Persistent Tinnitus Linked to Individual Metabolites and Metabolite Classes for the First Time

There’s growing evidence that tinnitus develops and persists because of complex interactions between individual-level and environmental factors. Metabolite levels reflect an individual’s diet, environment, and gut microbiome, and researchers at Brigham and Women’s Hospital recently became the first to find associations between plasma metabolomic profiles and persistent tinnitus.

Oana Alina Zeleznik, PhD, an instructor in the Channing Division of Network Medicine of the Department of Medicine, Sharon G. Curhan, MD, ScM, director of the CHEARS: Conservation of Hearing Study, and colleagues report their findings and the implications for drug development in JAMA Otolaryngology—Head & Neck Surgery.


The team drew data from two large prospective cohorts: the Nurses’ Health Study, initiated in 1976, which enrolled 121,700 U.S. female registered nurses ages 30 to 55, and the Nurses’ Health Study II, initiated in 1986, which enrolled 116,429 female registered nurses ages 25 to 42. Participants have been followed up biennially with health status questionnaires, and on two occasions, they were invited to provide blood samples.

The outcome of this study was self-reported persistent tinnitus, defined as “ringing, roaring or buzzing in your ears or head” experienced daily for five minutes or more during one or more years of follow-up. The analysis included 6,477 women (average age 52, 95% white) with metabolomic data available: 488 with persistent tinnitus and 5,989 controls who said they had never experienced tinnitus.

Individual Metabolites

466 metabolites were included in the study. In a fully adjusted model, eight were associated with tinnitus at a statistically significant level, although the effect sizes were modest. Six metabolites were positively associated:

  • Homocitrulline, an amino acid (OR, 1.32)
  • C38:6 phosphatidylethanolamine (OR, 1.24)
  • C36:4 phosphatidylethanolamine (OR, 1,22)
  • C40:6 phosphatidylethanolamine (OR, 1.22)
  • C52:6 triglyceride (OR, 1.22)
  • C56:7 triglyceride (OR, 1.21)

Triglycerides are vital components of fatty acid metabolism. Phosphatidylethanolamines, the second most abundant cellular phospholipids, are involved in protein biogenesis, oxidative phosphorylation, membrane fusion, and mitochondrial stability.

Two metabolites were significantly inversely associated with tinnitus:

  • α-keto-β-methylvalerate (OR, 0.68), a branched-chain amino acid
  • Levulinate (OR, 0.60), a food additive and calcium supplement

Metabolite Classes

In metabolite set enrichment analysis, three metabolite classes were positively associated with tinnitus:

  • Triglycerides
  • Phosphatidylethanolamines
  • Diacylglycerols—Neutral lipids that have a central role in multiple metabolic processes and signaling pathways

Metabolite classes inversely associated with tinnitus were:

  • Phosphatidylcholine plasmalogens—Common glycerophospholipids that rigidify membranes, facilitate signaling processes, scavenge for free radicals and protect membrane lipids from oxidation
  • Lysophosphatidylcholines—The preferred carrier of long-chain polyunsaturated fatty acids across the blood–brain barrier
  • Cholesteryl esters—A major component of high-density lipids

Associations of tinnitus with the individual metabolites and metabolite classes were strikingly stronger for participants with no hearing loss than those with moderate or severe hearing loss.

A Potential Foundation for Novel Therapies

Lipids play a fundamental role in the pathophysiology of neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis. Alterations of triglycerides, phosphatidylethanolamines, phosphatidylcholine plasmalogens, and cholesteryl esters have been observed in these diseases, so the results of this study suggest lipid dysregulation also has a role in tinnitus.

Tinnitus is probably driven by dysregulation of whole metabolomic pathways rather than alterations in individual metabolites. Metabolomic profiling is a promising approach to identifying therapeutic targets for this challenging disorder.

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