdgc.org/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e). The data generated or analyzed in this study are available in this published article and its Supplementary Information document.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eGilliland A, Chan JJ, De Wolfe TJ, Yang H, Vallance BA. Pathobionts in Inflammatory Bowel Disease: Origins, Underlying Mechanisms, and Implications for Clinical Care. Gastroenterology. 2024. 166(1): 44-58.\u003c/li\u003e\n\u003cli\u003ede Lange KM, Barrett JC. Understanding inflammatory bowel disease via immunogenetics. J Autoimmun. 2015. 64: 91-100.\u003c/li\u003e\n\u003cli\u003eMorshedzadeh N, Rahimlou M, Shahrokh S, Mirmiran P, Zali MR. Nutritional management of inflammatory bowel disease; an overview of the evidences. Diabetes Metab Syndr. 2022. 16(3): 102440.\u003c/li\u003e\n\u003cli\u003eAshton JJ, Beattie RM. Inflammatory bowel disease: recent developments. Arch Dis Child. 2024. 109(5): 370-376.\u003c/li\u003e\n\u003cli\u003eYadav V, Varum F, Bravo R, Furrer E, Bojic D, Basit AW. Inflammatory bowel disease: exploring gut pathophysiology for novel therapeutic targets. Transl Res. 2016. 176: 38-68.\u003c/li\u003e\n\u003cli\u003eZhang W, Xu L, Luo T, Wu F, Zhao B, Li X. The etiology of Bell\u0026apos;s palsy: a review. J Neurol. 2020. 267(7): 1896-1905.\u003c/li\u003e\n\u003cli\u003eHeckmann JG, Urban PP, Pitz S, Guntinas-Lichius O, G\u0026aacute;gyor I. The Diagnosis and Treatment of Idiopathic Facial Paresis (Bell\u0026apos;s Palsy). Dtsch Arztebl Int. 2019. 116(41): 692-702.\u003c/li\u003e\n\u003cli\u003eSandell A. Recent developments in Bell\u0026apos;s palsy: who should provide the care. BMJ. 2004. 329(7474): 1103; author reply 1104; discussion 1104.\u003c/li\u003e\n\u003cli\u003eAtan D, İkincioğulları A, K\u0026ouml;seoğlu S, et al. New Predictive Parameters of Bell\u0026apos;s Palsy: Neutrophil to Lymphocyte Ratio and Platelet to Lymphocyte Ratio. Balkan Med J. 2015. 32(2): 167-70.\u003c/li\u003e\n\u003cli\u003eLuu NN, Chorath KT, May BR, Bhuiyan N, Moreira AG, Rajasekaran K. Clinical practice guidelines in idiopathic facial paralysis: systematic review using the appraisal of guidelines for research and evaluation (AGREE II) instrument. J Neurol. 2021. 268(5): 1847-1856.\u003c/li\u003e\n\u003cli\u003eEviston TJ, Croxson GR, Kennedy PG, Hadlock T, Krishnan AV. Bell\u0026apos;s palsy: aetiology, clinical features and multidisciplinary care. J Neurol Neurosurg Psychiatry. 2015. 86(12): 1356-61.\u003c/li\u003e\n\u003cli\u003eSkuladottir AT, Bjornsdottir G, Thorleifsson G, et al. A meta-analysis uncovers the first sequence variant conferring risk of Bell\u0026apos;s palsy. Sci Rep. 2021. 11(1): 4188.\u003c/li\u003e\n\u003cli\u003eSkrivankova VW, Richmond RC, Woolf B, et al. Strengthening the Reporting of Observational Studies in Epidemiology Using Mendelian Randomization: The STROBE-MR Statement. JAMA. 2021. 326(16): 1614-1621.\u003c/li\u003e\n\u003cli\u003eDavies NM, Holmes MV, Davey Smith G. Reading Mendelian randomisation studies: a guide, glossary, and checklist for clinicians. BMJ. 2018. 362: k601.\u003c/li\u003e\n\u003cli\u003eLiu JZ, van Sommeren S, Huang H, et al. Association analyses identify 38 susceptibility loci for inflammatory bowel disease and highlight shared genetic risk across populations. Nat Genet. 2015. 47(9): 979-986.\u003c/li\u003e\n\u003cli\u003eZhao JH, Stacey D, Eriksson N, et al. Genetics of circulating inflammatory proteins identifies drivers of immune-mediated disease risk and therapeutic targets. Nat Immunol. 2023. 24(9): 1540-1551.\u003c/li\u003e\n\u003cli\u003eBirney E. Mendelian Randomization. Cold Spring Harb Perspect Med. 2022. 12(4): a041302.\u003c/li\u003e\n\u003cli\u003eCarter AR, Sanderson E, Hammerton G, et al. Mendelian randomisation for mediation analysis: current methods and challenges for implementation. Eur J Epidemiol. 2021. 36(5): 465-478.\u003c/li\u003e\n\u003cli\u003eZeng R, Wang J, Jiang R, et al. Investigating Causality and Shared Genetic Architecture between Neurodegenerative Disorders and Inflammatory Bowel Disease. Aging Dis. 2023. 14(4): 1349-1359.\u003c/li\u003e\n\u003cli\u003eLu C, Chen Q, Tao H, et al. The causal effect of inflammatory bowel disease on diffuse large B-cell lymphoma: two-sample Mendelian randomization study. Front Immunol. 2023. 14: 1171446.\u003c/li\u003e\n\u003cli\u003eOrr\u0026ugrave; V, Steri M, Sidore C, et al. Complex genetic signatures in immune cells underlie autoimmunity and inform therapy. Nat Genet. 2020. 52(10): 1036-1045.\u003c/li\u003e\n\u003cli\u003eFerro JM, Oliveira Santos M. Neurology of inflammatory bowel disease. J Neurol Sci. 2021. 424: 117426.\u003c/li\u003e\n\u003cli\u003eKınar A, Ulu Ş, Bucak A, Kazan E. Can Systemic Immune-Inflammation Index (SII) be a prognostic factor of Bell\u0026apos;s palsy patients. Neurol Sci. 2021. 42(8): 3197-3201.\u003c/li\u003e\n\u003cli\u003eBalog BM, Sonti A, Zigmond RE. Neutrophil biology in injuries and diseases of the central and peripheral nervous systems. Prog Neurobiol. 2023. 228: 102488.\u003c/li\u003e\n\u003cli\u003eZhang W, Wang H, Sun M, et al. CXCL5/CXCR2 axis in tumor microenvironment as potential diagnostic biomarker and therapeutic target. Cancer Commun (Lond). 2020. 40(2-3): 69-80.\u003c/li\u003e\n\u003cli\u003eMorgan M, Moffat M, Ritchie L, Collacott I, Brown T. Is Bell\u0026rsquo;s palsy a reactivation of varicella zoster virus. J Infect. 1995. 30(1): 29-36.\u003c/li\u003e\n\u003cli\u003eMcCormick DP. Herpes-simplex virus as a cause of Bell\u0026rsquo;s palsy. Lancet. 1972. 1(7757): 937-9.\u003c/li\u003e\n\u003cli\u003eZimmermann J, Jesse S, Kassubek J, Pinkhardt E, Ludolph AC. Differential diagnosis of peripheral facial nerve palsy: a retrospective clinical, MRI and CSF-based study. J Neurol. 2019. 266(10): 2488-2494.\u003c/li\u003e\n\u003cli\u003eAravalli RN, Hu S, Rowen TN, Palmquist JM, Lokensgard JR. Cutting edge: TLR2-mediated proinflammatory cytokine and chemokine production by microglial cells in response to herpes simplex virus. J Immunol. 2005. 175(7): 4189-93.\u003c/li\u003e\n\u003cli\u003eDragovich MA, Mor A. The SLAM family receptors: Potential therapeutic targets for inflammatory and autoimmune diseases. Autoimmun Rev. 2018. 17(7): 674-682.\u003c/li\u003e\n\u003cli\u003eGordiienko I, Shlapatska L, Kovalevska L, Sidorenko SP. SLAMF1/CD150 in hematologic malignancies: Silent marker or active player. Clin Immunol. 2019. 204: 14-22.\u003c/li\u003e\n\u003cli\u003eWei Q, Li J, Zhao C, et al. Blood-based inflammatory protein biomarker panel for the prediction of relapse and severity in patients with neuromyelitis optica spectrum disorder: A prospective cohort study. CNS Neurosci Ther. 2024. 30(6): e14811.\u003c/li\u003e\n\u003cli\u003eZhang P, Amarasinghe HE, Whalley JP, et al. Epigenomic analysis reveals a dynamic and context-specific macrophage enhancer landscape associated with innate immune activation and tolerance. Genome Biol. 2022. 23(1): 136.\u003c/li\u003e\n\u003cli\u003eMonini S, Lazzarino AI, Iacolucci C, Buffoni A, Barbara M. Epidemiology of Bell\u0026apos;s palsy in an Italian Health District: incidence and case-control study. Acta Otorhinolaryngol Ital. 2010. 30(4): 198..\u003c/li\u003e\n\u003cli\u003eMasouris I, Klein M, Angele B, et al. Quantitative proteomic analysis of cerebrospinal fluid from patients with idiopathic facial nerve palsy. Eur J Neurol. 2023. 30(4): 1048-1058.\u003c/li\u003e\n\u003cli\u003eFriedrich M, Diegelmann J, Schauber J, Auernhammer CJ, Brand S. Intestinal neuroendocrine cells and goblet cells are mediators of IL-17A-amplified epithelial IL-17C production in human inflammatory bowel disease. Mucosal Immunol. 2015. 8(4): 943-58.\u003c/li\u003e\n\u003cli\u003eCai Y, Jia X, Xu L, Chen H, Xie S, Cai J. Interleukin-17 and inflammatory bowel disease: a 2-sample Mendelian randomization study. Front Immunol. 2023. 14: 1238457.\u003c/li\u003e\n\u003cli\u003eKim CF, Moalem-Taylor G. Interleukin-17 contributes to neuroinflammation and neuropathic pain following peripheral nerve injury in mice. J Pain. 2011. 12(3): 370-83.\u003c/li\u003e\n\u003cli\u003ePeng T, Chanthaphavong RS, Sun S, et al. Keratinocytes produce IL-17c to protect peripheral nervous systems during human HSV-2 reactivation. J Exp Med. 2017. 214(8): 2315-2329.\u003c/li\u003e\n\u003cli\u003eIliev ID, Lin WY, Gaffen SL. When IL-17 gets on your nerves. Cell. 2023. 186(3): 466-468.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Two-sample Mendelian randomization, Inflammatory bowel disease, Bell’s palsy, inflammatory proteins","lastPublishedDoi":"10.21203/rs.3.rs-6043269/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6043269/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground: \u003c/strong\u003eThe relationship between Inflammatory Bowel Disease (IBD) and Bell’s palsy remains unsubstantiated. This study aims to investigate the causal relationship between IBD and Bell’s palsy.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods:\u003c/strong\u003e Using two-sample Mendelian randomization (MR) method to explore the relationship between IBD and Bell’s palsy. We applied Bell’s palsy summary statistics from GWAS statistics for 91 inflammatory proteins and FinnGen R10 and IBD summary statistics from the International Inflammatory Bowel Disease Genetics Consortium.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults: \u003c/strong\u003eThe two-sample MR study indicates a significant positive association between IBD and Bell’s palsy (OR: 1.13, 95% CI [1.03 to 1.23], P = 0.0065) and between Crohn’s disease and Bell’s palsy (OR: 1.10, 95% CI [1.02 to 1.18], P = 0.0088). After applying Bonferroni correction, IBD remained significantly correlated with Bell’s palsy. Subsequently, the causal relationship between circulating inflammatory proteins in Bell's palsy and inflammatory bowel disease samples was reevaluated. The results of MR study between inflammatory proteins among these two diseases suggests that the C-X-C Motif Chemokine Ligand 5 (CXCL5) is a potential protective factor and interleukin_17C (IL_17C) is a risk factor for these two diseases. Conversely, Signaling Lymphocytic Activation Molecule Family Member 1 (SLAMF1) is a protective factor for Bell's palsy and a risk factor for inflammatory bowel disease.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusions: \u003c/strong\u003eThe findings indicate that IBD may be a risk factor for Bell’s palsy at the genetic level. CXCL5, IL_17C, SLAMF1 are possible co-acting pathways between Bell's palsy and inflammatory bowel disease. These findings may provide new targets for the treatment of both diseases.\u003c/p\u003e","manuscriptTitle":"Exploring the causal relationship between inflammatory bowel disease and Bell's palsy based on inflammatory proteins: a Mendelian randomization study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-02-25 08:29:44","doi":"10.21203/rs.3.rs-6043269/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"c7dc9736-3340-439f-af6d-d1f95025f793","owner":[],"postedDate":"February 25th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-02-25T08:29:44+00:00","versionOfRecord":[],"versionCreatedAt":"2025-02-25 08:29:44","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-6043269","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6043269","identity":"rs-6043269","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}