Age-Related Differences in Bitter Taste and Efficacy of Bitter Blockers

Citation: Mennella JA, Reed DR, Roberts KM, Mathew PS, Mansfield CJ ( Age-Related Differences in Bitter Taste and Efficacy of Bitter Blockers Julie A. Mennella 0 Danielle R. Reed 0 Kristi M. Roberts 0 Phoebe S. Mathew 0 Corrine J. Mansfield 0 Maik Behrens, German Institute of Human Nutrition Potsdam-Rehbruecke, Germany 0 Monell Chemical Senses Center , Philadelphia, Pennsylvania , United States of America Background: Bitter taste is the primary culprit for rejection of pediatric liquid medications. We probed the underlying biology of bitter sensing and the efficacy of two known bitter blockers in children and adults. Methods: A racially diverse group of 154 children (3-10 years old) and their mothers (N = 118) evaluated the effectiveness of two bitter blockers, sodium gluconate (NaG) and monosodium glutamate (MSG), for five food-grade bitter compounds (quinine, denatonium benzoate, caffeine, propylthiouracil (PROP), urea) using a forced-choice method of paired comparisons. The trial was registered at clinicaltrials.gov (NCT01407939). Results: The blockers reduced bitterness in 7 of 10 bitter-blocker combinations for adults but only 3 of 10 for children, suggesting that efficacy depends on age and is also specific to each bitter-blocker combination. Only the bitterness of urea was reduced by both blockers in both age groups, whereas the bitterness of PROP was not reduced by either blocker in either age group regardless of TAS2R38 genotype. Children liked the salty taste of the blocker NaG more than did adults, but both groups liked the savory taste of MSG equally. Conclusions and Relevance: Bitter blocking was less effective in children, and the efficacy of blocking was both age and compound specific. This knowledge will pave the way for evidence-based strategies to help develop better-tasting medicines and highlights the conclusion that adult panelists and genotyping alone may not always be appropriate in evaluating the taste of a drug geared for children. - Data Availability: The authors confirm that all data underlying the findings are fully available without restriction. Data are deposited in the Digital Data Repository (dryad.org) under DOI number doi:10.5061/dryad.1jb04. Funding: The authors acknowledge the National Institute of Deafness and Other Communication Disorders (NIDCD), National Institutes of Health (NIH), for funding and support for this project (R01 DC011287). Genotyping was performed at the Monell at the Genotyping and DNA/RNA Analysis Core, which is supported, in part, by funding from NIH-NIDCD core grant P30DC011735. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. Unlike most adults, children have problems swallowing medicines in formulations such as pills or tablets, which have the advantage of encapsulating the active pharmaceutical ingredients (API). Instead, parents prefer that their children take medicine in liquid formulations, but here the central challenge becomes a matter of taste because APIs, by their nature, often are rejected because of their unpleasant tastes, with bitter being the primary culprit [1]. Most drugs work by changing physiological processes within cells, so APIs have the potential to be toxic when ingested in sufficient quantity. Bitter taste is thought to have evolved as a deterrent against ingestion of potentially harmful substances [2], which may explain why many drugs taste bitter. However, this bitter taste is also a major challenge to achieving medication compliance in pediatric patients. Bitter perception starts at the level of the receptor. These are about 25 different bitter receptors (T2Rs) with genes clustered primarily on chromosomes 7 and 12 [3,4]. The large number of receptors is needed because, of all the basic tastes, bitter is the most diverse [5]. Most T2Rs studied have binding profiles that involve several different bitter-tasting ligands [5,6]. Likewise, a given bitter-tasting ligand can activate more than one T2R. This system accommodates the range of molecules that are perceived as bitter. Bitter taste is also perceptually diverse, and people differ markedly in their perceptions of the same compound. As an example, the perception of 6-n-propylthiouracil (PROP), which is primarily recognized by the most intensively studied T2R genethe TAS2R38 bitter receptor [7]differs among people due to genetic variants within its receptor. Bitter taste biology has opened new avenues to better understand taste perception in children and how unpleasant tastes might be reduced [8,9]. Although several molecules that inhibit bitterness have been identified [10,11], there are few peerreviewed studies on the effectiveness of these bitter blockers (e.g., sodium salts, monosodium glutamate) in adults [8,12,13,14,15,16,17], and even fewer involving children [8]. To this end, the present study tested the efficacy of two food-grade bitter blockers, sodium gluconate (NaG) and monosodium glutamate (MSG), against five generally recognized as safe (GRAS) bitter agents in solution, in both children and adults. We used the same methodology in both age groups to determine if there were age-related differences in the efficacy of the blockers against quinine, denatonium benzoate (DB), caffeine, PROP, and urea, which represent a range of presumed classes of bitterness [18] but whose intensity can be as great as many oral formulations of medications, thus providing a useful model system for evaluating bitter blockers in children. Genetic variants of TAS2R38 affect an individuals perception of the bitterness of PROP, even in children [7,19], so each participant was genotyped for its receptor and phenotyped for PROP detection thresholds using a method that has shown reliability for children, adolescents, and adults [20]. Surprisingly, there have been no studies to date investigating whether the bitter taste of PROP can be blocked by either of these sodium salts. Participants Women with one or more children between the ages of 3 and 10 years were recruited from advertisements in local newspapers and Internet sites and from a database of past participants who asked to be notified of future research studies. During the telephone interview, the mothers were given detailed descriptions of the procedures for the taste study but were not told the goals of the study or hypotheses being tested. Women who were diabetic, pregnant, or lactating were not eligible; pregnancy tests were conducted on the day of testing to confirm they were not pregnant. The Office of Regulatory Affairs at the University of Pennsylvania approved all procedures. Written informed consent was obtained from each adult, and assent was obtained from each child 7 years of age or older. Mothers completed questionnaires regarding demographics and racial/ethnicity identity. The trial was registered at clinicaltr (...truncated)