Taste receptors in the gastrointestinal tract. IV. Functional implications of bitter taste receptors in gastrointestinal chemosensing

Changes in the luminal contents of the gastrointestinal tract modulate gastrointestinal functions, including absorption of nutrients, food intake, and protection against harmful substances. The current notion is that mucosal enteroendocrine cells act as primary chemoreceptors by releasing signaling molecules in response to changes in the luminal environment, which in turn activate nerve terminals. The recent discovery that taste receptors and G protein subunits alpha-gustducin and alpha-transducin, involved in gustatory signal transduction, are expressed in the gastrointestinal mucosa supports the concept of a chemosensory machinery in the gastrointestinal tract. An understanding of luminal sensing processes responsible for the generation of the appropriate functional response to specific nutrients and nonnutrients is of clinical importance since aberrant or unsteady responses to changes in luminal contents might result in disease states ranging from intoxication to feeding disorders and inflammation. The purpose of this theme article is to discuss the functional implications of bitter taste signaling molecules in the gastrointestinal tract deduced by their localization in selected populations of epithelial cells and their relationship with neural pathways responsible for the generation of specific responses to luminal contents.     

Taste receptors in the gastrointestinal tract. I. Bitter taste receptors and alpha-gustducin in the mammalian gut

Molecular sensing by gastrointestinal (GI) cells plays a critical role in the control of multiple fundamental functions in digestion and also initiates hormonal and/or neural pathways leading to the regulation of caloric intake, pancreatic insulin secretion, and metabolism. Molecular sensing in the GI tract is also responsible for the detection of ingested harmful drugs and toxins, thereby initiating responses critical for survival. The initial recognition events and mechanism(s) involved remain incompletely understood. The notion to be discussed in this article is that there are important similarities between the chemosensory machinery elucidated in specialized neuroepithelial taste receptor cells of the lingual epithelium and the molecular transducers localized recently in enteroendocrine open GI cells that sense the chemical composition of the luminal contents of the gut.     

G-protein-coupled receptors in intestinal chemosensation

Food intake is detected by the chemical senses of taste and smell and subsequently by chemosensory cells?in the gastrointestinal tract that link the composition of ingested foods to feedback circuits controlling gut motility/secretion, appetite, and peripheral nutrient disposal. G-protein-coupled receptors responsive to?a range of nutrients and other food components have been identified, and many are localized to intestinal chemosensory cells, eliciting hormonal and neuronal signaling to the brain and periphery. This review examines the role of G-protein-coupled receptors as signaling molecules in the gut, with a particular focus on pathways relevant to appetite and glucose homeostasis.     

T1R3 is expressed in brush cells and ghrelin-producing cells of murine stomach

Various digestive and enteroendocrine signaling processes are constantly being adapted to the chemical composition and quantity of the chyme contained in the diverse compartments of the gastrointestinal tract. The chemosensory monitoring that underlies the adaptive capacity of the gut is thought to be performed by so-called brush cells that share morphological and molecular features with gustatory sensory cells. A substantial population of brush cells is localized in the gastric mucosa. However, no chemosensory receptors have been found to be expressed in these cells so far, challenging the concept that they serve a chemosensory function. The canonical chemoreceptors for the detection of macronutrients are taste receptors belonging to the T1R family; these have been identified in several tissues in addition to the gustatory system including the small intestine. We demonstrate the expression of the T1R subtype T1R3, which is essential for the detection of both sugars and amino acids in the gustatory system, in two distinct cell populations of the gastric mucosa. One population corresponds to open-type brush cells, emphasizing the notion that they are a chemosensory cell type; T1R3 immunoreactivity in these cells is restricted to the apical cell pole, which might provide the basis for the detection of luminal macronutrient compounds. The second gastric T1R3-positive population consists of closed-type endocrine cells that produce ghrelin. This finding suggests that ghrelin-releasing cells, which lack access to the stomach lumen, might receive chemosensory input from macronutrients in the circulation via T1R3.     

Nerveless and gutsy: intestinal nutrient sensing from invertebrates to humans

The increasingly recognized role of gastrointestinal signals in the regulation of food intake, insulin production and peripheral nutrient storage has prompted a surge of interest in studying how the gastrointestinal tract senses and responds to nutritional information. Identification of metabolically important intestinal nutrient sensors could provide potential new drug targets for the treatment of diabetes, obesity and gastrointestinal disorders. From a more fundamental perspective, the study of intestinal chemosensation is revealing novel, non-neuronal modes of communication involving differentiated epithelial cells. It is also identifying signalling mechanisms downstream of not only canonical receptors but also nutrient transporters, thereby supporting a chemosensory role for "transceptors" in the intestine. This review describes known and proposed mechanisms of intestinal carbohydrate, protein and lipid sensing, best characterized in mammalian systems. It also highlights the potential of invertebrate model systems such as C. elegans and Drosophila melanogaster by summarizing known examples of molecular evolutionary conservation. Recently developed genetic tools in Drosophila, an emerging model system for the study of physiology and metabolism, allow the temporal, spatial and high-throughput manipulation of putative intestinal sensors. Hence, fruit flies may prove particularly suited to the study of the link between intestinal nutrient sensing and metabolic homeostasis.     

Copper-Impaired Chemosensory Function and Behavior in Aquatic Animals

Chemosensation is one of the oldest and most important sensory modalities utilized by aquatic animals to provide information about the location of predators, location of prey, sexual status of potential mates, genetic relatedness of kin, and migratory routes, among many other essential processes. The impressive sophistication of chemical communication systems among aquatic animals probably evolved because of the selective pressures exerted by water as a “universal solvent.” Impairment of chemosensation by toxicants at the molecular or cellular level can potentially lead to major perturbations at higher levels of biological organization. We have examined the consequences of metal-impaired chemosensory function in a range of aquatic animals that represents several levels of a typical aquatic ecosystem. In each case, low, environmentally relevant metal concentrations were sufficient to cause chemosensory dysfunction. Because the underlying molecular signal transduction machinery of chemosensory systems demonstrates a high degree of phylogenetic conservation, we speculate that metal-impaired chemosensation among phylogenetically disparate animal groups probably results from a common mechanism of impairment. We propose developing a chronic chemosensory-based biotic ligand model (BLM) that maintains the advantages of the current BLM approach, while simultaneously overcoming known difficulties of the current gill-based approach and increasing the ecological relevance of current BLM predictions.     

Review: Chemosensing of nutrients and non-nutrients in the human and porcine gastrointestinal tract

The gastrointestinal tract (GIT) is an interface between the external and internal milieus that requires continuous monitoring for nutrients or pathogens and toxic chemicals. The study of the physiological/molecular mechanisms, mediating the responses to the monitoring of the GIT contents, has been referred to as chemosensory science. While most of the progress in this area of research has been obtained in laboratory rodents and humans, significant steps forward have also been reported in pigs. The objective of this review was to update the current knowledge on nutrient chemosensing in pigs in light of recent advances in humans and laboratory rodents. A second objective relates to informing the existence of nutrient sensors with their functionality, particularly linked to the gut peptides relevant to the onset/offset of appetite. Several cell types of the intestinal epithelium such as Paneth, goblet, tuft and enteroendocrine cells (EECs) contain subsets of chemosensory receptors also found on the tongue as part of the taste system. In particular, EECs show specific co-expression patterns between nutrient sensors and/or transceptors (transport proteins with sensing functions) and anorexigenic hormones such as cholecystokinin (CCK), peptide tyrosine tyrosine (PYY) or glucagon-like peptide-1 (GLP-1), amongst others. In addition, the administration of bitter compounds has an inhibitory effect on GIT motility and on appetite through GLP-1-, CCK-, ghrelin- and PYY-labelled EECs in the human small intestine and colon. Furthermore, the mammalian chemosensory system is the target of some bacterial metabolites. Recent studies on the human microbiome have discovered that commensal bacteria have developed strategies to stimulate chemosensory receptors and trigger host cellular functions. Finally, the study of gene polymorphisms related to nutrient sensors explains differences in food choices, food intake and appetite between individuals.     

Chemical sensing in Drosophila

Chemical sensing begins when peripheral receptor proteins recognise specific environmental stimuli and translate them into spatial and temporal patterns of sensory neuron activity. The chemosensory system of the fruit fly, Drosophila melanogaster, has become a dominant model to understand this process, through its accessibility to a powerful combination of molecular, genetic and electrophysiological analysis. Recent results have revealed many surprises in the biology of peripheral chemosensation in Drosophila, including novel structural and signalling properties of the insect odorant receptors (ORs), combinatorial mechanisms of chemical recognition by the gustatory receptors (GRs), and the implication of Transient Receptor Potential (TRP) ion channels as a novel class of chemosensory receptors.     

Chemosensory signaling in C. elegans

The nematode Caenorhabditis elegans can sense and respond to hundreds of different chemicals with a simple nervous system, making it an excellent model for studies of chemosensation. The chemosensory neurons that mediate responses to different chemicals have been identified through laser ablation studies, providing a cellular context for chemosensory signaling. Genetic and molecular analyses indicate that chemosensation in nematodes involves G protein signaling pathways, as it does in vertebrates, but the receptors and G proteins involved belong to nematode-specific gene families. It is likely that about 500 different chemosensory receptors are used to detect the large spectrum of chemicals to which C. elegans responds, and one of these receptors has been matched with its odorant ligand. C. elegans olfactory responses are also subject to regulation based on experience, allowing the nematode to respond to a complex and changing chemical environment.     

Shuttling of information between the mucosal and luminal environment drives intestinal homeostasis

The gastrointestinal tract is a passageway for dietary nutrients, microorganisms and xenobiotics. The gut is home to diverse bacterial communities forming the microbiota. While bacteria and their metabolites maintain gut homeostasis, the host uses innate and adaptive immune mechanisms to cope with the microbiota and luminal environment. In recent years, multiple bi-directional instructive mechanisms between microbiota, luminal content and mucosal immune systems have been uncovered. Indeed, epithelial and immune cell-derived mucosal signals shape microbiota composition, while microbiota and their by-products shape the mucosal immune system. Genetic and environmental perturbations alter gut mucosal responses which impact on microbial ecology structures. On the other hand, changes in microbiota alter intestinal mucosal responses. In this review, we discuss how intestinal epithelial Paneth and goblet cells interact with the microbiota, how environmental and genetic disorders are sensed by endoplasmic reticulum stress and autophagy responses, how specific bacteria, bacterial- and diet-derived products determine the function and activation of the mucosal immune system. We will also discuss the critical role of HDAC activity as a regulator of immune and epithelial cell homeostatic responses.     

Nutrient sensing in the gastrointestinal tract: Possible role for nutrient transporters

Although it is well established that the presence of nutrients in the gut lumen can bring about changes in GI function, the mechanisms and pathways by which these changes occur has not been fully elucidated. It has been known for many years that luminal nutrients stimulate the release of hormones and regulatory peptides from gut endocrine cells and that luminal nutrients activate intrinsic and extrinsic neural pathways innervating the gut. Activation of gut endocrine cells and neural pathways by nutrients in the gut lumen is key in coordination of postprandial GI function and also in the regulation of food intake. Recent evidence suggests that these pathways can be modified by long term changes in diet or by inflammatory processes in the gut wall. Thus it is important to determine the cellular and molecular mechanisms underlying these processes not only to increase our understanding of as part of basic physiology but also to understand changes in these pathways that occur in the presence of pathophysiology and disease. This review summarizes some of the latest data that we have obtained, together with information from the other laboratories, which have elucidated some of the mechanisms involved in nutrient detection in the gut wall. The focus is on monosaccharides and protein hydrolysates as there is some evidence for a role for nutrient transporters in detection of these nutrients.     

The effects of sex on chemosensory communication in a terrestrial salamander (Plethodon shermani)

Although much evidence reveals sexually dimorphic processing of chemosensory cues by the brain, potential sex differences at more peripheral levels of chemoreception are understudied. In plethodontid salamanders, the volume of the vomeronasal organ (VNO) is almost twice as large in males as compared to females, both in absolute and relative size. To determine whether the structural sexual dimorphism in VNO volume is associated with sex differences in other peripheral aspects of chemosensation, we measured sex differences in chemo-investigation and in responsiveness of the VNO to chemosensory cues. Males and females differed in traits influencing stimulus access to VNO chemosensory neurons. Males chemo-investigated (“nose tapped”) neutral substrates and substrates moistened with female body rinses more than did females. Compared to females, males had larger narial structures (cirri) associated with the transfer of substrate-borne chemical cues to the lumen of the VNO. These sex differences in chemo-investigation and narial morphology likely represent important mechanisms for regulating sex differences in chemical communication. In contrast, males and females did not differ in responsiveness of VNO chemosensory neurons to male mental gland extract or female skin secretions. This important result indicates that although males have a substantially larger VNO compared to females, the male VNO was not more responsive to every chemosensory cue that is detected by the VNO. Future studies will determine whether the male VNO is specialized to detect a subset of chemosensory cues, such as female body rinses or female scent marks.     

Vitamin A and vitamin D regulate the microbial complexity,barrier function,and the mucosal immune responses to ensure intestinal homeostasis

Diet is an important regulator of the gastrointestinal microbiota. Vitamin A and vitamin D deficiencies result in less diverse, dysbiotic microbial communities and increased susceptibility to infection or injury of the gastrointestinal tract. The vitamin A and vitamin D receptors are nuclear receptors expressed by the host, but not the microbiota. Vitamin A- and vitamin D-mediated regulation of the intestinal epithelium and mucosal immune cells underlies the effects of these nutrients on the microbiota. Vitamin A and vitamin D regulate the expression of tight junction proteins on intestinal epithelial cells that are critical for barrier function in the gut. Other shared functions of vitamin A and vitamin D include the support of innate lymphoid cells that produce IL-22, suppression of IFN-γ and IL-17 by T cells, and induction of regulatory T cells in the mucosal tissues. There are some unique functions of vitamin A and D; for example, vitamin A induces gut homing receptors on T cells, while vitamin D suppresses gut homing receptors on T cells. Together, vitamin A- and vitamin D-mediated regulation of the intestinal epithelium and mucosal immune system shape the microbial communities in the gut to maintain homeostasis.     

RNA-Seq Analysis of Human Trigeminal and Dorsal Root Ganglia with a Focus on Chemoreceptors

The chemosensory capacity of the somatosensory system relies on the appropriate expression of chemoreceptors, which detect chemical stimuli and transduce sensory information into cellular signals. Knowledge of the complete repertoire of the chemoreceptors expressed in human sensory ganglia is lacking. This study employed the next-generation sequencing technique (RNA-Seq) to conduct the first expression analysis of human trigeminal ganglia (TG) and dorsal root ganglia (DRG). We analyzed the data with a focus on G-protein coupled receptors (GPCRs) and ion channels, which are (potentially) involved in chemosensation by somatosensory neurons in the human TG and DRG. For years, transient receptor potential (TRP) channels have been considered the main group of receptors for chemosensation in the trigeminal system. Interestingly, we could show that sensory ganglia also express a panel of different olfactory receptors (ORs) with putative chemosensory function. To characterize OR expression in more detail, we performed microarray, semi-quantitative RT-PCR experiments, and immunohistochemical staining. Additionally, we analyzed the expression data to identify further known or putative classes of chemoreceptors in the human TG and DRG. Our results give an overview of the major classes of chemoreceptors expressed in the human TG and DRG and provide the basis for a broader understanding of the reception of chemical cues.     

Chemosensory function of salt and water transport by the amphibian skin

Solute and water transport mechanisms of anuran skin mediate chemosensory functions that permit evaluation of ionic and osmotic properties of hydration sources in a manner similar to taste receptors in the mammalian tongue. Histochemical observations demonstrated apparent connections between spinal nerve endings and epithelial cells of the skin and we used neural and behavioral responses as measures of coupling between transport and chemosensation. The inhibition of transcellular Na+ transport by amiloride partially reduced the neural response and the avoidance of hyperosmotic NaCl but not KCl solutions. Cetylpyridinium chloride (CPC) reduced the neural response to hyperosmotic salt solutions, suggesting a chemosensory role for vanilloid receptors in the skin. Avoidance of hyperosmotic salt solutions was reduced by impermeant anions suggesting paracellular conductance is important for chemosensation. The effects of blocking the transcellular and paracellular pathways was additive but did not eliminate the avoidance of osmotically unfavorable solutions by dehydrated toads. The timing of the neural response to deionized water was similar to the onset of water absorption behavior and increased blood flow to the pelvic skin. Water absorption from 50 mM NaCl was greater than from deionized water when toads were fully immersed, but not when contact was limited to the ventral surface.     

Taste receptors in the gastrointestinal tract. II. L-amino acid sensing by calcium-sensing receptors: implications for GI physiology

The extracellular calcium-sensing receptor (CaR) is a multimodal sensor for several key nutrients, notably Ca2+ ions and L-amino acids, and is expressed abundantly throughout the gastrointestinal tract. While its role as a Ca2+ ion sensor is well recognized, its physiological significance as an L-amino acid sensor and thus, in the gastrointestinal tract, as a sensor of protein ingestion is only now coming to light. This review focuses on the CaR's amino acid sensing properties at both the molecular and cellular levels and considers new and putative physiological roles for the CaR in the amino acid-dependent regulation of gut hormone secretion, epithelial transport, and satiety.     

Epithelial cells and their neighbors. II. New perspectives on efferent signaling between brain, neuroendocrine cells, and gut epithelial cells

Surface sensory enteroendocrine cells are established mucosal taste cells that monitor luminal contents and provide an important link in transfer of information from gut epithelium to the central nervous system. Recent studies now show that these cells can also mediate efferent signaling from the brain to the gut. Centrally elicited stimulation of vagal and sympathetic pathways induces release of melatonin, which acts at MT2 receptors to increase mucosal electrolyte secretion. Psychological factors as well mucosal endocrine cell hyperplasia are implicated in functional intestinal disorders. Central nervous influence on the release of transmitters from gut endocrine cells offers an exciting area of future gastrointestinal research with a clinical relevance.     

Nitric oxide modulates sodium taste via a cGMP-independent pathway

Insects, like other animals, require sodium chloride (NaCl) as part of their normal diet and detect it with contact chemoreceptors on the body surface. By adjusting the responsiveness of the chemosensory neurons within these receptors insects can modify the intake of salt and other nutrients, and it has been hypothesized that the responsiveness of chemosensory neurons is regulated by nitric oxide (NO). To identify potential sources of NO in the periphery, the authors applied the NO-sensitive fluorescent probe 4,5-diaminofluorescein and the universal NO synthase antibody, and found that in locusts NO is synthesized within one particular class of cells of the epidermis, the glandular cells, from where it may diffuse to neighboring chemosensory neurons. The effects of NO on chemosensory neurons were investigated by recording from contact chemoreceptors on the leg while perfusing it with drugs that interfere with NO signaling. Results showed that both endogenous and exogenous NO decreased the frequency of action potentials in chemosensory neurons in response to stimulation with NaCl by acting via a cyclic guanosine monophosphate-independent pathway. Variation of the NaCl concentration in the perfusion solution demonstrated that the synthesis of NO in glandular cells depends on the NaCl concentration in the hemolymph. By contrast NO increased the frequency of action potentials in chemosensory neurons in response to sucrose stimulation. The authors suggest that NO released from glandular cells modulates the responsiveness of chemosensory neurons to regulate NaCl intake, and hypothesize that NO may play a key role in the signaling of salt and sugars.