Certain Plasma Metabolites and Metabolite Classes Linked to Persistent Tinnitus

Metabolites are downstream of the genetic transcription process, reflecting direct input from the diet, environment, and intestinal microbiome. Systematic analyses of metabolites have identified biological pathways underlying several neurodegenerative disorders.

Mass General Brigham researchers recently completed the first human study that examined links between metabolites and persistent tinnitus. In JAMA Otolaryngology–Head & Neck Surgery, they say metabolomic profiling is a promising approach to pinpointing tinnitus biomarkers and should provide valuable insights into the pathophysiology of the disorder.

The authors are Oana A. Zeleznik, PhD, an epidemiologist in the Channing Division of Network Medicine of the Department of Medicine at Brigham and Women’s Hospital and instructor in Medicine at Harvard Medical School , D. Bradley Welling, MD, PhD, of the Department of Otolaryngology–Head and Neck Surgery at Mass Eye and Ear, Sharon G. Curhan, MD, ScM, a physician and epidemiologist in the Channing Division of Network Medicine and assistant professor of Medicine at Harvard Medical School, and colleagues.


The researchers analyzed data from CHEARS: The Conservation of Hearing Study, which includes two large, richly characterized cohorts of U.S. women:

  • The Nurses’ Health Study (NHS), which enrolled 121,700 female registered nurses, ages 30 to 55, in 1976
  • The Nurses’ Health Study II (NHS II), which enrolled 116,429 female registered nurses, ages 25 to 42, in 1986

Participants complete questionnaires about reproductive history, lifestyle factors, diet, medication use, and new disease diagnoses every two years. In 1989–1990 and 1996–1999, subsets of participants provided blood samples to study a range of conditions. 466 individual metabolites and 22 metabolite classes were included in the current study.

Information on tinnitus was collected in 2012 and 2016 for the NHS and in 2009, 2013, and 2017 for the NHS II. 6,477 women, mean age 52, had information on tinnitus and measured plasma metabolomics. 488 had persistent tinnitus, defined as daily tinnitus that lasted 5 minutes or longer.

Individual Metabolites and Metabolite Classes

Six metabolites were independently significantly positively associated with tinnitus:

  • Homocitrulline—OR, 1.32 (95% CI, 1.16-1.50)
  • C38:6 phosphatidylethanolamine (PE)—OR, 1.24 (95% CIs, 1.12-1.38)
  • C52:6 triglyceride—OR, 1.22 (95% CIs, 1.10-1.36)
  • C36:4 PE—OR, 1.22 (95% CIs, 1.10-1.35)
  • C40:6 PE—OR, 1.22 (95% CIs, 1.09-1.35)
  • C56:7 triglyceride—OR, 1.21 (95% CIs, 1.09-1.34)

Two metabolites were independently significantly inversely associated with tinnitus:

  • α-keto-β-methylvalerate—OR, 0.68 (95% CIs, 0.56-0.82)
  • Levulinate—OR, 0.60 (95% CIs, 0.46-0.79)

Significant associations were also observed for several metabolite classes. The triglycerides (normalized enrichment score [NES], 2.68), PEs (NES, 2.48), and diglycerides (NES, 1.65) were positively associated with tinnitus. Phosphatidylcholine plasmalogens (NES, −1.91), lysophosphatidylcholines (NES, −2.23), and cholesteryl esters (NES, −2.3) were inversely associated.

Effect of Hearing Status

The team noted striking differences in metabolite profiles according to hearing status (moderate or severe hearing loss vs. no hearing loss). For example:

  • Several triglycerides and vitamin A were positively associated with tinnitus only among participants without hearing loss, and cholesteryl esters were inversely associated.
  • Positive associations were observed for diglycerides and organic acids only among participants without hearing loss, whereas inverse associations were observed for phosphatidylcholine plasmalogens, lysophosphatidylcholines, and cholesteryl esters.
  • In contrast, strong positive associations were observed for steroids and steroid derivatives only among participants with moderate or severe hearing loss.

The Complexity of Identifying Therapeutic Targets

Although individual metabolites were significantly associated with tinnitus in this study, the effect sizes were modest. That suggests the development of tinnitus is driven by the dysregulation of whole metabolic pathways involving the interplay of several individual metabolites.

Tinnitus is complex in another way: it is a heterogeneous disorder and may be associated with metabolic alterations related to hyperlipidemia, atherosclerosis, hypertension, diabetes, and genetic and environmental factors that may affect inflammation, oxidative stress, neural transmission, and neuroplasticity. All of these factors may play a role in its pathophysiology.

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