Hearing Loss (HL) is a common sensory disorder affecting individuals of all ages, with significant impacts on quality of life. It is broadly classified into Sensorineural Hearing Loss (SNHL), Conductive Hearing Loss (CHL), and Mixed conductive and sensorineural Hearing Loss (MHL).1 SNHL, caused by damage to the cochlea or auditory nerve, is the most common type, with sudden cases (Sudden Idiopathic Hearing Loss; SIHL) affecting 5–27 per 100,000 annually in the United States and prevalence increasing significantly with age.2 CHL, caused by impaired sound transmission in the outer or middle ear, commonly arises from otitis media and affects approximately 1.7% of children globally, with a substantially higher burden in low- and low-middle-income regions.3 MHL combines elements of both. Risk factors for HL include genetic predisposition, infections, ototoxic medications, noise exposure, and systemic conditions such as Autoimmune Diseases (ADs).4,5

ADs are conditions characterized by immune system dysregulation, leading to attacks on the body’s own tissues, with examples including Rheumatoid Arthritis (RA), Type 1 Diabetes (T1D), Systemic Lupus Erythematosus (SLE), and Sjögren’s Syndrome (SS).6 These diseases share mechanisms like autoantibody production, chronic inflammation, and cytokine imbalances, resulting in tissue damage and impaired immune tolerance.7 ADs are increasingly recognized as risk factors for HL due to their potential to mediate immune-driven damage to auditory structures.8 Mechanistically, autoantibodies and inflammatory cytokines disrupt the blood-labyrinth barrier, impair cochlear microcirculation, and induce oxidative stress, leading to hair cell apoptosis and auditory dysfunction.9 Chronic inflammation further destabilizes neural signaling and endolymphatic homeostasis, exacerbating HL.10 These processes highlight the vulnerability of auditory structures to immune-mediated damage.

While the association between ADs and HL has been reported, the causal relationship remains unclear. To address this, Mendelian Randomization (MR) analysis offers a robust approach to investigate potential causality between ADs and HL. MR utilizes genetic variants, typically Single Nucleotide Polymorphisms (SNPs) identified through Genome-Wide Association Studies (GWAS), as Instrumental Variables (IVs) to assess the causal relationship between an exposure and an outcome.11 By minimizing confounding and reverse causality, MR provides a reliable method to identify causal links that may not be feasible to explore through randomized controlled trials.12 This study employs a two-sample MR approach to investigate the genetically predicted causal relationship between ADs and HL. The findings may contribute to a better understanding of their connection and inform future research on preventive and therapeutic approaches.

This study provides evidence of causal relationships between ADs and HLs using MR analysis. Notable associations included AS-SNHL, AS-MHL, AS-CHL, AS-SIHL, SLE-CHL, UC-MHL, MS-SIHL, and CD-CHL and CD-SIHL. These results highlight the role of immune dysregulation in the pathogenesis of HL.

The association between AS and multiple HL subtypes highlights its potential role in auditory dysfunction. AS is a chronic inflammatory disease primarily affecting the axial skeleton, characterized by excessive immune activation, pro-inflammatory cytokine release, and systemic inflammation, which can contribute to vascular damage and multisystem involvement, including the auditory system.28 A systematic review and meta-analysis reported a 42.4% prevalence of HL in patients with AS, with significantly higher odds of HL and impaired hearing thresholds compared to individuals without AS.29 HL occurs when damage to the auditory system disrupts the function of inner ear cells and associated neural structures due to inflammation, oxidative stress, or vascular impairment.30 Pro-inflammatory cytokines elevated in AS, such as TNF-α and IL-6,31 disrupt cochlear microcirculation, leading to ischemic damage and impaired auditory function.32 Chronic inflammation in AS increases oxidative stress,33 which damages inner ear cells and contributes to HL. Vascular abnormalities frequently associated with AS, such as vasculitis and endothelial dysfunction,34 compromise blood flow to the cochlea, exacerbating auditory damage.35 These mechanisms provide a plausible explanation for the broad AS-HL associations observed in our study. Clinically, the robust AS-HL association warrants attention to auditory function in AS patients, particularly those with severe systemic inflammation or prolonged disease duration. Routine auditory monitoring may help identify early signs of HL and mitigate its impact on quality of life.

Following AS, Inflammatory Bowel Diseases (IBD), including CD and UC, were the second most frequently associated ADs with HL, demonstrating significant relationships with MHL, CHL, and SIHL. HL associated with CD may result from neuropathy of the cochlear nerve due to vitamin B1 deficiency, a common complication in CD caused by malnutrition, vomiting, or chronic inflammation.36 Additionally, SNHL in UC may be driven by autoimmune inner ear disease, immune-mediated damage to the cochlea, systemic inflammation, or ototoxic effects of medications commonly used in IBD treatment.37 Furthermore, mutations in the STXBP3 gene, implicated in very early onset IBD, disrupt epithelial cell polarization and immune regulation, which may contribute to bilateral SNHL in IBD, highlighting a genetic component to this association.38 Subclinical cochlear involvement, often beginning at high frequencies, has been documented in pediatric IBD patients and is proposed to result from vasculitis and immune complex deposition in cochlear vessels as additional mechanisms for HL.39 These findings underscore the importance of implementing early auditory screening and monitoring strategies in IBD patients with pediatric onset or severe systemic inflammation to prevent or mitigate HL progression effectively.

Significant associations were also found for SLE-CHL and MS-SIHL. SLE causes HL predominantly through immune complex deposition in the stria vascularis and endolymphatic sacs, leading to ischemia and cytotoxic damage to cochlear hair cells, with secondary SS further exacerbating the risk.40 Similarly, MS-SIHL may result from neuroinflammatory and neurodegenerative processes characteristic of MS, including oxidative stress, mitochondrial dysfunction, and demyelination within auditory pathways. The accumulation of toxic tau proteins in MS further disrupts neuronal function, potentially impairing auditory signal transmission and contributing to SNHL.41 Both SLE and MS involve inflammatory mechanisms that impair cochlear function, highlighting the need for targeted approaches to manage HL in these conditions.

This study provides novel evidence of robust AD-HL associations using MR methods. However, the relatively smaller sample sizes for certain conditions, such as SLE and less common HL subtypes may reduce statistical power. Additionally, the possibility of residual pleiotropy and confounding remains despite sensitivity analyses. The lack of longitudinal data further limits the ability to evaluate the temporal dynamics and potential reversibility of HL. Addressing these issues in future studies through larger datasets, refined statistical approaches, and longitudinal designs will enhance the robustness and clinical applicability of the findings.

This study identified significant causal associations between ADs and specific subtypes of HL. These findings underscore the role of immune dysregulation in the pathogenesis of auditory dysfunction and highlight the need for early audiological assessment and targeted therapeutic strategies in AD management to mitigate HL and improve patient outcomes.

Yutong Huang: 0000-0002-0906-687X

Shengli Gao: 0000-0002-3523-2333

Renzhong Luo: 0000-0003-1521-4602

Yutong Huang carried out the studies, participated in collecting data, performed the statistical analysis and drafted the manuscript. Renzhong Luo and Shengli Gao participated in its design. All authors read and approved the final manuscript.

This study was supported by supported by scientific research foundation for Ph.D of Guangzhou Women and Children's Medical Center, Guangzhou Medical University (2021BS027, Applications of Electrically Evoked Cortical Auditory Evoked Potentials in Cochlear Implant), basci and applied basic research program of Guangzhou Municipal Science and Technology Bureau (2023A04J1240, Applications of Electrically Evoked Cortical Auditory Evoked Potentials in Postoperative Evaluation for Pediatric Cochlear), and Science and Technology Project of Guangzhou (2023A03J0909, etiology and genetic analysis of severe sensorineural hearing loss in children in the Pearl River Delta).

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

All data generated or analysed during this study are included in this published article and its Supplementary Information File.