Hormonal and Multi-Omic Factors Associated with Tinnitus Incidence and Remission in Women - ABSTRACT Over 50 million Americans experience tinnitus, a phantom perception of a sound in the absence of an external stimulus, which can cause considerable suffering and disability. Up to 20% of those with recent onset tinnitus report subsequent remission ~2 years later, but the factors that lead to remission are unclear. Tinnitus arises from neuroplastic changes in auditory and nonauditory brain regions. Female hormones, the gut-brain axis and metabolic factors are key regulators of neuroplasticity, but the role of these factors in tinnitus development and remission has not been well-studied. Estrogen (E) and progestogens (P) modulate neuroplasticity, particularly during female hormonal transition periods across the lifecourse, influencing functional connectivity, neurotransmission and brain structure. Growing evidence highlights the role of the gut-brain axis in neuroplasticity and in microbial-related alterations in neurotransmitters implicated in tinnitus, such as gamma- aminobutyric acid (GABA) and serotonin (5-HT). We found certain metabolic pathways and plasma metabolites are associated with prevalent tinnitus, yet evidence for how the hormonal milieu, gut microbiome and plasma metabolites influence tinnitus incidence and the likelihood of remission is needed. We hypothesize that hormonal, gut microbial and plasma metabolomic factors are associated with tinnitus incidence and remission. Unraveling this complex interplay will provide a strong scientific framework for prevention and treatment strategies. We will evaluate the temporal associations of these factors in the Nurses' Health Studies (NHS, NHS2), leveraging data from decades of prospectively collected information, including plasma hormone, stool microbiome, plasma metabolomic measurements and repeated tinnitus assessments, to examine the role of these factors in the development of incident persistent tinnitus and in tinnitus remission. In Aim 1, we will examine (a) the longitudinal associations of endogenous and exogenous E and P exposures across the life- course (e.g. reproductive factors, menopausal hormone therapy) (n>100,000) and previously measured plasma E and P (n>6000) and risk of incident persistent tinnitus, and (b) the likelihood of tinnitus remission. In Aim 2, we will investigate the role of the gut microbiome in targeted and agnostic analyses. In two separate nested case- control studies (300 cases/300 controls each), we will examine gut microbial composition and function in (a) the development of incident tinnitus and (b) in tinnitus remission. In Aim 3a, we will leverage plasma metabolomics data (N=9187;1573 incident cases) to identify plasma metabolomic factors associated with risk of incident tinnitus. In Aim 3b, we will conduct a nested case-control study in 400 women with recent onset tinnitus at the time of the blood collection, 20% of whom reported subsequent remission ~2 years later, to identify metabolomic factors associated with tinnitus remission. Findings from this project will further scientific understanding of tinnitus incidence and remission, elucidate opportunities for prevention and new avenues for clinical treatment, and have substantial public health impact.
