Who are highly sensitive to bitterness are less likely to get COVID-19


If you can’t stand broccoli, celery or kale, you may be a supertaster, and it just might protect you from COVID-19.

Supertasters are folks who are highly sensitive to bitterness. They’re not only less likely to get COVID-19 than people who aren’t so sensitive to sharp, pungent flavors, they’re also less likely to wind up hospitalized with it, researchers said.

What’s more, supertasters in a new study experienced COVID-19 symptoms for only about five days, compared with an average 23 days among non-tasters.

Exactly how or even if taste affects COVID-19 risk isn’t fully understood, but researchers do have a theory.

Bitter taste receptors – including one called T2R38 – are found in the taste buds of your tongue.

“When T2R38 is stimulated, it responds by producing nitric oxide to help kill or prevent further replication of viruses in the respiratory mucosa,” said researcher Dr. Henry Barham, an ear, nose, and throat specialist in Baton Rouge, La. These mucus membranes line your respiratory system and provide a point of entry for viruses, including SARS-CoV-2, which causes COVID-19.

“The results carry important implications, like allowing people to make more informed choices and potentially prioritizing vaccination administration,” Barham said.

Several studies are looking at how bitter taste receptors affect risk for COVID-19 and other upper respiratory infections, he added.

This study included close to 2,000 people (average age 46) whose ability to taste was tested using paper strips. All were tested before having COVID-19, as it could compromise their sense of taste and smell.

The participants were placed into one of three groups: Non-tasters, supertasters, and tasters.

Non-tasters are folks who can’t detect certain bitter flavors at all. Supertasters, on the other hand, are extremely sensitive to bitterness and can detect exceedingly small levels. Tasters fit somewhere in between.

During the study, 266 participants tested positive for COVID-19. Non-tasters were much more likely than supertasters to get infected and were also more likely to have severe COVID-19.

Tasters were likely to display mild-to-moderate COVID-19 symptoms, often not requiring hospitalization. Those who had underlying conditions or were older with decreased ability to taste bitterness were the exception, the study found.

The findings were published online May 25 in JAMA Network Open.

Dr. Alan Hirsch, neurological director of the Smell & Taste Treatment and Research Foundation in Chicago, has spent his career studying the effects of lost smell and taste on disease. He reviewed the study results.

“The new findings make a lot of sense,” he said. Hirsch suggested that folks would benefit from finding out their own tasting status.

“If you are unable to taste bitterness, you should be that much more careful and wear masks for a longer duration to protect yourself from COVID-19,” Hirsch said. Unfortunately, he added, most people don’t know which type of taster they are.

Home- and office-based tests can tell you where you fit on the taste spectrum.

But here’s an easier option: “If celery tastes bitter to you,” Hirsch said, “you’re a supertaster, and if it doesn’t, be careful.”

A cluster of viral pneumonia cases associated with a novel Coronavirus (2019-nCoV) was first identified in Wuhan, Hubei Province, China, in December 2019 and has rapidly spread around the world, causing a global health crisis. The disease was subsequently named Coronavirus Disease-2019 (COVID-19) by the World Health Organization and has been designated Severe Acute Respiratory Syndrome-Coronavirus 2 (SARS-CoV-2). Significant concern has arisen within the global community regarding the potential risks of infectious transmission of SARS-CoV-2 [1].

The outbreak is still progressing and the pandemic is still uncontrolled, and the morbidity, mortality, and transmissibility of this novel coronavirus remain unresolved. Without the availability of effective antiviral therapies, compulsory measures have to be taken to prevent person-to-person transmission. However, for those severe cases, the chances of death remain elevated [2,3]. Factors such as social and psychological stress, economic hardship, and inconsistent virulence of SARS-CoV-2 are likely contributing to the apparent lack of adherence to the advised behavior modifications.

The ability to identify those individuals whose health is most at risk by SARS-CoV-2 may allow society to balance social re-engagement more efficiently with protection of public health. School attendance, mass gatherings, travel, and so forth, may be able to resume more fully.

Despite some suggestions, there are no drugs available to cure the patients affected by this catastrophic disease [4]. The identification of effective medicines to fight this disease is urgently needed. Existing host-directed therapies, which have proven to be safe, were suggested to help fight COVID-19 infections [5,6,7].

To identify more therapeutic drugs, we focused on a special G-protein-coupled receptor (GPCR) family named type 2 taste receptors (T2Rs), which was shown to play a critical role in host defense pathways [8,9]. Originally, T2Rs, whose ligands are bitter substances, were thought to be only expressed in the tongue. However, recent studies revealed that they are widely expressed in extraoral tissues, such as the central nervous system, respiratory tract, breast, heart, gastric and intestinal mucosa, bladder, pancreas, testes, and others [10,11].

This suggests that T2Rs might have functions other than bitter taste perception. Indeed, they were suggested to be involved in appetite regulation, the treatment of asthma, the regulation of gastrointestinal motility, and the control of innate immunity [9,11,12,13]. T2Rs can be classified into broadly, narrowly, and intermediately tuned receptors according to the agonist spectra [14].

In the airway, T2Rs are present on ciliated epithelial cells and solitary chemosensory cells (SCC). T2R38, one of the many isoforms of T2Rs, is a receptor that is localized to motile cilia in humans, and is agonized by phenylthiocarbamide (PTC) and propylthiouracil (PROP) [15]. When T2R38 is stimulated by agonists, nitric oxide (NO) is produced to increase mucociliary clearance (MCC) and kill pathogens in the human respiratory mucosa [16].

Interestingly, in a prior study evaluating the effects of NO on SARS-CoV, Åkerström et al. found that NO inhibits the replication of SARS-CoV by two distinct mechanisms. Firstly, NO or its derivatives cause a reduction in the palmitoylation of nascently expressed spike (S) protein which affects the fusion between the S protein and its cognate receptor, angiotensin-converting enzyme 2 (ACE2). Secondly, NO or its derivatives cause a reduction in viral RNA production in the early steps of viral replication, and this could possibly be due to an effect on one or both of the cysteine proteases encoded in Orf1a of SARS-CoV [17].

Three single nucleotide polymorphisms in the gene that encodes T2R38, TAS2R38, confer two common haplotypes including the functional variant PAV (proline–alanine–valine) and the nonfunctional variant AVI (alanine–valine–isoleucine). Homozygotes for the functional allele (PAV/PAV) perceive T2R38 agonists like PTC and PROP as intensely bitter, while homozygotes for the nonfunctional allele (AVI/AVI) are unable to perceive this bitterness. Heterozygotes (PAV/AVI) demonstrate a wide range of bitter taste perception depending on the level of expression of the nonfunctional and functional alleles [18,19].

The homozygotes for the functional alleles, nonfunctional alleles, and heterozygotes were classified as supertasters, nontasters, and tasters, respectively. Sinonasal epithelial cells cultured from AVI/AVI individuals compared to cells cultured from PAV/PAV individuals also demonstrate reduced NO release with a resultant decrease in ciliary beat frequency (CBF) and MCC. Compared to PAV/PAV CRS patients, AVI/AVI patients also demonstrate increased susceptibility to upper respiratory infections [20,21].

Prior studies have shown evidence for an association between the PTC/PROP taste test and sinonasal innate immunity, concluding that the ability to assess airway taste receptor variation with an inexpensive taste test has broad implications, as differences in airway taste receptor function may reflect impaired innate immunity and predisposition to certain respiratory infections and inflammatory disorders, and T2R38 functionality in the tongue correlates with nasal symptoms in healthy individuals [22,23].

In a retrospective study performed by Barham et al. on 100 positive cases of COVID-19 confirmed by polymerase chain reaction (PCR), phenotypic expression of T2R38 with taste strip testing appeared to associate with the clinical course and symptomatology specific to each individual as 100% of the patients requiring inpatient admission were classified as nontasters. Conversely, supertasters represented 0% of the patient population, suggesting the possibility of innate immunity to SARS-CoV-2 [1].

As previously mentioned, T2Rs in the upper airway are not limited to ciliated epithelial cells, but are also on solitary chemosensory cells (SCCs), which are rare, nonciliated, epithelial cells which express both sweet (T1R2/3) and T2R receptors. While acyl-homoserine lactones (AHLs) in the human nose stimulate T2Rs on ciliated cells to activate NO production, in vitro studies have found that activation of T2Rs present on human SCCs by denatonium benzoate (DB) and other bitter-tasting compounds such as absinthin, parthenolide, and amoraogentin results in a release of intracellular Ca2+, which propagates to the surrounding epithelial cells via gap junctions and stimulates release of antimicrobial peptides(AMPs) stores [16].

AMPs include β-defensin-1 and 2 in the epithelial cells of the respiratory tract that can vigorously block the interaction between the virus and its receptor. Significantly, this immune activation does not occur with AHL stimulation of human SCCs. It is hypothesized that an as yet unidentified bacterial product/byproduct triggers T2Rs on human SCCs to activate this robust antimicrobial defense pathway [24]. Markogenin et al. found that the stimulation of T2Rs on SCC via DB resulted in inhibition of human respiratory epithelial two-pore potassium current in polarized nasal epithelial cells (via a cAMP-dependent signaling pathway), leading to lower threshold for human β-defensin-2 release [25].

One proposed hypothesis suggested that any bitter-tasting drug could have some unintended effects in the body through the activation of T2Rs [26]. With the widespread distribution of the approximately 25 T2Rs in human tissues, inhaled or orally administered bitter drugs could also exhibit off-target effects that are beneficial to the system [27]. There are few reports of bitter-tasting antibiotics activating T2Rs.

Ofloxacin has been shown to activate T2R9, and chloramphenicol and erythromycin activate multiple T2Rs [19,28]. Analysis of the structural features of antibiotics from classes including fluoroquinolones, aminoglycosides, and macrolides reveals their close identity with or as derivatives of the parent structures of the aforementioned bitter-tasting compounds. Thus, many of the prescribed antibiotics might also interact with T2Rs expressed in the extraoral tissues [29].

In a prior study, Jaggupilli et al. performed experiments to determine the bitterness of the antibiotics by electronic taste sensor analysis or electronic tongue (E-tongue) analysis. The E-tongue does not contain actual taste receptors; it predicts the taste of test compounds in reference to known compounds based on physiochemical properties and conductivity measurements. It is commonly used to predict the taste of pharmaceutical formulations including antibiotics which might be harmful. The data for the antibiotics tested presented different ranges of predicted bitterness score, with a high predicted bitterness for the azithromycin (15.8), and lower bitterness scores for levofloxacin (4.5) and tobramycin (3.5). Interestingly, the antibiotic with the highest bitterness score, azithromycin, activated T2R4 [29].

Quinine derivatives bind to the T2Rs (expressed in SCCs) and airway smooth muscle cells [30] with the resultant stimulation of airway smooth muscle cells leading to airway relaxation [31]. Chloroquine (CQ) has been tested in a prophylactic and treatment model of allergic airways disease (murine asthma) and was able to mitigate airway inflammation, remodeling, mucus secretion, and airway hyperresponsiveness, some of the cardinal features of allergen-induced asthma in mice [32]. CQ has been shown to have an antimitogenic effect on airway smooth muscle, inhibiting the growth of human airway smooth muscle cells by activating T2Rs [33], and it may provide additional beneficial effects particularly as an immunomodulator [32,34].

Based on the aforementioned, we proposed a treatment protocol for COVID-19 patients based on their T2R38 phenotype (supertasters, tasters, and nontasters) dependent on the fact that supertasters have two copies of the functional alleles (PAV/PAV) and should not require agonists to their T2Rs, as they have high levels of NO to eliminate infection. On the other hand, tasters (those with one functional allele; PAV/AVI) would require a T2R agonist to boost their NO levels.

That is why we proposed the supplying of azithromycin, not only as an anti-inflammatory drug, but also as a T2R agonist. The same protocol is provided for the nontaster (T2R38) group, but for a longer duration. Hydroxychloroquine (HCQ) was used in tasters as quinine derivatives, which are known agonists of T2Rs. Dexamethasone was added to all three groups to limit their nasal inflammations, congestion, and cytokine storm, and assist in olfaction preservation.

reference link : https://www.mdpi.com/1999-4915/13/3/503/htm

More information: Henry P. Barham et al, Association Between Bitter Taste Receptor Phenotype and Clinical Outcomes Among Patients With COVID-19, JAMA Network Open (2021). DOI: 10.1001/jamanetworkopen.2021.11410


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