Relationship between Metabolomics Profile of Perilymph in Cochlear-Implanted Patients and Duration of Hearing Loss

Abstract

Perilymph metabolomic analysis is an emerging innovative strategy to improve our knowledge of physiopathology in sensorineural hearing loss. This study aims to develop a metabolomic profile of human perilymph with which to evaluate the relationship between metabolome and the duration of hearing loss. Inclusion criteria were eligibility for cochlear implantation and easy access to the round window during surgery; patients with residual acoustic hearing in the ear to be implanted were excluded. Human perilymph was sampled from 19 subjects during cochlear implantation surgery. The perilymph analysis was performed by Liquid Chromatography−High-Resolution Mass and data were analyzed by supervised multivariate analysis based on Partial Least-Squares Discriminant Analysis and univariate analysis. Samples were grouped according to their median duration of hearing loss. We included the age of patients as a covariate in our models. Statistical analysis and pathways evaluation were performed using Metaboanalyst. Nineteen samples of human perilymph were analyzed, and a total of 106 different metabolites were identified. Metabolomic profiles were significantly different for subjects with ≤12 or >12 years of hearing loss, highlighting the following discriminant compounds: N-acetylneuraminate, glutaric acid, cystine, 2-methylpropanoate, butanoate and xanthine. As expected, the age of patients was also one of the main discriminant parameters. Metabolic signatures were observed for duration of hearing loss. These findings are promising steps towards illuminating the pathophysiological pathways associated with etiologies of sensorineural hearing loss, and hold open the possibilities of further explorations into the mechanisms of sensorineural hearing loss using metabolomic analysis.

Metabolomic Studies in Inner Ear Pathologies

“…Perilymph was used in six of thirteen studies; perilymph has the advantage of being closer to metabolic mechanisms because hair cell bodies are immersed in this fluid [ 13 , 14 ] The volumes obtained for analysis were small, ranging from <1 μL in humans [ 8 , 15 ] to 5 μL in guinea pigs [ 16 , 17 ]. Two studies collected human perilymph during cochlear implantation [ 8 , 15 ]. Three studies involved the metabolomic analysis of guinea pig perilymph [ 16 , 17 , 18 ].…”

“…The analytical methods used to perform the metabolomic analyses were NMR spectrometry in one study [ 7 ], GCMS in four studies [ 16 , 23 , 24 , 25 ], and LCMS in eight studies [ 15 , 17 , 18 , 19 , 20 , 21 , 22 ]. Mass spectrometry (GCMS and LCMS) has a greater sensitivity than NMR spectrometry; however, this technique suffers from limited reproducibility [ 26 ].…”

“…The most frequent metabolites were asparagine and lactate [ 8 ]. An analysis between the metabolomic profile of the perilymph and the duration of hearing loss was performed [ 15 ]. A total of 106 different metabolites were found using the LCMS technique in the 19 included patients [ 8 ].…”

“…With the exception of two papers [ 21 , 22 ], the etiologies were unknown. This allowed for the observation of the impairment of certain metabolic pathways and correlations, such as with N-acetylneuraminate and the duration of hearing loss [ 15 ] or ceramide accumulation [ 21 ]. Metabolomic analysis using in vitro models may allow for preliminary discovery of the pathophysiology of hearing loss and may be an initial step towards using drug therapeutics in animals.…”

Extracellular Biomarkers of Inner Ear Disease and Their Potential for Point‐of‐Care Diagnostics

“…However, the intensity of mass spectrometry signals for creatinine was very high in human perilymph, whereas lactate had the greatest intensity in both humans and guinea pigs. [ 44 ] Further human cohort studies are now required to elucidate which metabolite biomarkers are useful indicators of human inner ear health and at which age they may be most useful (as the perilymph metabolomic profile is different between children ≤12 years old and those >12 years of age [ 45 ] ).…”