Introduction

Taste is fundamentally linked to quality of life, and is vital in determining food choice. However, as well as to assay the appeal of foods with appetitive characteristics, the taste system chemically interrogates the food we eat, serving as a gatekeeper, protecting against the ingestion of aversive, unpalatable items that may cause harm if taken into the body. The immune system serves an analogous function, detecting things that are harmful, or that bear the molecular signals of those that have been harmful in the past, acutely activating against systemic insult as a first line of defense. In the time necessary for an adaptive immune response to generate, a pathogen may have grown to a problematic degree within the host, and therefore the innate immune response gives an “always on” protection to the body from novel pathogens it may be initially naive to. The innate immune response utilizes an array of cells, signaling factors and proteins to isolate, destroy and recycle potential pathogens before they can reproduce to the point where they may become harmful to the host. Without an index of specific pathogens to identify, the innate immune response instead relies on detecting common molecules which are absent in the host, but which are often signs of a pathogenic entity, the classical example being Lipopolysaccharides, molecules commonly found in the external membranes of Gram-negative bacteria. Upon detection, the innate immune system responds to neutralize a perceived threat with both phagocytosis, whereby a potential intruder is engulfed and ingested, and with inflammation.

As the basic roles of immunity and taste share some overlap in function, it is unsurprising then that recent evidence has begun to suggest that these systems may interact, and further may influence one another. Most visibly in the past year during the Covid-19 pandemic, infection with the novel coronavirus was strongly and publicly associated with anosmia, a loss of smell [1], in a manner that may correlate with an activated inflammatory response [2], as well as with ageusia, a loss of taste, and further loss of oral perception of irritants [3••]. Taste cells and their canonical signaling cascades are commonly implicated in auto and hyperimmune diseases. Many genes associated with the innate immune response are over-expressed in taste cells, particularly in those isolated from taste cells bearing the molecular signals of type II taste cells [4], the cells responsible for sweet, umami and bitter taste detection. In the taste buds of humans, inflammation and innate immune-associated genes are readily up-regulated in obese compared to lean individuals [5••]. Being overweight or obese (a condition affecting over 65% of adults in the USA), is associated with chronic low-grade inflammation, and is linked to alterations in taste or food intake patterns, usually promoting overconsumption, and correlating with a loss of taste function. Taken together, evidence points toward a feedback relationship between the immune and taste systems that may have implications for how the body functions to keep us safe from pathogens, and for our metabolic health in general.

In this review, we will concentrate on recent findings (primarily those from the past 5 years) regarding immunity, inflammation, and taste to provide a snapshot of our current understanding of how these systems interact, and highlight further interesting questions that future work may explore.

Search strategy and selection criteria

PubMed and Google Scholar were used to search for primary research articles, over the previous 5 full years from 2016 to 2020, with a small number of important articles from earlier than this also included for context. Search terms included “taste”, “inflammation”, “immunity”, “autoimmune”, “obesity”, “cancer”, and various combinations thereof. Summaries and reviews were largely excluded to concentrate on most recent primary literature from the lab or clinic. Recent studies in non-human animals are highlighted in Table 1, with studies in human subjects in Table 2.

Table 1 Studies in non-human models of inflammation and their consequences for taste from 2016 to 2020
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Table 2 Studies with human models of inflammation and their taste consequences from 2016 to 2020
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Molecular markers of inflammation

Inflammation as a term encompasses the activation of the immune system toward an insult. This is characterized on the macroscale by an increase in blood flow leading to redness, swelling, and an increase in temperature, along with pain and potentially a temporary loss of function [18], and on the cellular scale by the recruitment of neutrophils, macrophages, and monocytes, as well as proinflammatory cytokines like Tumor Necrosis Factor alpha (TNFα) [19] and Interluekin-6 (IL-6) [20], other markers of inflammation like C-Reactive Protein (CRP) [21] and chemokines like Monocyte Chemoattractant Protein-1 (MCP-1) [20]. This contrasts with the more specific actions of the adaptive immune system acting post antigen presentation via B or T cells, to an already familiar threat.

While, in many cases, these acute phase effectors resolve after insult, a chronic low-grade inflammation, or metaflammation [22], has been observed in overnutrition and obesity [23]. Overfeeding also leads to hyperinsulemia and hyperleptinemia [24], as resistance to the effects of insulin or leptin necessitates their overproduction. Evidence points to proinflammatory cytokines directly acting on the insulin [25] receptor, and leptin receptors (among other mechanisms of leptin resistance [26, 27]) to affect this change. Interestingly, many proinflammatory signaling factors associated with inflammation also have their cogent receptors expressed in taste buds [28,29,30], proffering a potential mechanism for their up- or down-regulation being associated with a modulation of taste function. TNFα knock out (KO) mice are less sensitive to bitter stimuli than wild type animals [31], and exogenous TNFα seems to blunt sodium taste by inhibiting sodium flux in taste buds [32].

Bacterial infection

Lipopolysaccharide (LPS), an inducer of acute inflammation of bacterial origin, has been utilized by multiple groups to model the influence of systemic inflammation on the taste system. Exogenous LPS resulted in a reduction in the proliferative capacity of taste buds [33] which are constantly renewing in nature, and altered licking response to NaCl in mice [32, 34], supported by reduced activity in the chorda tympani nerve which takes taste information from the anterior tongue to the brain, in response to various taste stimuli [34••]. Serum-LPS is also elevated in mice experiencing systemic inflammation through consuming a high-fat diet (HFD) [11••]. In one intriguing study, the bitter tastant (of recent infamy), chloroquine, was found to exhibit protective effects on pre-term birth in mice, when induced through LPS injections (inflammation is a key risk factor for pre-term labor) [35]. Protective effects were much weaker in animals lacking the G-protein alpha-subunit Gustducin (originally thought to be taste-specific, although now associated with many chemosensory cells throughout the body), suggesting that protective effects were mediated in a manner analogous to taste signaling, via bitter receptors which were found expressed in myometrial cells. Interestingly, the primary receptor for LPS, TLR4 [30], is also expressed in taste buds, whereby taste preference is altered in mice deficient in TLR4, with KO mice displaying a reduced preference for sugars, lipids, and umami [36], further suggesting that an innate inflammatory response may alter taste function. Taken together with earlier work, this suggests a dual function for the LPS/TLR4 pathway; (1) as a sensor of inflammation which can damage taste buds, and (2) as an integral part of the sensory transduction pathway, without which taste sensations are altered.

A critical recent finding that will doubtlessly accelerate our understanding of the nexus between innate immunity and taste is that taste organoid cultures are also able to model an inflammatory response such as that in bacterial infiltration in vivo, with rapid induction of TNF and IL-6 observed in these in vitro cultures after stimulation with LPS [37]. These taste organoids also expressed many other classical markers of the immune response, including all members of the NF-κB protein complex (NF-κB1, NF-κB2, RelA, RelB, c-Rel,) and multiple Toll-like receptors, most markedly TLR2, 3, 4, and 5.

The gastrointestinal tract

Several autoimmune diseases are also linked to taste dysfunction, notably Sjögren’s Syndrome (SS) [38], Inflammatory Bowel Disease (IBD) [39], and Systemic Lupus Erythematosus (SLE) in mice [40]. Each of these diseases impact taste signaling in their own way. For example, in SS, patients experience an infiltration of macrophages, plasma, and T cells into their lacrimal and salivary glands [41]. This leads to a reduction in salivary production, which itself reduces the ability to detect taste compounds, though not necessarily through a direct action on taste cells. In a mouse model of autoimmune disease with a phenotype akin to that of lupus or Sjögren's syndrome, taste buds were smaller, and fewer taste cells regenerated from taste stem cells in the native turnover process the a taste bud relies on to maintain fidelity [42]. In humans with IBD, taste sensitivity was generally blunted versus healthy controls, save for sour taste, which was elevated in IBD. Sour is thought to be transduced through Type III taste cells [43]; however, most of the receptors associated with the immune response that are reported to be present in the taste bud tend to be expressed in Type II cells [29, 44, 45]. In human colonic mucosa, the number of bitter-receptor (T2R38) expressing cells is higher in those who are obese than lean, and is confined to cells seeming to fit an enteroendocrine phenotype [46]. These cells would presumably be responsible for the chemical sensing of luminal contents, with their abundance strongly correlating with BMI in this sample. Interestingly, the stimulation of T2R108 receptors in enteroendocrine cells in the guts of diet-induced obese mice with a bitter extract from hops was linked to GLP-1 release, and an improvement in multiple metabolic measures including fat mass, glucose homeostasis and insulin sensitivity [47].

Airway immunity

When encountering microbes in the airway, the innate immune response must detect and respond to potentially harmful invaders, in a manner thought to be partially dependent on the T2R family of bitter receptors (for review see [44]). A recent report suggested that cells in the trachea expressing bitter taste receptors also expressed the tuft cell marker (a chemosensory cell located in the epithelium, linked to type 2 immunity through the taste-linked signaling channel TRPM5 (Transient receptor potential cation channel subfamily M member 5) [14••], DCLK1 (microtubule-linked protein kinase 1), comprising around 4% of epithelial cells [48]. When isolating mRNA from these cells, sequencing revealed RNA for multiple additional taste signaling elements, as well as for multiple cytokines implicated in the immune response.

Interestingly, many of the antibiotics commonly used to treat airway infections (including levofloxacin, tobramycin, and azithromycin) are also capable of activating the T2Rs (T2R1, T2R4, T2R14, and T2R20) present in the airway, validated in an in vitro FLAG tagged HEK cell system [49]. These receptors are expressed in smooth muscle cells within the airway walls, functioning in a manner that seems ancillary to the inflammatory response, to relax smooth muscles and aid in bronchodilation [50]. Using cultured human sinonasal epithelial cells, Lee et al. [51••] were able to demonstrate that solitary chemosensory cells in the airway express the same T1R2/T1R3 receptor heterodimers present in taste buds used for sweet taste detection. While amino acids have a range of tastes, some D-amino acids are able to activate the T1R2/T1R3 receptor, where in the mouth this would correlate to the eliciting of a sweet taste [52]. Lee et al. found that not only do bacterial isolates, for example Staphylococcus, from human airways produce several of such T1R-activating D-amino acids (D-Leucine, D-Isoleucine, D-Phenylalanine), but also D-amino acids taken from these isolates were able to inhibit biofilm formation in a T1R-dependant manner.

Cancer and its treatment

Cancer, the inflammatory state association with it, and the treatment side-effects thereof are also all associated with changes in taste in humans [53, 54]. In mice, the effects of cyclophosphamide, a common chemotherapeutic agent, are acutely damaging to taste cells, in particular type II and III cells [55]. This loss of taste cells seems to act through apoptosis, and be particularly damaging to the progenitor cells responsible for resupplying the taste bud. When fractionating doses of cyclophosphamide, a practice common in cancer treatment that can alleviate some of the more negative side effects commonly encountered, loss of taste was in fact prolonged, and more severe [56]. As taste loss can discourage eating, leading to broad negative outcomes, and further result in a significant reduction in quality of life, careful consideration should be made of the implications of these findings.

As cancer patients are at risk of cachexia (a wasting disorder characterized by severe extreme weight loss along with loss of muscle and body fat, and marked by a loss of appetite) and its associated morbidity and mortality, a recent study worked to untangle the attribution of each [15]. Counter to the hypothesis that treatment which damages rapidly dividing cells would impact taste cell renewal, the authors found no impact of chemotherapy on taste detection in hospitalized patients. They did find altered taste perception in both the chemotherapy and acute inflammatory group versus healthy controls; however, the marker CRP, and leukocyte counts did not correlate with dysfunction. This suggests that a broader inflammatory state may be affecting both populations. Care should be taken in interpreting these results as the study populations were, by the nature of the study, not standardized.

Obesity, inflammation and taste

While acute inflammation in the form of infection is well characterized, a chronic low-grade inflammation associated with obesity [57] is a remarkably widespread manifestation of long-term activation of the immune system. In obesity, white adipose tissue (WAT) is broadly remodeled, and is itself a source of cytokines [58], and a harbor for macrophages that promote systemic inflammation [59]. Further, pathologies associated with obesity such as atherosclerosis have an immune component themselves, with associated plaques composed of several types of immune cells, including macrophages and neutrophils [60]. Obesity is associated with lower levels of adiponectin, and higher levels of TNFα [61], IL-6, and C-Reactive Protein (CRP) [62]. IL-6 and CRP are associated with disease complications [63, 64], while TNFα is associated with insulin resistance and hyperleptinemia [65, 66]. One recent study also implicated various signaling elements of taste (T1R2, T1R3, Gα-Gustducin, phospholipase C-beta 2, and TRPM5 channels) expressed in renal tissues in stimulation of the inflammasome, in a diabetic mouse model, where activation of the inflammasome could further be partially mediated by the sweet taste blocker lactisole [67].

A great deal of studies associate taste changes with obesity, with the preponderance of evidence supporting a reduction taste acuity [7, 68,69,70], although some work does show the opposite effect [71] or no change at all [72]. Recent work from our own group suggested a reduction in taste bud abundance in both mice [10••] and humans [7] with adiposity, alongside a reduction in expression of various taste-linked signaling elements in mice [7]. The latter result is paralleled in humans in work from Archer et al. [5••], where a pioneering RNA sequencing experiment examined differential expression patterns of obese and lean Caucasian women, from isolated fungiform taste papillae. In fact, 2 of the 3 ontological groupings of genes found to vary significantly between subjects were those associated with the immune response, and with sensory signaling.

Interestingly, in regions of the brain related to energy homeostasis (the hypothalamus and brainstem), both taste receptors (T1R3, T2R116) and taste signaling elements (Gα14, TRPM5) are down-regulated by obesity in mice [73], in a manner which, we might speculate, seems itself homeostatic in nature. Although in an acute model of taste loss panelists tend to select foods of a higher sensory impact, and thus caloric content [16], a large genome-wide association study found limited evidence for an association between taste response and polymorphisms in taste genes, although GNAT3 alleles associated with greater sweet taste response were negatively associated with sugar intake in one sample [74]. Studies of patients undergoing bariatric surgery point toward rapid changes in taste after extreme weight loss [75,76,77], which may be inflammation-linked, as well as depending on the hormonal remodeling common in such interventions. Further work even implicates dampened CNS reward circuity linked to taste with an increase in obesity in adults [78, 79], which may differ from that seen in children [80].

Taste buds, or more specifically the population of specialized epithelial cells that make them up, are constantly renewed from a population of stem cells, which produce taste progenitor cells that further differentiate into 3 functionally and morphologically distinct taste cells [81], each cell type having a distinct half-life [82], or supporting keratinocytes. This complex and constant state of development requires a finely tuned balance of developmental and transcriptional regulators within the taste bud to ensure the judicious turnover of taste cells within the bud. The recent report by Archer [5••] showed a downregulation of genes expressed in the Type II taste cells responsible for sweet, bitter or umami detection in the fungiform papillae of obese versus lean women, as well as a reduction in expression of sonic hedge-hog (SHH), a morphogen vital for taste cell development [83, 84]. Kaufman et al. showed a similar decrease in taste cell developmental markers in obese mice [7], with a concomitant increase in inflammatory markers and fewer taste buds in obese mice from an earlier work [10••].

Conclusions and future work

Taste perception in humans is sensitive to disease states, including obesity and acute infection. Circulating factors arising from our inflammatory state can also interact with taste cells themselves, their progenitor cells, innervating nerves, and with processing within the brain.

Recent work has made it clear that the taste system is plastic and responds to inflammatory insult, whether acute or chronic, and thus inflammation has a role in taste function and intake which cannot be discounted as we work toward behavioral approaches to treat metabolic diseases. Further, the identification of cells strikingly similar in phenotype to those we think of as taste cells throughout the body, which are seemingly fulfilling an immune sentinel role, highlights further links between immunity and taste. Future work should take advantage of the expanding array of molecular techniques available to study taste cells in vitro, and aim for longitudinal studies of taste and immunity pre- and post-obesity, to further elucidate the complex relationship between our perception of foods, and the consequences of over consumption.