nutrients
Review
Do Gut Microbes Taste?
Ryan Leung 1
and Mihai Covasa 1,2, *
1
2
*
Department of Basic Medical Sciences, College of Osteopathic Medicine, Western University of Health
Sciences, Pomona, CA 91766, USA; ryan.leung@westernu.edu
Department of Health and Human Development, University of Suceava, 7200229 Suceava, Romania
Correspondence: mcovasa@westernu.edu
Abstract: Gut microbiota has emerged as a major metabolically active organ with critical functions
in both health and disease. The trillions of microorganisms hosted by the gastrointestinal tract are
involved in numerous physiological and metabolic processes including modulation of appetite and
regulation of energy in the host spanning from periphery to the brain. Indeed, bacteria and their
metabolic byproducts are working in concert with the host chemosensory signaling pathways to
affect both short- and long-term ingestive behavior. Sensing of nutrients and taste by specialized G
protein-coupled receptor cells is important in transmitting food-related signals, optimizing nutrition
as well as in prevention and treatment of several diseases, notably obesity, diabetes and associated
metabolic disorders. Further, bacteria metabolites interact with specialized receptors cells expressed
by gut epithelium leading to taste and appetite response changes to nutrients. This review describes
recent advances on the role of gut bacteria in taste perception and functions. It further discusses how
intestinal dysbiosis characteristic of several pathological conditions may alter and modulate taste
preference and food consumption via changes in taste receptor expression.
Keywords: gut microbiota; taste function; microbiome; intestinal dysbiosis; appetite
Citation: Leung, R.; Covasa, M. Do
Gut Microbes Taste? Nutrients 2021,
13, 2581. https://doi.org/10.3390/
nu13082581
Academic Editors: Connie Weaver
and Ghada A. Soliman
Received: 11 May 2021
Accepted: 24 July 2021
Published: 27 July 2021
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4.0/).
1. Introduction
The human body houses trillions of microbes along its surfaces and cavities. The
gastrointestinal tract is the main location site that harbors approximately 4 × 1013 microorganisms that include not only bacteria but also fungi, archaea and virus-like particles [1].
Gut microbiota has been termed as the invisible metabolic organ for its important roles in
host immunity, gut barrier integrity, metabolism, growth, fermentation of non-digestible
complex carbohydrates, xenobiotic and drug metabolism, among other roles. These microbial communities, however, differ significantly along the gastrointestinal tract dependent
on environmental variations in pH, oxygen exposure, and nutrient abundance [2]. Along
with these environmental variations comes unique anatomical features that encourage
distinct microbial colonization in proximity to taste receptors. As such, microbial colonies
are topographically and strategically located near taste receptor cells in the mouth and
intestine to facilitate optimal communication. Although many factors can influence the
composition and function of gut microbiota, diet is the major modifier of intestinal microbial ecosystem. Likewise, microbes are also hypothesized to influence host eating behavior
through a multitude of potential mechanisms involving gut–microbiota–brain axis. Among
these, the evidence for microbial influence on taste perception and preference has been
steadily increasing. Taste receptors are expressed in the gastrointestinal tract and they
mediate nutrient assimilation via several mechanisms including secretion of gut peptides
by enteroendocrine cells in response to stimulation by taste stimuli. The function of taste
receptors in the detection of nutrients and the resultant effects on gustatory and digestive
processes has been shown to implicate byproducts of gut microflora metabolism, such as
short chain fatty acids, which can also serve as stimuli for taste receptors. Preservation
of taste functions has been shown to depend on an intact gut microbiota [3] therefore,
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disruptions in the gut microbiota composition profile can results in taste changes. Taste,
in this context, is not limited to gustatory function, but rather extends to the physiological detection of nutrients located throughout the gastrointestinal tract. Therefore, the
focus of this review is to explore the supporting and growing evidence of how oral and
intestinal microbial communities influence the host’s taste perception, and in turn, affect
eating behavior. It further describes how taste receptors respond to changes in gut microbiota composition profile in disease conditions such as inflammatory bowel disease,
chemotherapy and bariatric surgery.
2. Taste and Taste Receptors
Humans can recognize five primary distinct taste qualities: sweet, bitter, sour, salty and
savory (or umami) and are also able to detect fat properties, although this is debatable [4,5].
This is accomplished via specialized taste receptor cells (TRCs) located within the taste
buds that are distributed across tongue papillae and palate epithelium and epiglottis. The
taste buds comprise approximately 50–100 taste cells that are embedded in fungiform,
foliate and circumvallate papillae [6]. In response to a range of sapid stimuli, taste cells
release neurotransmitters and other signaling molecules that convey taste information such
as quality, intensity and hedonic value, to the rostral, gustatory portion of the nucleus
tractus solitarius (NTS) that are then conveyed to several second order brain regions
including the thalamus reaching the gustatory cortex, via facial, glossopharyngeal and
vagus nerves [7]. The perception of sweet, umami and bitter tastes are mediated via
G-coupled protein receptors (GPCRs) embedded in Type II taste cells. The sweet taste
receptor is composed of TAS1R2 and TAS1R3 subunits while the bitter compounds are
detected by 25 different taste receptors that belong to TAS2R family [8]. The umami receptor
is a heterodimer composed of TAS1R1 and TAS1R3 subunits. Salty and sour tastes are
presumably transduced via epithelial ion channels for sodium and hydrogen, respectively,
on Type III cells, although less is known about these pathways [9]. Oral fat perception was
long considered to solely be dependent on textural (trigeminal) and olfactory cues [10].
The identification of the fatty acid transporter CD36 as well as lipid specific GPCRs in taste
bud cells have supported its gustatory qualities [11]. A recent study demonstrating chorda
tympani nerve stimulation to linoleic acid specifically lends further credence to the notion
of fat as a unique taste quality [12]. Once the tastant binds to the receptor it dissociates
the heterotrimneric G protein (α-gustducin, Gβ3, and Gγ13) leading to increase in C-β2
(PLC-β2) activity. Activation of PLC-β2 results in production of diacylglycerol (DAG)
and inositol 1,4,5-triphosphate (IP3) from phosphatidylinositol 4,5-bisphosphate. This
activates inositol 1,4,5-trisphosphate receptor type 3 (IP3R3) receptors leading to release
of calcium from intracellular stores and the gating of a transient receptor potential ion
channel, TRPMP5 [13]. Activation of TRPM5 channel by calcium allows entry of Na+ that
results in the depolarization of action potential, ATP release and convey the information
to CNS. How primary afferent neurons respond to taste stimuli, particularly sweets, has
been a matter of considerable debate with some suggesting that they respond best to sweet
tastants from a range of taste stimuli while others suggest that they respond exclusively
to sweet tastants. The “specialist” versus “generalist” responses or one taste quality
versus “broadly tuned” has been shown to depend on the concentration of stimuli used,
the type of the taste buds and the type of stimuli and whether single or in combination.
While for sweet, bitter and umami, both specialist and broadly tuned responses have
been shown, there is a dedicated labeled-line for the sour taste quality [4,14]. The brain
gustotopic coding of taste quality responses is still unclear although it is more consistent
with the concept of a distributed and wide brain network with highly variable responses
between and within individuals [15,16]. This has important behavioral significance since
overconsumption of taste stimuli such as sugars have been proposed as main contributors
to obesity epidemic [17,18]. Several studies show that excess consumption of high sugar or
high fat diet results in reduced response to sugar or fats as well as diminished neuronal
responses to such stimuli [19–23]. Therefore, deficits in sweet or fat responses can drive
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metabolic disorders such as obesity and diabetes. Among the numerous factors that are
implicated in appetitive and consummatory behavior, the bacteria populating the digestive
tract from the oral cavity to its distal segments play a critical role in modulating taste
responses as reviewed in the next sections.
Modulation of Taste Receptors by Nutrients
Sugars, minerals, organic acids, alkaloids and amino acids in foods act as chemical
messengers by binding to their corresponding taste receptors [9]. This interaction represents
one of the interfaces between internal and external milieus and transduces conscious
gustatory perception through five known taste qualities: sweet, salty, bitter, sour, and
umami [11]. Interestingly, the evidence has been growing for a sixth taste quality for fat
and will be considered in this review [10]. The existence of these distinct taste qualities
implies that each taste has a specific coding mechanism mediated by specialized taste
receptors [11]. As such, the great variety of taste perception among individuals [24]
leaves taste receptor expression and abundance as a potential variable dictating sensitivity
and threshold levels. Due to its influence on eating behavior, genetic predisposition to
taste perception, especially bitterness, has been a major focus of research over the last
decades [25]. Increasingly, however, nongenetic factors like the gut and oral microbiota are
being researched for their potential role in modulating receptor abundance and, in effect,
taste perception. Perception can be defined as the intensity by which a signal is transduced
and can be thought in terms of sensitivity and threshold.
Since identifying the chemical composition of foods is vital to homeostatic processes,
it is not surprising that the same taste receptors of the tongue are also found in the gastrointestinal tract. These receptors then transduce nutrient signals into neuropeptide hormones,
vagus nerve activation, or nutrient utilization [9]. Interestingly, the presence of intestinal
hormones in isolated taste cells further points to the functionally similar role of lingual
and intestinal nutrient sensors [26]. As such, it may be useful to consider both modalities
when studying the modulatory effects of nongenetic factors like the microbiota. Current
literature is generally consistent with the notion that when more receptors are expressed
and activated, the signal to the brain is interpreted as more intense [27]. For example,
Lipchock et al. [27] found that subjects who produced more bitter receptor mRNA perceived more bitterness when they tasted caffeine. This pattern of receptor abundance
dictating perception has roots in observations of papilla and taste bud number on the
tongue predicting taste intensity [28]. When extrapolating this to eating behavior, the
general assumption is that the less sensitive to a taste (i.e., hyposensitive), the higher the
consumption of that taste stimuli in order to reach the same stimulus [25]. This inverse
correlation does not always apply, however, as other studies report the contrary claiming
that a reduction in taste ability downregulates positive associations [29]. Links between
tastes should also be noted as with supertasters: hypersensitivity to bitterness results in
an aversion to vegetables, while a hypersensitivity to sugar results in increased hedonic
response and higher consumption of sweet foods [25].
3. The Link between Gut Microbiome and Taste
The complexity of the gut microbiome such as richness and abundance have been
used as a predictive factor of the host metabolic health. Diet and dietary habits are the main
modifiers of the gut microbiome composition profile. Not surprisingly some determinants
of obesity such as taste perceptions that influence changes in appetite regulation and energy
metabolism have been linked with the gut microbiome. This relationship between taste
and oral and intestinal microbiome is reviewed in the next sections.
3.1. Oral Microbiome and Taste
The oral microbiome is one of the most stable and diverse ecosystems in the body due
to the variety of niches present in the mouth and the abundance of exogenous nutrients
during feeding and endogenous nutrients in salivary production [30,31]. Specifically, the
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tongue dorsum forms a unique ecological site that encourages accumulation of a biological
film composed of saliva, oral debris, and microorganisms, an ideal habitat for microbial
influence on taste perception [32]. Anatomically, the papillary structure of the tongue forms
numerous depressions, effectively creating a reservoir for biofilm buildup and a large
surface area for potential interactions. Although there is a continuous shedding of tongue
epithelium, the tongue dorsum is hardly ever free from bacteria, such as Staphylococci and
Streptococci [32]. Since the adherence of the tongue film is situated at the interface between
tastants and taste receptors (localized in taste buds situated in the clefts of taste papillae), its
consideration remains an important variable in taste perception studies [33,34]. Microbial
tongue films can affect taste perception via two potential mechanisms of peri-receptor
modulation: first, bacteria setting a physical barrier limiting access of taste molecules to
taste receptors; second, bacterial metabolism modulating the concentration of peri-receptor
tastants, thereby influencing taste receptor activation and taste sensitivity [33] (Figure 1).
Figure 1. Microbes influence taste perception through biofilm and bioactive metabolites. The shape
of the tongue dorsum forms a unique ecological site that encourages accumulation of a biological
film composed of microorganisms. Bacteria can affect taste perception by acting as a physical barrier
(top left) limiting access of taste molecules to taste receptors. Secondly, bacteria metabolism can
modulate the concentration of peri-receptor tastants (top left), influencing taste receptor activation
and taste sensitivity. Intestinal enteroendocrine cells (EEC) express the same receptors as lingual
taste cells. Therefore, these potential mechanisms for bacterial taste alterations hold true for EEC as
well (bottom left), allowing for further potential modulation of nutrient sensing.
For tastants to be perceived, they must first diffuse through the film coating the tongue
and pass through the taste pore before binding to their corresponding receptor on taste
buds [35]. Therefore, the microbial buildup of plaque likely blocks taste pores and prevents
access to the receptors [36]. The bacterial load of tongue film can be measured by weight
which was negatively correlated to taste sensitivity [33]. These findings are consistent with
studies that seek to improve taste sensitivity by reducing tongue plaque through tongue
brushing. For example, three months of tongue brushing in older adults significantly
reduced tongue coating and improved the subjective and objective taste sensation of sweet,
salty, sour and bitter, but not umami compounds [36]. This improvement was attributed to
the removal of tongue plaque thus unblocking access to the taste pores.
Microbial Metabolites and Taste
Another possibility by which oral microbiome influences taste perception is through
the consumption of tastants (sugars, amino acids) or synthesis of bioactive metabolites
(organic acids, SCFA) before receptor interaction, ultimately inducing sensorial adaptation
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(Figure 1). Takahashi characterized the metabolic pathways of oral bacteria and how they
may influence their environment. Streptococcus (Firmicutes), Actinomyces (Actinobacteria),
and Lactobacillus (Firmicutes) species degrade carbohydrates into organic acids while Prevotella (Bacteroidetes) and Porphyromonas (Bacteroidetes) species break down proteins into
amino acids and SCFAs [37]. While these characterizations were foundational for numerous gustatory studies, questions remain whether these bacterial metabolites are produced
in significant enough concentrations to affect taste perception. A recent study by Gardner [38] used metabolomics to address this and provided supporting evidence that the
net metabolic activity of oral microflora does in fact influence host taste perception. The
authors measured consumption of the nutrient sucrose by the tongue biofilm by determining lactate/pyruvate ratios. A high lactate/pyruvate ratio was significantly associated
with low-sensitivity sucrose perceivers compared to high-sensitivity perceivers, and these
metabolic differences were hypothesized to be attributed to a higher abundance of efficient
lactogenic microbes like Streptococci [38].
While bacterial metabolism may deplete sucrose, certain species can also enrich
sensory-active molecules like acids in the medium near the taste receptors. This microbial
production of acid does not induce a conscious sour sensation but rather increases sour
detection thresholds through the sensory adaptation phenomenon. In this context, taste
ability was reduced in the acutely hospitalized elderly, particularly those with high Lactobacilli growth [39]. By analogy, the presence of SCFAs was shown to be inversely associated
with oral sensitivity to oleic acid [40]. In this latter study, fat detection hyposensitive
subjects had an increased production of SCFAs which suggested the involvement of the
oral microbes. Further studies have also indicated that certain bacterial phyla are positively
correlated with an increase in taste sensitivity. For example, the presence of Actinobacteria
and Bacteroidetes in tongue film are linked to an increase in taste sensitivity, especially to
bitterness [33]. The mechanistic explanations are unclear; however, certain bacteria are
known to produce secondary metabolites that act as precursors of some bitter acids. For
instance, Actinobacteria produce phenols which can enhance the sensation of astringency
and the bitter taste in food products [41]. When examining the differences between supertasters (high responsiveness to bitter PROP, ST) and non-tasters (low responsiveness to
bitter PROP, NT) in the context of bacteria composition lining the tongue dorsum, Cattaneo
et al. found that diversity did not differ significantly between ST and NT samples in
terms of both taxonomic richness and evenness. However, at the level of single taxonomic
units, they identified five bacterial genera whose relative abundances were significantly
higher in ST than NT: Gram-positive Actinomyces (Actinobacteria), Oribacterium (Firmicutes),
Solobacterium (Firmicutes) and Catonella (Firmicutes); and the Gram-negative Campylobacter
(Proteobacteria) [42]. Taken together, these studies demonstrate how changes in the tongue
microbial ecosystem can modulate taste perception (Table 1).
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Table 1. Effects of bacteria on taste.
Microbes
Effect on Taste
Reference
Physical barrier through microbial
tongue film
[26]
Streptococcus, Actinomyces,
Lactobacillus
Degrade carbohydrates into organic
acids
[31]
Prevotella, Porphyromonas
Degrade protein to amino acids and
SCFAs
[31]
Staphylococci, Streptococci
Dampen sweet, salty, sour, and bitter
tastes
Potential Mechanism
Streptococci
Alter sweet taste sensitivity
Degrade carbohydrate to lactate
[32]
Lactobacilli
Decrease sour taste sensitivity
Bacterial products raise sour detection
thresholds
[33]
Actinobacteria and
Bacteroidetes
Increase taste sensitivity, especially
bitter
Bacteria produce secondary metabolites
that act as precursors of some bitter
acids
[27]
Actinomyces, Oribacterium,
Solobacterium, Catonella,
Campylobacter
Associated with high responsiveness to
bitter
[36]
Clostridia
Associated with protein/fat-rich diets
and negatively associated with fiber
intake
[42]
Proteobacteria, Prevotella
Associated with vegetable-rich diets
[42]
Bacteroidetes, Bacterolidia
Associated with decreased perception
of all tastes in obese children
[43]
Streptococci Mutans
Decreased sensitivity for bitter taste
and increased risk of dental caries
[44]
Germ Free mice
High preference for sweet taste
Increased number of sweet taste
receptors in proximal intestine
[3]
Increased preference for fat
Changes in lingual and intestinal fatty
acid receptors; increased lipid
consumption and decreased
post-ingestive feedback satiety signals
[45]
Germ Free mice
3.2. Intestinal Microbiome and Taste
Due to the high environmental variations in the distal gut, the density and composition of intestinal microbial communities differ greatly from those in the oral microbiota.
Whereas oral microbes must endure periods of time without exogenous nutrients, gut microbes have a continual source of nutrients in the form of dietary fiber [38]. Although taste
receptors are abundantly expressed in the oral cavity, they are also present in extra-oral
tissues and are involved in many metabolic functions such as chemoreception, nutrient
sensing, release of appetite hormones and other gastrointestinal functions. The mechanisms
linking taste receptors and gut microbiota are not entirely known. Enteroendocrine cells
(EEC) lining the GI tract are morphologically and strategically positioned in the intestinal
epithelium to detect the presence of nutrients, as well as microbes and their metabolites.
They express taste transduction molecules such as T1R2, T1R3 receptors and G-protein
gustducin. The distribution of EECs varies based on the type, for instance, L-cells are
present in high density in the ileum and colon. These areas contain the highest abundance
of bacteria and therefore suggest an intimate relationship between bacteria and EECs [46]
(Figure 1).
Intestinal Microbes and Taste Receptors
Taste receptors such as TAS2R are responsive to microbial-quorum sensing molecules
and toxins by protecting against harmful microbes. For example, activation of TAS38
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receptor increases the release of anti-microbial B-defensin and the hormone cholecystokinin.
In response to changes in intestinal luminal environment, specialized EEC cells secrete
a myriad of gut peptides such as CCK, GLP-1, GLP-2 and PYY. This complex regulatory
process is mediated by a large family of cell-surface G-protein-coupled receptors (GPRC),
expressed on the apical domain of EEC with a high degree of specificity for nutrient
and taste sensing as well as microorganisms and toxic compounds. Interestingly, the
GPCRs responsible for taste sensing and found in the lingual epithelium are also present
in the intestine. For example, T1R2, T1R3, gustducin and GLP-1 are co-expressed in
the same enteroendocrine cell. Therefore, the intestinal epithelium contains GPCR for
detection of all nutrients, including fatty acids. Of interest is the fact that, indole, a
tryptophan derivate and bacteria byproduct that modulates gut microbiota stimulate
enteroendocrine cells to release GLP-1. It is known that GLP-1 receptors are expressed
in gustatory neurons and are involved in transmission of taste signals, particularly sweet
taste [47]. Furthermore, gut microbiota derived tryptophan metabolites reach the central
nervous system and influence disease processes. For example, tryptophan undergoing
microbial degradation is taken up by serotonergic neurons and glia and convert it to
serotonin, a neurotransmitter that processes high order brain functions such as emotion,
learning and memory. Compelling evidence also demonstrate the influence of gut microbes
and tryptophan metabolites in the development of several neurological disorders such
as Alzheimer’s disease, Parkinson’s disease and multiple sclerosis and indole derivatives
have been used for neuroprotection [48]. Together, these studies show how gut bacteria
can control maturation and function of CNS specialized cells through SCFA, vagal transit
and metabolite production that cross the blood–brain barrier. This may also provide a
signaling pathway to taste stimuli reaching the brain. Indeed, it has been reported that
tryptophan acts as an agonist for bitter taste receptors and that indole interacts with TAS2R
receptors. This suggests that other bacteria metabolites may act as ligands for taste receptor
modulation leading to changes in phenotype [45].
The link between gut microbiota metabolites and enteroendocrine cells has been
well documented [46]. Therefore, it is beyond the scope of this review to describe the
mechanisms by which gut microbes-derived metabolites such as SCFA interact with EECs
receptors. However, suffice to say that microbiota convert indigestible carbohydrates to
SCFAs which signal to EE cells via free fatty acid receptors or activation of nuclear histone
deacetylases (HDAC). Further, microbiota convert primary bile acids to secondary bile
acids, which then signal to EE cells via the membrane G protein-coupled bile acid receptor
(TGR5). Finally, structural components of the microbiota such as flagellin and bacterial
lipopolysaccharide (LPS) activate Toll-like receptors (TLRs) with a role in maintaining
gut barrier integrity, synthesis of antimicrobial peptides, inflammation and overall gut
homeostasis. Aberrant TLRs activation results in dysbiosis and increased susceptibility to
inflammatory and other metabolic disorders [1].
4. Microbes Modulate Taste Receptor Expression
In order to provide further insight into the complexities of human eating preference, a
growing number of studies are seeking to characterize oral microbiota composition against
the backdrop of taste sensitivity. A recent study by Cattaneo [25] found that generally,
hyposensitivity towards a certain taste led to its increased consumption. In terms of
relative abundance on tongue dorsum, Clostridia class was positively associated with
protein/fat-rich diets and negatively associated with fiber intake. Proteobacteria phylum
and Prevotella genus showed opposite associations and were more abundant in vegetablerich diets. In a previous study, Cattaneo et al. [25] sought to differentiate oral microbiota
compositions between supertasters (high PROP responsiveness, ST) and non-tasters (low
PROP responsiveness, NT). In particular, the most responsive group (Supertasters) had an
overrepresentation of five bacterial genera: the Gram-positive Actinomyces, Oribacterium,
Solobacterium, and Catonella, and the Gram-negative Campylobacter (Table 1). In a
cross-sectional study analyzing taste sensitivity in obese children, researchers found that
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subjects with a lower ability to perceive all taste qualities, especially bitter, had increased
proportions of Bacteroidetes and Bacteroidia but decreased Proteobacteria [43]. A study that
was centered around dental caries found that a decreased taste sensitivity for PROP was
associated with increased risk for dental caries and higher Streptococci Mutans counts [44].
While these correlations between bacteria taxa and gustatory function do not yet
have systematic explanations, a potential mechanism of receptor modulation by bacteria
does arise from germ-free murine studies. In 2011, Swartz et al. found that germ-free
mice had both a higher preference for sweets and a greater number of T1R2/3 sweet
taste receptors in the proximal intestine compared to normal mice. While the absence of
intestinal bacteria did not change lingual expression of T1R2/3, the increase of intestinal
receptors seemed to have promoted long-term acceptance and preference for nutritive sweet
stimuli. This phenomenon was primarily attributed to the post-oral nutrient feedback,
reinforcing oral cues or taste associations, thus stimulating further consumption [3]. This
study was important in that it described a compensatory mechanism for germ-free mice to
consume more sugar in the absence of energy normally available from extraction by the
gut microbiota. While this does not seem to influence gustatory sensitivity, the increase in
gut T1R2/3 clearly affects the perception of sugar in the proximal intestine. However, in
as much as these findings suggest the ability of microbes to modulate taste receptors, the
ability of specific bacterial communities to restore the taste deficits in the germ-free animal
model has not been tested.
This role of gut microbes is not limited to sweet tastants. In a similar study, germ-free
mice showed an increased preference for intralipid emulsion that was associated with
changes in lingual and proximal intestine fatty-acid receptors [29]. In absence of intestinal
microbes necessary for optimal metabolism, the hypothesis was that the germ-free mice
would exhibit a two-fold compensatory mechanism by increasing lipid consumption and
decreasing post-ingestive feedback satiety signals. First, germ-free mice had increased lingual CD36 fat receptors which was associated with more fat consumption, contrary to other
hyposensitivity eating behaviors [25]. Second, germ-free mice showed a decrease in intestinal fatty-acid GPRs and alterations in the abundance of enteroendocrine cells, ultimately
resulting in a decreased hormonal satiety response and increased fat consumption [29].
These studies have established that the absence of microbes can lead to an altered receptor
expression and potential gustatory changes. However, it is not clear what mechanisms
or systems microbes utilize to maintain their influence on taste perception. The current
literature indicates two likely pathways of modulation, the first one via the host immune
system and the second via hormone secretion.
4.1. Microbes Influence Taste Perception through the Immune System
Taste buds face a unique challenge against pathogens being exposed to the oral cavity
without a strong physical barrier. The presence of commensal microbes in proximity to
taste and nutrient-sensing cells is complex and may also lead to an immune response in
some instances. Indeed, microbial elements like lipopolysaccharide (LPS) and flagellin can
induce inflammatory processes that have effects both locally and systemically. While these
inflammatory expression patterns normally protect taste bud and nutrient-sensing cells
from pathogens, it may also play a role in the modulating taste perception as well as the
pathogenesis of taste dysfunctions [49].
Inflammation is initiated by the activation of Toll-like receptors (TLRs) by microbial
pathogen-associated molecular patterns (PAMPs), as well as other inflammatory agents
from damaged tissues or stress [50]. TLR signaling induces the expression of a variety of
cytokines that then orchestrate an immune reaction (Figure 2). Wang et al. distinguished
that in comparison to non-taste lingual epithelial cells, taste bud cells are enriched with
several key inflammatory processing molecules. They showed how the LPS receptor
TLR4, as well as other TLRs, are preferentially expressed in taste bud cells, suggesting
a comparatively stronger response to PAMPs [49]. Interestingly, taste bud cells are not
all uniform in their response to LPS. Upon close investigation, Feng et al. found that
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different subsets of taste cell types selectively produce specific cytokines such as tumor
necrosis factor (TNF), interferon-γ
γ
γ (IFN-γ), and IL-10 [51]. In mouse taste buds, TNF is
predominantly produced by T1R3-positive sweet/umami receptor cells [52] whileγIFN-γ is
selectively expressed by a subset of type II cells and most type III cells [53]. The expression
of the anti-inflammatory cytokine IL-10 was found exclusively in bitter receptor cells [54].
Similarly, a complex interplay also exists where these cytokines only affect specific types
of taste cells with their associated receptors [51]. These studies show the existence of
cell type-specific expression and transduction of cytokines taste type cells; however, the
significance and their contributions to taste are still being studied.
Figure 2. Microbes influence taste perception through the immune system and hormones. The
microbial element, lipopolysaccharide (LPS), can induce inflammatory processes and hormone
secretion that have local and systemic effects. Lingual LPS administration (top left) triggers a TLR
α
γ
response of inflammatory cytokine (TNF-α, INF-γ and IL-10) secretion and apoptosis of taste bud
cells.
α LPS
γ in the gut lumen (bottom center) interacts with TLRs to induces cytokine secretion (TNFα, INF-γ and IL-6) into the blood stream that spreads to taste bud cells and alters tastant receptor
expression and therefore taste thresholds. LPS also interacts with Enteroendocrine cells (EEC) (bottom
left) stimulating release of gut hormones (CCK, PYY, GLP-1) that enter systemic circulation. These
hormones are known to act as gustatory signaling molecules in taste bud cells. Microbial-induced
taste responses (bottom right) might trigger a direct vagal mechanism to the brain.
Activation of the immune system can modulate taste perception by two means: acuity
and sensitivity. The average turnover rate of taste cells is 8–12 days; therefore, a continuous
supply of differentiated taste receptor cells is crucial for normal taste function [54]. A
decrease in acuity can arise from a reduction in taste bud cell renewal and lifespan, an
effect attributed to LPS-induced inflammation [53,55]. However, these effects on taste bud
cells do not necessarily occur in isolation. Changes in sensitivity for specific tastes can
arise simultaneously due to modification in taste receptor expression or through other
means [56]. Several studies have further pointed to the immune system’s regulatory role in
taste by measuring behavioral changes to specific cytokine deficiencies. For instance, TNFknockout mice exhibit a decreased response to various bitter compounds, but not other
tastes [52]. Additionally, IL-10-knock out mice have a reduced number of taste buds [54].
They also showcase an increased inflammatory response to LPS. These findings suggest
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that taste buds may use separate populations of taste receptor cells to modulate local
inflammatory responses. Recent technological advancements of culturing taste organoids
from progenitor cells promise a tool for broader manipulation and a deeper understanding
of transduction mechanisms [57].
4.1.1. Microbial-Induced Inflammation and Taste
Administration of LPS is an effective method for mimicking bacterial infection. Depending on where and how LPS is introduced, the immune response in taste buds can vary
from hours to days later [56]. Therefore, it becomes imperative to distinguish either the
location of bacteria presence or the mode of LPS delivery, lingual, systemic circulation,
or via ingestion. Orally delivered LPS has been used to mimic exposure to bacterially
contaminated food or water. Wang et al. [49] showed that acute lingual LPS administration
triggered inflammatory cytokine release and apoptosis of taste bud cells. This resulted in
abnormal cell turnover and a net loss of taste bud cells; however, it was unknown if this
interfered with taste performance. Similarly, it is unclear if this phenomenon occurs during
chronic low-grade inflammatory states, as seen in obesity [10]. In distinguishing how taste
is affected by commensal lingual bacteria and not through LPS-induced inflammatory
processes, Besnard et al. [58] sought to characterize what constitutes an “obese tongue”.
It has been well documented that obese subjects have an impaired ability to detect lipids,
which may lead to higher lipid consumption. They determined that obesity state and
salivary LPS levels were both poor predictors for lipid sensitivity. They did, however,
find specific bacterial compositions (increase in Bacteroidaceae family) in lipid non-tasters,
irrespective of obesity status. These findings lend itself to the notion that lipid tasters
may have an overall anti-inflammatory microenvironment while lipid non-tasters host
pro-inflammatory bacteria. Interestingly, obesity amplified the phenotypic differences
found between tasters and non-tasters, suggesting that this taste difference is mainly due
to obesity once established.
Another method of measuring taste change has been through the systemic injection
of LPS. For example, LPS injected intraperitoneally finds its way through mesenteric
absorption and circulation to taste bud cells. This route represents an acute bacterial
infection and has been shown to lead to the expression of inflammatory cytokine expression
(TNF-α, INF-γ and IL-6) around circumvallate and foliate papillae. This LPS-induced
inflammation was shown to inhibit the proliferation of taste progenitor cells and reduce
the number of newly born cells entering taste buds. This also moderately shortened the
average lifespan of mature taste bud cells [55]. Intraperitoneal injection of LPS has also
been used to study its effect on Na+ transportation in taste buds, linked to salt taste
perception. As such, Kumarhia et al. [59] found that LPS elicited an expression of the
inflammatory cytokines TNF-α and IL-1β in taste bud cells. These cytokines had rapid
effects attributed to modulation of channels (ENaC) responsible for Na+ transport: TNF-α
reduced flux while IL-1β increased flux and was a more effective modulator. These results
demonstrate that inflammation elicits swift changes in Na+ taste function, which may
lead to heightened Na+ sensitivity during infection [59]. Interestingly, a previous study
described how neutrophil recruitment to subcutaneous lingual injection of LPS might be
responsible for observed sodium taste impairment. The neutrophil production of TNF-α
and IL-1β has been suggested as possible mechanism; however, these cytokines were not
measured in this study [60].
Lastly, the ingestion of LPS is a multifactorial vehicle that mimics consumption of
harmful microbes and has been shown to affect taste. The timing of response following
ingestion becomes a critical variable to consider. For instance, mice who ingested Grampositive LPS bacteria exhibited a decrease in neural responses to sucrose during a single
overnight period. A decrease in sucrose sensitivity was observed 7 days after injection,
in parallel with decreased expression of sweet taste receptors T1R2+T1R3. These results
did not occur in acute-, and lingual-treated LPS treated mice nor in TLR4 knockout mice,
indicating that ingestion and proper immune responses were necessary to suppress sucrose
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response. Modulation of certain gut hormones known to affect peripheral taste function
was listed as the potential mechanism of communication between the gut and taste bud
cells [56]. In addition, gut permeability plays an important role since this method of LPS
delivery introduces pathogenic material at intestinal interfaces.
While there are many protective mechanisms preventing LPS from crossing the gut
barrier and entering systemic circulation, permeability has been shown to increase from gut
dysbiosis induced by high-fat diets [61]. It has also been well documented that obese mice
subjected to a high-fat diet exhibit a blunted ability to detect low concentrations of sweet
solutions [62]. This effect was reversed following prebiotic supplementation that restored
the eubiotic environment, demonstrating the role of gut microbiota on nutrient sensing [63].
Low-grade inflammation of adipose tissue might also be a factor influencing taste-driven
reward behavior for foods rich in sugar and fat. As stated above, the communication
between gut microbiota and other sensory systems such as taste require immune activation;
however, this is not always the case. In fact, microbiota can elicit behavioral responses in
absence of an immune response. For example, administration of the pathogen, C. jejuni,
produced a rapid anxiety-like response in mice through a vagal pathway [64]. Since
taste responses are also mediated by the vagus nerve, it is reasonable to hypothesize that
microbial-induced taste responses might trigger a direct vagal mechanism to the brain.
4.1.2. Microbes and Taste Sensing via TLRs
Toll-like receptors play a crucial role in sensing the intestinal microbes via recognition of pathogen-associated molecular patterns (MMAPs) that are derived from various
microbes, triggering inflammatory and immune responses. Some TLR, such as TLR4 has
been shown to influence anorexigenic signals [65]. For example, the pro-inflammatory
lipopolysaccharides, acting mainly through activation of TLR4 receptors have also shown
to increase GLP-1 secretion. Although some TLRs are expressed by EEC and administration of TLR agonists such as LPS or bacteria-derived lipoproteins stimulate secretion of
gut hormones such as CCK and serotonin, TLR4 are expressed on the tongue gustatory
papillae [49] and are involved in taste perception, food preference and intake [66] (Figure 2).
However, only systemic and not lingual bacterial endotoxin mediated sweet taste functions
via Tas1r2/3 receptors. Taken together, these findings demonstrate the intricate and intriguing mechanisms mediating taste signaling by bacteria. This has phenotypic correspondence
in which germ-free mice consume more sucrose than conventional counterparts which was
associated with increased intestinal T1R3 mRNA expression [3]. More recently, it has been
shown that stimulation of the bitter taste receptors (TAS2Rs) present in gastrointestinal
tract modulates enteroendocrine cell secretion and control food intake [67]. Although the
exact mechanisms are not known, it is possible that microbial byproducts such as SCFAs
acting on EEC cells and subsequent stimulation of gut peptides such as GLP-1, CCK and
PYY might also contribute to this effect.
4.2. Microbes Influence Taste Perception through Hormones
Human taste bud cells secrete a number of diverse peptides as well as express cognate
receptors [68]. These peptides are not only found in the gustatory system but rather play
integral parts in regulating the body’s physiological response by acting on nervous or
endocrine tissues. There are numerous studies demonstrating the gut microbiota’s ability
to influence secretion of peptide hormones controlling appetite and energy regulation [46].
Thus, there is an emerging model of gut microbial influence on peripheral taste perception
through these peptides and their autocrine, paracrine, and endocrine signaling. These large
number of peptides expressed by taste bud cells are primarily studied in the context of
metabolism, feeding, and satiety; however, at the lingual level, they may act to modulate
adjacent taste cells and activate afferent nerve fibers [69] (Figure 2). The notion that
these bioactive peptides play a role in processing taste information is supported by the
expression of various cognate receptors by taste bud cells. While the precise functions
of these peptides in taste buds are not fully understood, studies suggest that some act
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to modulate the responsiveness of the peripheral gustatory apparatus to certain taste
stimuli [70].
Numerous studies over the years have sought to characterize the gustatory effects of
these peptides [71] and showed their effect on taste qualities. For example, leptin decreases
sensitivity to sweet [72] while endocannabinoids increase sensitivity to sweet [73]. Likewise,
Glucagon Like Peptide-1 (GLP-1) increases sensitivity to sweet and decreases sensitivity to
umami [74,75]. Cholecystokinin (CCK) may affect bitter taste [76]; Vasoactive Intestinal
Polypeptide (VIP) modulates sweet, bitter and sour [77]; Peptide YY (PYY) increases
responses to bitter and fat [78,79]; Neuropeptide Y affects bitter taste [80]; Oxytocin affects
sweet and salty taste [81] and ghrelin increases responses to salty and sour [82]. While
these peptides have been shown to locally affect taste perception, the question is whether
circulating gastrointestinal peptides could influence taste buds in the same way. Indeed, the
premise that peripheral taste functions are modulated by the metabolic state [68], supports
this model of hormonal influence. Additionally, high concentrations of circulating leptin,
along with TNF-a and insulin-like growth factor-1, have been found in individuals with
increased taste responsiveness [83].
As stated above, the gut is the largest hormone-producing organ in the body [84]
and houses the majority of the body’s microbiota. This complex interaction lends itself
to the likelihood of microbes inducing downstream effects, consequently affecting an
individual’s hormonal milieu and, in turn, their taste perception. Increasing evidence
suggests that these gut microbes affect endocrine functions through two pathways: directly
through the production of bioactive metabolites like SCFAs, and indirectly, as modulators
of inflammatory responses, immune responses and hormonal secretion [85]. Importantly,
SCFAs are directly implicated in the release of hormones and neuropeptides, such as GLP-1
and PYY from intestinal enteroendocrine cells [86,87]. For example, intestinal infusion
of E. coli proteins also leads to an increase in plasma PYY and GLP-1 levels [88]. Further,
ninety-five percent of SCFAs produced in the gut are represented by acetate, propionate
and butyrate [89] and activate FFAR2 and FFAR3 receptors expressed in EECs with different
potency or act via histone deacetylase (HDAC) inhibition. Both receptors activate Gαi/o
signaling; however, FFAR2 also signals Gαq/11 to release intracellular calcium leading to
secretion of gut hormones [90] Recently, Shackley and colleagues reported upregulation of
the umami taste receptor subunit TAS1R1 following exposure of EECs to SCFAs in STC-1
cells and murine intestinal organoids models. This data demonstrate how SCFAs can
induce remodeling of GPCR gustatory signaling system [91].
The model of the gut microbiota as a stimulator of the immune system intersects with
its role in hormone regulation (Figure 2). LPS is known to acutely increase circulating leptin
levels in mice and rats via IL-1β [92]. In addition, mouse ingestion of LPS decreased taste
responsiveness to sucrose, an effect attributed to changes in sweet enhancing hormones
such as endocannabinoids, glucagon and GLP-1 [56]. Since leptin is derived from both
gastric and adipose origin [93], the nutritional state should also be considered when
studying associations between bacteria and hormone secretion. In conditions such as
obesity, bacterial signals from the gut might compete with increased plasma levels of
anorexigenic hormone signals like leptin [94] while prebiotic treatment improved leptin
sensitivity [95]. Finally, changes in microbiota composition after bariatric surgery changed
taste perception that may also be due to gut microbiota altering circulating hormone
levels [84]. Taken together, these studies demonstrate that gut bacteria exert significant
effects on circulating hormones which, in turn, influence taste.
5. Diet-Induced Changes in Gut Microbiota and Taste Perception
There are many known factors that drive food choices and habits, with taste considered
as one of the main predictors [96]. This relationship between taste and food, however, can
be described as bidirectional with dietary habits establishing taste perception as well. The
previous sections described several mechanisms by which microbes influence taste percep-
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tion. Since the role of diet in shaping oral and gut microbiota is widely recognized [25,97],
diet-induced alterations in microbial signatures may contribute to gustatory changes.
Popular nutrition advice often claims that one can “retrain taste buds” by adhering
long enough to a diet low in sugar, salt and fat [98]. Indeed, a randomized control trial
found that reduced dietary intake of simple sugars altered subjects’ perceived sweetness
intensity [99]. This study also found perceived pleasantness of these added sugar solutions
to be unchanged, indicating that hedonic responses were not responsible for the change in
taste perception [99]. This phenomenon of dietary modifications leading to taste perception
changes is widely observed in murine studies as well, where exposure to high-fat diet
decreases lingual sensitivity to fat [10]. The mechanisms by which oral and gut microbiota
are reciprocally influenced are not yet fully understood; however, recent studies have found
that the composition of oral cavity and stool bacteria overlap in 45% of subjects [100]. Therefore, one may hypothesize that dietary habits could affect these two microbial ecosystems
in similar ways [25], and thus subsequent changes in peripheral taste and nutrient-sensing
functions. In this context, potential parallels on taste and nutrient-sensing models can be
drawn when discussing habitual diets.
Turner et al. [101] recently highlighted the gut microbiota’s likely involvement in
altered nutrient sensing ability following regular consumption of artificial or intense sweetener (IS). Artificial sweeteners have been shown to have direct bacteriostatic effects on common gut microflora (E. coli) leading to dysbiosis (increased Firmicutes) [102]. Furthermore,
receptor expression levels may change in response to this alteration in bacterial composition,
resulting in altered metabolic functions like insulin resistance and obesity [101,103,104].
The gut microbiome’s role in these IS-consuming metabolic conditions is further supported
by studies with fecal microbial transplant. Importantly, IS-induced glucose intolerance was
fully transferable to germ-free mice and was shown to be eliminated through antibiotic
treatment [105].
Another indication that the habitual consumption of certain foods leads to changes
in gut microbiota and nutrient-sensing ability is evident from studies on consumption of
inulin, a dietary fiber found in plants. A recent murine study by Weninger et al. [106] found
significant improvement of small intestinal nutrient-sensing after 6 weeks of oligofructose
(OFS) rich diet, a subgroup of inulin. Specifically, OFS improved intestinal lipid-sensing
mechanisms by increasing CD36 expression, which is known to mediate the lipid-induced
release of GLP-1. This improvement was attributed to changes in the gut microbiota
as transplant of microbiota reproduce these results [106]. The correlation between inulin
consumption and peripheral taste function has yet to be determined. Interestingly, however,
a 2-week inulin-rich vegetable diet was found to reduce desires for sweet, salty, and fatty
foods, while also increasing hedonic attitudes toward some inulin-rich vegetables [107].
Sucrose detection threshold did not change during the intervention, but considering the
Weninger et al. [106] study, fat detection may be another variable to study in this regard.
Eating disorders associated with taste responsiveness might lend itself to the influence
of gut microbiota [108]. These modifications in taste signaling mechanisms theoretically
could lead to increased consumption of food substrates preferred by specific microbes for
survival [103]. Indeed, obesity is associated with lower responsiveness to sweet and fat,
which may be attributed to specific oral and gut microbial signatures functioning through
immune and hormonal responses as presented previously [58,63]. For example, children
with obesity had lower counts of fungiform papilae compared to normal weight subjects,
which was associated with different salivary bacterial alpha-diversity and a lower ability to
correctly identify taste qualities [43]. Furthermore, several bacterial genera differ between
individuals with different taste sensitivity independent of the nutritional status, and that
oral bacteria such as Selenomonas could be biomarkers for excess adiposity, suggesting
a direct link between taste and specific microbiota signature [109]. At the same time,
individuals with anorexia nervosa exhibit impaired taste perception, namely with sweet,
salty and umami tastes [110,111]. These impairments have been shown to improve with
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weight gain [112] and while the role of the gut microbiota in this disorder is still unclear,
current evidence suggests it could be a potent therapeutic option [113].
6. Clinical Implication of Microbiota/Taste Interactions
6.1. Taste in Inflammatory Conditions
Inflammatory diseases such as bowel disease (IBD) are associated with alterations
in taste sensitivity. For example, in a human IBD case-control study, taste sensitivity was
significantly reduced in all tastes except for sour [114]. Similarly, Melis et al. [115] found
the same reduction in taste sensitivity as well as a significant increase in sour perception for
IBD patients. The exact mechanism for taste alteration is not clearly understood; however,
the oral microbiome and its interaction with the salivary enzyme gustin CAVI is thought to
be central [115]. Gustin CAVI is a zinc-dependent enzyme that regulates the pH balance
of the saliva and its disruption leads to a more acidic oral cavity environment [115]. Low
salivary pH can lead to oral dysbiosis, and this has been observed in IBD patients who
exhibit an increase in bacteria-derived acid metabolites [116], potentially contributing to
sour perception alterations [115]. Gustin CAVI is also a trophic factor that promotes the
development of taste buds [117] and its disruption may be a key factor in the overall
decreased taste function of IBD patients [118]. Thus, it appears that intestinal dysbiosis
precedes the onset of IBD [119] and this can cause intestinal malabsorption and zinc
deficiencies [120]. Since gustin CAVI is zinc-dependent, the deficiency of this mineral
due to dysbiosis may be linked to the inactivity of the gustin enzyme, changes in salivary
pH, the progression of oral dysbiosis, and therefore taste alterations characteristic in IBD
patients [115].
6.2. Taste and COVID-19
The SARS-CoV-2 spike glycoprotein (S) binds to angiotensin-converting enzyme-2
(ACE2) receptors that is abundantly expressed in the intestinal enterocytes’ brush border and colonic epithelial cells, supporting SARS-CoV-2 replication [121]. This results in
local inflammation, disruption in resident microbiota and gut barrier dysfunction, thus
decreasing secretion of antimicrobial peptides and facilitating bacterial metabolomes and
byproducts to enter the circulation leading to systemic inflammation [122–124]. Several
studies have shown that patients with COVID-19 have an altered microbiome characterized by an overall decline in microbial diversity, enrichment of opportunistic pathogens
Clostridium hathewayi, Actinomyces viscosus, Bacteroides nordii, Streptococcus, Rothia, Erysipelatoclostridium and Veillonella along with significant depletion of beneficial commensals
such as Lachnospiraceae bacterium, Eubacterium rectale, Ruminococcus obeum, Fusicatenibacter,
Eubacterium hallii, Anaerostipes, Agathobacter, Roseburia, Dorea formicigenerans, Clostridium
butyricum, Clostridium leptum and Faecalibacterium prausnitzii [125,126]. Some of these beneficial bacteria which includes butyric acid producing bacteria have been linked to reduced
inflammation. Further, the probiotic bacteria, Lactobacillus and Bifidobacterium are also
decreased in COVID-19 patients. It is not known whether changes in the gut microbiota
environment due to COVID-19 are linked with taste changes in infected patients. It is
widely known that a significant number of COVID-19 patients report taste changes, as
well as changes in the overall oral sensitivity to commonly used condiments and spices.
Recently, however, Doyle et al. demonstrated that ACE2 receptors are also present on a
subpopulation of Type II cells, PLCβ2 positive, in taste buds, thus facilitating the entry
of SARS-CoV-2 virus in the oral cavity [127]. Further, taste stem cell proliferation and
turnover were reduced during the infection and lasted long after the onset of the infection.
The authors hypothesized that the acute taste changes during COVID-19 are due to the
replication of the virus and subsequent infection within taste buds, since sensory afferents
of taste cranial nerves that carry gustatory signals to the brain do not express ACE2 receptors [128,129]. Oral microbiota is also disturbed in COVID-19 patients with significant
diminution in species richness and marked differences in beta diversity. Specifically, there
was a decrease in butyric acid-producing bacteria and an increase in lipopolysaccharide-
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producing bacteria. Therefore, changes in the microbiota composition profile are associated
with aberrant inflammation that is present both in the oral cavity as well as in the lower
gut of COVID-19 patients. In fact, abundance of certain gut bacteria such as Coprobacillus,
Clostridium ramosum and Clostridium hathewayi, correlated with COVID-19 severity. Taste
sensitivity is reduced in inflammatory conditions [126]; however, the contribution of systemic inflammation to taste changes in the oral cavity is not known. It is interesting to
note that, Type II cells “taste” amino acids and ACE2 in the gut is involved in amino acid
absorption [130]. Whether or not host ACE2 receptors co-localize with intestinal nutrients
and taste receptors and how that might impact food choices remains to be investigated.
Furthermore, oral microbial signatures can be used as a potential non-invasive diagnostic
tool for COVID-19.
6.3. Taste, Chemotherapy, Drugs and Microbiome
Taste changes occur in up to 84% of patients undergoing chemotherapy treatments [131].
Recent studies report that taste disorders were more frequent in gastrointestinal than in
breast cancer patients [132]. Patients who experience gastrointestinal symptoms during chemotherapy are also associated with an increased odd of having taste perception
changes [133]. Cancer therapy is frequently associated with a disrupted microbiota, which
may cause a release of inflammatory response ligands like LPS, bacterial DNA, and protein
flagellin [134]. Previous studies have described how changes in gut microbiota are related
to taste alterations in mice and this may be implicated in chemotherapy patients [3,29].
Wang et al. [135] have also proposed that the disruption of oral microbiota by chemotherapy agents could result in a local inflammatory response resulting in the observed taste
changes. Indeed, oral mucositis is closely associated with alterations in taste and frequently
reported in cancer patients undergoing chemotherapy [136]. While re-establishment of the
microbiota in cancer patients has yet to be explored as a therapeutic treatment for taste
dysfunctions, intensified nutritional counseling with taste and smell training has been
shown to improve taste perception in these patients [132]. It should also be noted that many
prescription and non-prescription drugs, including antibiotics, angiotensin-converting enzyme inhibitors, lipid-lowering agents, proton pump inhibitors, chemotherapy drugs, and
metformin are known to affect taste as well as disrupt the gut microbiota. Whether these
drugs can also impact the composition of the oral microbiota or its metabolites and induce
taste changes is not known.
6.4. Taste, Bariatric Surgery and Microbiome
Several studies have shown that obesity is associated with taste changes, particularly
a reduction in taste acuity and taste bud abundance. For example, hypothalamic and
brainstem T1R3 and T2R116 taste receptors as well as signaling molecules such as Gα14
and TRPM5 were downregulated by obesity in mice [137,138]. In humans, loss of taste was
associated with selection of high caloric foods [139]; however, the evidence linking taste
responses and taste gene polymorphism is limited [140] Conversely, weight loss such in
patients undergoing bariatric surgery results in rapid changes in taste which may be due to
the overall reduction in inflammation and/or in response to physiological and metabolic
changes due to the anatomical reconfiguration of the GI tract [141,142]. Indeed, bariatric
procedures, such as Roux-en-Y gastric bypass (RYGB) and laparoscopic sleeve gastrectomy
(LSG), results in significant changes in the anatomy, function, diet and intraluminal milieu
of the gastrointestinal tract affecting the gut microbiota [143,144]. Gut microbiota plays
a key role in pathogenesis of obesity and obesity has been characterized by a dysbiotic
microbiota, with differences in both salivary and fecal microbiota composition profile and
bacterially derived metabolites such as γ-amino butyric acid and butyrate between obese
and normal weight individuals [126]. Changes in the gut microbiota composition profile
are rapid, as early as one week after surgery, and are due to multiple factors including
changes in diet, antibiotic treatment, anatomical reconfiguration of the gastrointestinal
tract and weight loss. Bariatric surgery results in long-term weight loss, improvement
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of metabolic comorbidities like type 2 diabetes, increased satiety, decreased appetite and,
interestingly, change in eating behavior [144]. Differences in microbiota composition
profile, including salivary microbiota [145] between obese and lean individuals are well
documented; however, how these changes impact taste is not clearly established. Similarly,
the results from studies examining the effects of bariatric surgery on taste preference
thus far are inconsistent. Some studies suggest changes in taste detection thresholds and
acceptance to sweets. For example, RYGB patients had increased taste acuity for bitter and
sour and increased threshold sensitivity for salt and sweets while in other studies patients
showed high sour taste threshold or no difference in sensitivity thresholds for sweetness,
bitterness or saltiness after RYGB compared with vertical sleeve gastrectomy (VSG) [146].
In a systematic review, Ahmed et al. [144] concluded that taste sensitivity to sweet and
fatty stimuli appear to increase post-operatively bariatric surgery. Additionally, patients
experience a reduced hedonic response to these stimuli. While the complex mechanisms
leading to changes in eating patterns is still being investigated, some have hypothesized
that an altered gut microbiota may play an indirect role [143]. As discussed previously,
changes in the microbiota can alter circulating hormones levels, which might mediate the
change in taste perception observed after bariatric surgery [68]. Increased levels of GLP-1
and PYY have been consistently demonstrated in rodent models of RYGB surgery [84]. Sanmiguel et al. [143] found that obese women who underwent bariatric surgery experienced
reduced appetite and hedonic eating, which was associated with distinct gut microbial
signatures. This study did not measure taste sensitivity, however. It is worth mentioning
that hedonic responses are distinct from taste sensitivity and should be distinguished when
discussing changes in eating behavior. Weight loss influencing eating behavior should also
be considered as a confounding variable in RYGB studies. For example, Pepino et al. [147]
found that women who experienced a 20% reduction in body weight post-operative RYGB
reported a shift in sweetness palpability leading to a decrease in sweet food consumption.
This change in eating behavior was not associated with changes in taste sensitivity, however, suggesting other unknown mechanisms. Finally, changes in microbiome post bariatric
surgery have been associated with brain connectivity between precuneus and putamen
regions of the brain that are involved in addictive behavior [148]. Therefore, the dramatic
shift in the gut microbiota composition due to bariatric surgery may contribute to changes
in taste and food cues in core regions of the brain similar to those seen in addiction behavior; however, this hypothesis needs to be investigated. Gustatory changes have also been
identified in Type 2 diabetic patients who report decreased taste sensitivity for sweets, salty
and sour stimuli [149] and are deficient in detecting fatty taste [150]. Furthermore, changes
in lipid detection of diabetic patients have been associated with changes in the bacterial
composition in the circumvallate papillae. As such, low lipid tasters had a greater bacterial
diversity and proinflammatory profile with high bacteroides/lactobacillus ratio compared to
high lipid tasters [150] that might explain reduction in fatty taste sensitivity. These changes
in microbiota composition profile in high lipid tasters were associated with increases in
bacterial metabolism involving catecholamine and ascorbate pathways.
7. Conclusions
Taste plays a significant role in food choices and is the most important driver of food
consumption [151]. The increased hedonic value and motivation for palatable, energydense foods readily available in the current obesogenic food environment underscores
the need for understanding the mechanisms by which enhanced motivation results in
excess eating and seek new strategies to address dysfunctional eating behavior. Likewise,
alterations in metabolic health can affect taste perception and preference. Taste is influenced
by a myriad of factors including genetics, biological, physiological, metabolic, psychological
and cultural. Although great strides have been made in understanding the role of gut
microbiota on regulatory signaling controlling food intake and regulation of energy balance,
including those involved in hedonic feeding such as taste, there remains much to learn.
To better substantiate our knowledge of the complex and intricate interactions between
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the human host and gut microbes, the microbe to microbe interactions, their byproducts
and effects on energy homeostasis, questions related to individuals’ microbial composition,
host health status, taste polymorphism, genetics, internal and external influences, to
name a few, must be answered. The differential regulation of the multiple microbial
and antimicrobial compounds in both health and disease states and how these changes
might impact consummatory behavior should be systematically dissected and study with
deserved accuracy. These will lead to a better understanding of how to design prevention,
diagnostic and treatment strategies in order to curb non-homeostatic excess eating, on one
hand, and improve taste qualities in disease conditions, on the other hand.
Author Contributions: All authors contributed to the conceptualization, writing and article preparation. All authors have read and agreed to the published version of the manuscript.
Funding: This research was funded by the project “The analysis of interrelationship between gut
microbiota and the host with applications in the prevention and control of type 2 diabetes” cofinanced by European Regional Development Fund through Competitiveness Operational Program
under the contract number 120/9.16.2016.
Conflicts of Interest: The authors declare no conflict of interest.
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