Taste dysfunction in long COVID.

Persistent taste dysfunction is frequently reported in individuals with post-acute sequelae of infection by SARS-CoV-2 (Long COVID). The mechanisms and pathological correlates underlying this taste dysfunction are unknown. This study investigates the underlying pathology in 28 non-hospitalized subjects diagnosed with COVID-19 and who experienced taste disturbances more than 12 months after testing positive for SARS-CoV-2. To objectively establish the nature of taste deficit, we used the WETT taste test, which quantifies the subject’s ability to taste each of the five taste qualities: sweet, umami, bitter, sour, and salty. We then biopsied five to eight fungiform taste papillae (FP) in 20 of the 28 subjects. The FPs were analyzed histologically for overall taste bud structure and innervation, and by quantitative PCR (qPCR) for mRNA expression of markers for different taste receptor cells. Although all subjects had reported taste dysfunction, only three showed overall taste scores below the 10th percentile for a normal population adjusted for age and sex. However, 11 of the 28 subjects exhibited total loss of one or more taste qualities. Loss of PLCβ2-dependent taste qualities (sweet, umami, bitter) was significantly more common and was correlated with reduced expression of PLCβ2 and Tas1R3 mRNAs. Histological analysis revealed generally preserved taste bud structure and innervation, but with occasional disorganized taste buds and abnormal, isolated PLCβ2-positive cells in the epithelium. Our findings suggest long-term taste dysfunction after COVID-19 occurs rarely -- more frequently involving PLCβ2-dependent taste qualities -- but is not due to wholesale disruption of the taste periphery.

Oral sensory neurons of the geniculate ganglion (GG) innervate taste papillae and buds on the tongue and soft palate. Electrophysiological recordings of these neurons and fibers revealed complexity in the number of unique response profiles observed, suggesting there are several distinct neuronal subtypes. Molecular descriptions of these subpopulations are incomplete. We report here the identification of a subpopulation of GG oral sensory neurons in mice by expression of tyrosine hydroxylase (TH). TH-expressing geniculate neurons represent 10–20% of oral sensory neurons and these neurons innervate taste buds in fungiform and anterior foliate taste papillae on the surface of the tongue, as well as taste buds in the soft palate. While 35–50% of taste buds on the tongue are innervated by these TH+ neurons, 100% of soft palate taste buds are innervated. These neurons did not have extragemmal processes outside of taste buds and did not express the mechanosensory neuron-associated gene Ret, suggesting they are chemosensory and not somatosensory neurons. Within taste buds, TH-expressing fibers contacted both Type II and Type III cells, raising the possibility that they are responsive to more than one taste quality. During this analysis we also identified a rare TH+ taste receptor cell type that was found in only 12–25% of taste buds and co-expressed TRPM5, suggesting it was a Type II cell. Taken together, TH-expressing GG oral sensory neurons innervate taste buds preferentially in the soft palate and contact Type II and Type III taste bud receptor cells.

Many reports detail taste dysfunction in humans and animals with obesity. For example, mice consuming an obesogenic diet for a short period have fewer taste buds than their lean littermates. Further, rats with diet-induced obesity (DIO) show blunted electrophysiological responses to taste in the brainstem. Here, we studied the effects of high energy diet (HED)-induced peripheral taste damage in rats, and whether this deficiency could be reversed by returning to a regular chow diet. Separate groups of rats consumed a standard chow diet (Chow), a HED for 10 weeks followed by a return to chow (HED/chow), or a HED for 10 weeks followed by a restricted HED that was isocaloric with consumption by the HED/chow group (HED/isocal). Fungiform taste papilla (FP) and circumvallate taste bud abundance were quantified several months after HED groups switched diets. Results showed that both HED/chow and HED/isocal rats had significantly fewer FP and lower CV taste bud abundance than control rats fed only chow. Neutrophil infiltration into taste tissues was also quantified, but did not vary with treatment on this timeline. Finally, the number of cells undergoing programmed cell death, measured with caspase-3 staining, inversely correlated with taste bud counts, suggesting taste buds may be lost to apoptosis as a potential mechanism for the taste dysfunction observed in obesity. Collectively, these data show that DIO has lasting deleterious effects on the peripheral taste system, despite a change from a HED to a healthy diet, underscoring the idea that obesity rather than diet predicts damage to the taste system.

Deficient dietary intake of vitamin E in patients with taste and smell dysfunctions:: is vitamin E a cofactor in taste bud and olfactory epithelium apoptosis and in stem cell maturation and development?

Cancer and its treatment therapies, such as chemotherapy and radiotherapy, have negative effects on taste and smell functions. It is easy to explain smell and taste dysfunctions when a cancer involves the peripheric end organs or neurologic pathways of smell and taste. However, it is difficult to understand how distortion in sensory perception develops as cancer progresses and cancer therapies are applied, because few studies on this subject have described heterogeneous oncological patient populations who are receiving different treatment regimens. A literature review was performed about the chemical senses of the patients with various cancer types, and also about the possible mechanisms of taste and smell dysfunctions in cancer patients. Chemotherapy and radiotherapy may cause taste and smell alterations by destroying taste and olfactory receptor cells, creating alterations on the surfaces of cells and receptors as well as interrupting neural coding. The prevalence of taste dysfunctions in cancer patients has been reported to be up to 77%. Unlike taste dysfunction, diminished sensitivity of smell in cancer patients is described infrequently and the available literature contains some conflicting results for smell dysfunction in cancer patients. Further studies are needed on the loss of appetite in cancer patients, and specific treatments should be identified according to the pathologic mechanism responsible for anorexia and particularly for taste and smell dysfunctions. Because sufficient nutrition and energy intake can help patients overcome the cancer and its treatment-related complications.

COVID-19, mainly manifested as acute respiratory distress syndrome, has afflicted millions of people worldwide since 2019. Taste dysfunction is a common early-stage symptom of COVID-19 infection that burdens patients for weeks or even permanently in some cases. Owing to its subjectivity and complexity, the mechanism of taste disorder is poorly studied. Previous studies have reported that the COVID-19 entry receptors are highly expressed in taste buds, thereby intensifying the cytocidal effect. Taste receptor cells are vulnerable to inflammation, and the COVID-19-induced cytokine storm causes secondary damage to taste function. Interferon and various proinflammatory cytokines can trigger cell apoptosis and disrupt the renewal of taste bud stem cells. This immune response can be further enhanced by the accumulation of Angiotensin II (Ang II) caused by an unbalanced local renin-angiotensin system (RAS) system. In addition, severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) is neurotropic and can invade the brain through the olfactory bulb, affecting the nervous system. Other factors, such as host zinc deficiency, genetic susceptibility, sialic acid, and some neurotransmitters, also contribute to the pathogenesis process. Although several medical interventions have displayed effectiveness, only a few strategies exist for the treatment of postinfectious dysgeusia. Stem cell-based taste regeneration offers promise for long-term taste disorders. Clinical studies have demonstrated that stem cells can treat long COVID-19 through immune regulation. In dysgeusia, the differentiation of taste bud stem cells can be stimulated through exogenous epithelial-derived and neural-derived factors to regenerate taste buds. Tongue organoids are also emerging as functional taste buds, offering new insights into the study of taste regeneration. This review presents the current evidence of the pathogenesis of COVID-19-related dysgeusia, summarizes currently available treatments, and suggests future directions of taste regeneration therapy.

Neuroactive substances play important roles as transmitters and neuromodulators. Although many of these substances and/or their receptors are known to be present in taste receptor cells and nerve fibers innervating taste buds, physiological functions of these substances are not well understood (Nagai et al., 1996). Using Ca2+ imaging and immunocytochemical techniques, we have examined the physiological responses of taste receptor cells to acetylcholine (ACh), classified the types of ACh receptors, and determined the underlying signaling mechanisms in taste receptor cells. Our results suggest that ACh may be involved in cell-to-cell communication within the taste bud and in neuromodulation of taste transduction mechanisms. In Ca 2+ -imaging study, freshly isolated taste receptor cells were loaded with Ca2+-sensitive fluorescent dye Fura-2 and intracellular Ca2+ levels were measured ratiometrically. ACh induced increases in intracellular Ca 2+ levels ([Ca 2+ ]i) in taste receptor cells of mouse, rat and mudpuppy. The magnitude of the peak Ca 2+ response to ACh was concentration-dependent with half-maximum responses around 1 µM. To determine which subtypes of ACh receptors and signaling pathway were involved, we examined the effect of receptor antagonists and inhibitors for selective pathway. Atropine (0.5 µM), a muscarinic ACh receptor antagonist, blocked the ACh response, while D-tubocurarine (250 µM), a nicotinic ACh receptor antagonist, had no effect. In addition, the phospholipase C (PLC) inhibitor U73122 (5 µM) and the Ca 2+ -ATPase inhibitor thapsigargin (1 µM), which depletes intracellular Ca 2+ stores, blocked the ACh responses. These results suggest that ACh binds to muscarinic ACh receptors, which activates PLC, resulting in the production of IP3 and the subsequent release of Ca 2+ from the IP3-sensitive-intracellular stores. Since it is known that binding of ACh to muscarinic receptor subtypes M1/M3/M5 activates the PLC signaling pathways (Caulfield, 1993), our data indicates the presence of at least one of these receptors in taste receptor cells. Additionally, we found that prolonged stimulation (>1 min) with ACh (10 µM) induced a biphasic response with a transient followed by a sustained [Ca 2+ ]i increase. The sustained phase of the [Ca 2+ ]i increase was dependent on Ca 2+ influx as removal of extracellular Ca 2+ eliminated the response. Subsequently adding external Ca 2+ induced increases in [Ca2+] i , suggesting Ca2+ entry through Ca2+permeable channels. This is consistent with our previous studies showing presence of Ca 2+ store-operated channels (SOC) in taste cells (Ogura, 2002; Ogura et al., 2002). SOCs are activated solely by store depletion without requirement of a receptor-mediated mechanism, a mechanism also known as ‘capacitative calcium entry’. Thus it is possible that the sustained part of the ACh-induced calcium response is mediated by Ca 2+ influx through SOCs. In immunocytochemical study, sections containing rat circumvallate and foliate papillae were immunoreacted with an antiserum against the M1 subtype of muscarinic ACh receptors. Positive reaction was observed in many taste cells of each taste bud. In crosssections of rat circumvallate papillae, roughly half of the taste cells were immunolabeled. No selective labeling was observed in control sections, in which primary antibody was omitted. Preabsorption with antigen significantly reduced the labeling. This result suggests that taste receptor cells express M1 subtype of ACh receptor. Thus ACh can bind to the M1 subtype of the muscarinic receptors and activate the PLC/IP3 pathway. To study whether ACh is stored in synaptic vesicles in taste receptor cells and/or adjacent nerve fibers, we immunolabeled the vesicular ACh transporter (VAChT), a key element of AChcontaining vesicle in mouse taste tissue. A subset of taste receptor cells exhibited positive immunoreactivity to the antibody against VAChT. In addition, certain nerve fibers surrounding or within taste buds are positively reacted to antibodies against VAChT. These results suggest that taste receptor cells could release ACh for cell-tocell communications among taste receptor cells and/or synaptic transmission from taste receptor cells to taste sensory fibers. The presence of VAChT in adjacent nerve fibers also reveals a possibility of cholinergic modulations of taste receptor cells via the muscarinic receptors. Taken together, our results demonstrate ACh responses and its signaling pathway in taste receptor cells. Since ACh increases [Ca 2+ ]i via PLC-mediated pathway, ACh may regulate taste responses by means of changing [Ca 2+ ]i levels or PLC signaling. It is known that

Sensory organs are specialized to detect and decode stimuli in terms of intensity and quality. In the gustatory system, the process of identifying and distinguishing taste qualities (e.g. bitter versus sweet) begins in taste buds. A central question in gustatory research is how information about taste quality is extracted by taste receptor cells. For instance, whether and how individual taste cells respond to multiple chemical stimuli is still a matter for debate. A recent study showed that taste cells expressing bitter-responsive taste receptors do not also express sweet-responsive taste receptors and vice versa. These results suggest that the gustatory system may use separate cellular pathways to process bitter and sweet signals independently. Results from electrophysiological studies, however, reveal that individual taste receptor cells respond to stimuli representing multiple taste qualities. Here we used non-invasive Ca2+ imaging in slices of lingual tissue containing taste buds to address the issue of quality detection in murine taste receptor cells. We recorded calcium transients elicited by chemical stimuli representing different taste qualities (sweet, salty, sour and bitter). Many receptor cells (38 %) responded to multiple taste qualities, with some taste cells responding to both appetitive (‘sweet’) and aversive (‘bitter’) stimuli. Thus, there appears to be no strict and separate detection of taste qualities by distinct subpopulations of taste cells in peripheral gustatory sensory organs in mice.

Sensory organs are specialized to detect and decode stimuli in terms of intensity and quality. In the gustatory system, the process of identifying and distinguishing taste qualities (e.g. bitter versus sweet) begins in taste buds. A central question in gustatory research is how information about taste quality is extracted by taste receptor cells. For instance, whether and how individual taste cells respond to multiple chemical stimuli is still a matter for debate. A recent study showed that taste cells expressing bitter-responsive taste receptors do not also express sweet-responsive taste receptors and vice versa. These results suggest that the gustatory system may use separate cellular pathways to process bitter and sweet signals independently. Results from electrophysiological studies, however, reveal that individual taste receptor cells respond to stimuli representing multiple taste qualities. Here we used non-invasive Ca(2+) imaging in slices of lingual tissue containing taste buds to address the issue of quality detection in murine taste receptor cells. We recorded calcium transients elicited by chemical stimuli representing different taste qualities (sweet, salty, sour and bitter). Many receptor cells (38 %) responded to multiple taste qualities, with some taste cells responding to both appetitive ("sweet") and aversive ("bitter") stimuli. Thus, there appears to be no strict and separate detection of taste qualities by distinct subpopulations of taste cells in peripheral gustatory sensory organs in mice.

Taste substances are detected by taste receptor cells in the taste buds in the oral epithelium. Individual taste receptor cells contribute to evoking one of the five taste qualities: sweet, umami, bitter, sour, and salty (sodium). They are continuously replaced every few weeks by new ones generated from local epithelial stem cells. A POU transcription factor, Pou2f3 (also known as Skn-1a), regulates the generation and differentiation of sweet, umami, and bitter cells. However, the molecular mechanisms underlying terminal differentiation into these Pou2f3-dependent taste receptor cells remain unknown. To identify the candidate molecules that regulate the differentiation of these taste receptor cells, we searched for taste receptor type-specific transcription factors using RNA-sequence data of sweet and bitter cells. No transcription factor gene showing higher expression in sweet cells than in bitter cells was found. Eyes absent 1 (Eya1) was identified as the only transcription factor gene showing higher expression in bitter cells than in sweet cells. In situ hybridization revealed that Eya1 was predominantly expressed in bitter cells and also in the putative immature/differentiating taste bud cells in circumvallate and fungiform papillae and soft palate. Eya1 is a candidate molecule that regulates the generation and differentiation of bitter cells.

Developing and regenerating a sense of taste.

Gustatory neurons transmit chemical information from taste receptor cells, which reside in taste buds in the oral cavity, to the brain. As adult taste receptor cells are renewed at a constant rate, nerve fibers must reconnect with new taste receptor cells as they arise. Therefore, the maintenance of gustatory innervation to the taste bud is an active process. Understanding how this process is regulated is a fundamental concern of gustatory system biology. We speculated that because brain-derived neurotrophic factor (BDNF) is required for taste bud innervation during development, it might function to maintain innervation during adulthood. If so, taste buds should lose innervation when Bdnf is deleted in adult mice. To test this idea, we first removed Bdnf from all cells in adulthood using transgenic mice with inducible CreERT2 under the control of the Ubiquitin promoter. When Bdnf was removed, approximately one-half of the innervation to taste buds was lost, and taste buds became smaller because of the loss of taste bud cells. Individual taste buds varied in the amount of innervation each lost, and those that lost the most innervation also lost the most taste bud cells. We then tested the idea that that the taste bud was the source of this BDNF by reducing Bdnf levels specifically in the lingual epithelium and taste buds. Taste buds were confirmed as the source of BDNF regulating innervation. We conclude that BDNF expressed in taste receptor cells is required to maintain normal levels of innervation in adulthood.

Rationale: Gustation is important to several biological functions in mammals. However, chemotherapy drugs often harm taste perception in cancer patients, while the underlying mechanism is still unclear for most drugs and there is no effective way to restore taste function. This study investigated the effects of cisplatin on the taste cell homeostasis and gustatory function. Methods: We used both mice and taste organoid models to study the effect of cisplatin on taste buds. Gustometer assay, gustatory nerve recording, RNA-Sequencing, quantitative PCR, and immunohistochemistry was performed to analyze the cisplatin-induced alteration in taste behavior and function, transcriptome, apoptosis, cell proliferation and taste cell generation. Results: Cisplatin inhibited proliferation and promoted apoptosis in the circumvallate papilla, leading to significant impairment in taste function and receptor cell generation. The transcriptional profile of genes associated with cell cycle, metabolic process and inflammatory response was significantly altered after cisplatin treatment. Cisplatin inhibited growth, promoted apoptosis, and deferred taste receptor cell differentiation in taste organoids. LY411575, a γ-secretase inhibitor, reduced the number of apoptotic cells and increased the number of proliferative cells and taste receptor cells, potentially suggesting as a taste tissue protective agent against chemotherapy. LY411575 treatment could offset the increased number of Pax1+ or Pycr1+ cells induced by cisplatin in the circumvallate papilla and taste organoids. Conclusion: This study highlights the inhibitory effects of cisplatin on taste cell homeostasis and function, identifies critical genes and biological processes regulated by chemotherapy, and proposes potential therapeutic targets and strategy for taste dysfunction in cancer patients.

Background and Objectives: Disruption to taste and smell are common symptoms of COVID-19 infection. The current literature overlooks taste symptoms and tends to focus on the sense of smell. Persisting cases (>28 days) of taste dysfunction are increasingly recognised as a major future healthcare challenge. This study focuses on the severity and recovery of COVID-19 induced taste loss and association with olfactory symptoms, lifestyle and oral health factors. Materials and Methods: This study was a cross-sectional survey comparing 182 rapid taste recovery participants (≤28 days) with 47 participants with prolonged taste recovery >28 days. Analyses of taste loss in association with smell loss, age, sex, illness severity, diet, BMI, vitamin-D supplementation, antidepressants, alcohol use, smoking, brushing frequency, flossing, missing teeth, appliances and number of dental restorations were conducted. Differences in the severity of the loss of sour, sweet, salt, bitter and umami tastes were explored. Results: Both the severity and the duration of taste and smell loss were closely correlated (p < 0.001). Salt taste was significantly less affected than all other taste qualities (p < 0.001). Persisting taste loss was associated with older age (mean ± 95% CI = 31.73 ± 1.23 years vs. 36.66 ± 3.59 years, p < 0.001) and reduced likelihood of using floss (odds ratio ± 95% CI = 2.22 (1.15–4.25), p = 0.047). Conclusions: Smell and taste loss in COVID-19 are closely related, although a minority of individuals can experience taste or smell dysfunction in the absence of the other. The taste of salt may be less severely affected than other taste qualities and future work exploring this finding objectively is indicated. The association of flossing with rapid taste recovery adds to the growing evidence of a link between good periodontal health and favourable COVID-19 outcomes.

Taste buds are collections of heterogeneous taste receptor cells (TRCs) that detect sweet, sour, salt, bitter and umami. TRCs are relatively short‐lived and continually replaced by proliferative progenitor cells situated adjacent to taste buds. In mouse embryos, taste bud precursors are first evident as small clusters of columnar epithelial cells or placodes on the developing tongue surface. Each taste placode comprises 10–20 cells that express both cytokeratin (K) 8 and the secreted protein Sonic Hedgehog (SHH). Previously we showed that SHH+ placode cells differentiate into TRCs in the first postnatal week, but do not give rise to the K14+ progenitor population that supports adult TRC renewal (Thirumangalathu et al., 2009 Development). This raised the questions of how and when TRC turnover commences. Using 3D image analysis, we find that taste placode and taste bud cell number are static during embryonic development and within 1–2 days of birth, respectively; instead EdU incorporation studies and K14 genetic lineage tracing reveal that the progenitor contribution to taste buds begins by postnatal day (P) 2, steadily increasing through P14. Work from our lab and others has shown that SHH is a negative regulator of taste cell fate in embryos but paradoxically SHH promotes TRC differentiation in adults. Thus, we hypothesized that the switch in SHH function coincides with the onset of taste cell renewal. We are currently testing this idea using K14CreER to drive SHH overexpression at specific postnatal time points. In cultured embryonic tongues, excess SHH represses formation of taste placodes, whereas in adult mice, this genetic manipulation induces formation of ectopic taste buds throughout the anterior lingual epithelium (Castillo et al., 2014 Development). Additionally we are using RNAseq analysis to identify candidate regulators of the embryo‐to‐adult transition, and more specifically to define the emerging taste bud progenitor pool in postnatal animals.Support or Funding InformationSupported by R01 DC012383 to LAB and F32 DC015958 to EJGThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.