Nutrient-Sensing Receptors outside and inside Gastrointestinal System

Nutrient-Sensing Receptors outside and inside Gastrointestinal System: Comparison

Please note this is a comparison between Version 2 by Peter Tang and Version 1 by Edit Posta.

Intestinal nutrient-sensing receptors act as a crosstalk between dietary components, the gut microbiota, and the regulation of immune, endocrinological, and neurological responses.

nutrient-sensing receptor
gastrointestinal
IBD

1. Sweet and Bitter Taste Receptors (T1Rs and T2Rs)

Sweet and bitter taste receptors are expressed throughout the body.

Sweet taste receptors are widely expressed in the brain and the hypothalamic arcuate nucleus. Some neurons are sensitive to higher concentrations of glucose and are referred to as high-glucose-excited (HGE) neurons. These HGE neurons not only express sweet taste receptors but also sodium-glucose-linked transporters (SGLT1 and SGLT3). The exact role of sweet taste receptors in the brain is not known. They may have a role in the regulation of glucose homeostasis, the blood-brain barrier permeability, the circadian rhythm, and feeding behavior based on mouse model studies [15,16]^[1][2].

Interestingly, a previous study found that T2R38 was expressed on the fetal side of the human placenta; the amnion epithelium and the syncytiotrophoblast had strong positivity for T2R38, while on the maternal side, a weak expression signal was detected. T2R38 was also expressed in JEG-3 cells, a human placental cell line [17]^[3]. In another study, T2R14 expression was detected immunohistochemically in human syncytiotrophoblast and extravillous trophoblast, while in a human placental cell line, T2R14 agonists (flufenamic acid, chlorhexidine, and diphenhydramine) caused intracellular calcium release. The exact roles of these natural ligands are currently unknown [18]^[4].

T2R plays a role in the recognition of bacterial products and host-pathogen interactions. In a systematic review and meta-analysis, the single-nucleotide polymorphisms (SNPs) of four different genes (TAS1R2, TAS2R38, TAS1R3, and GLUT2) were associated with dental caries experience and oral health [19]^[5]. In a small but well-designed study, T2R38 polymorphisms were associated with the composition of the oral microbiome of rheumatoid arthritis (RA) patients, but there was no relation with anti-citrullinated protein levels (the most important antibody in RA) [20]^[6].

Acyl-homoserine lactone (AHL) molecules are secreted by Gram-negative bacteria such as Pseudomonas aeruginosa. AHLs can activate T2R38 receptors, which are expressed in human sinonasal cilia. This could act as a signal to activate nitrogen oxide synthase-dependent nitrogen oxide production. There are solitary chemosensory cells in the upper airway system, which express T1R and T2R receptors, and the activation of these receptors may lead to antimicrobial peptide secretion (ß-defensin 1 and 2) [21]^[7]. This secretion is very rapid, with the majority occurring within 5 min, while TLR-mediated ß-defensin secretion takes hours after the activation of TLRs. This means that the difference between Toll-like receptor (TLR)-mediated secretion of antimicrobial peptides and that mediated by T1R and T2R receptors is the timescale. Activation of T1Rs inhibits T2R-dependent calcium signaling in human solitary chemosensory cells. Interestingly, in previous research, an elevated glucose concentration was measured in the airway surface liquid of patients with rhinosinusitis but without diabetes mellitus in contrast to healthy controls. This could lead to sufficient antimicrobial peptide secretion. In contrast, during acute infections, bacteria consume glucose locally, so T1Rs cannot be activated [22,23]^[8][9]. In the urinary tract, there are chemosensory brush cells, which express T1Rs and T2Rs. These cells can activate the bladder detrusor muscle and respond to uropathogenic E. coli strains, suggesting that they have a role in antimicrobial innate immunity [23]^[9].

T2R and T1R are expressed in human neutrophil granulocytes, T cells, and B cells. T2R38 is expressed on lymphocytes and may have a role in adaptive immune responses and migration. It is also expressed on skin-infiltrating lymphocytes in atopic dermatitis [24]^[10]. The sweet taste receptor T1R3 is expressed on T and B lymphocytes. Saccharin can induce neutrophil migration, whereas lactisole, which is a selective inhibitor of T1R3, can inhibit neutrophil migration [25]^[11]. T2R38 is expressed on myeloid cells but on macrophages rather than monocytes. Previous in vitro studies have suggested that it is activated by a Gram-negative bacterial product, AHL-12, and based on a human in vitro investigation, T2R38 may play a role in the detection of bacterial biofilms [26]^[12]. T2R receptor activation enhances the phagocytosis of human macrophages in vitro via the elevation of intracellular calcium release, and endothelial nitric oxide synthase (eNOS) activation via the cyclic GMP (cGMP) pathways [27]^[13]. In an animal model of allergic asthma, treatment with T2R agonists (chloroquine and quinine) inhibits mucus secretion, allergen-induced airway inflammation, remodeling, MMP release, and neutrophil chemotaxis in a dose-dependent manner in mice [28]^[14]. Moreover, T2R agonists inhibit immunoglobulin E (IgE)-dependent mast cell activation and decrease histamine and/or prostaglandin D2 release in mice [29]^[15]. In an in vitro model of diabetic nephropathy, T1R3 receptors took part in reactive oxygen species-NLRP3 inflammasome activation after high-glucose treatment [30]^[16].

Based on these studies, sweet and bitter receptors not only take part in innate immunity, leukocyte migration, bacterial recognition, and chemotaxis but may also have a role in allergic and infectious diseases.

These receptors are expressed not only on immune cells of the gastrointestinal mucosa but also on multiple cell types, including enteroendocrine cells, tuft cells, goblet cells, and Paneth cells [14]^[17]. These cells can detect antimicrobial peptides through TLRs, and this leads to the secretion of cytokines and peptide hormones.

Enteroendocrine cells secrete incretins, which are variable peptide hormones (i.e., ghrelin, gastrin, leptin, somatostatin, cholecystokinin, glucose-dependent insulinotropic polypeptide (GIP), and glucagon-like peptide-1 (GLP-1)) along the gastrointestinal tract, depending on their localization (Table 1) [31]^[18]. Not only T1Rs detect luminal glucose concentration and regulate incretin hormone secretion, but T2Rs may have a role in the pathogenesis of diabetes mellitus. Four single-nucleotide polymorphisms (SNPs) of T2Rs show an association with type 2 diabetes mellitus [32]^[19]. In a previous study, the expression of T1R2 taste receptors was inversely regulated by glucose levels in healthy controls (n = 14), but not in type 2 diabetes mellitus patients (n = 13), which means that sweet taste receptor regulation is altered [33]^[20]. These hormones could modulate innate and adaptive immune responses, as well as intestinal permeability, and act as cytokines. In clinical studies, the serum levels of the above hormones show significant changes in inflammatory bowel diseases [34,35,36,37]^{[21][22][23][24]}. The SGLT1 glucose transporter is essential in glucose metabolism regulation and is expressed by absorptive enterocytes. Its expression is regulated by EEC-secreted peptide hormones such as GLP-1,2. [38]^[25]. GLP-1,2 and GIP stimulates pancreatic ß-islet insulin secretion, inhibit gastric emptying, and reduce food ingestion. GLPs are rapidly degraded by dipeptidyl peptidase-4 (DPP-4), and thus, incretin hormones have a short half-life. GLP-agonist and DPP4 inhibitor antidiabetic drugs affect the incretin inflammatory axis, and the role of intestinal inflammation and immune regulation is debated. A question arises as to what the impact on the risk and course of inflammatory bowel diseases and the risk of cancer might be, so further investigations and clinical studies are needed [39]^[26].

Table 1. Taste receptors and their ligands of enteroendocrine cells and changes incretin hormone secretion in IBD patients [9,10,11,12,13,14].

Taste receptors and their ligands of enteroendocrine cells and changes incretin hormone secretion in IBD patients ^{[17][27][28][29][30][31]}.

Enteroendocrine Cell Type	Localization	Secreted Hormones	Taste Receptors	Serum Hormone Level Changes during IBD
X/A-cells	stomach	ghrelin, nesfatin1	sugars, amino acids bitter LCFAs T1R3 T2R FFAR4 CaSR	elevated

Enteroendocrine Cell Type

Localization

Secreted Hormones

Taste Receptors

Serum Hormone Level Changes during IBD

X/A-cells

stomach

ghrelin, nesfatin1

sugars, amino acids

bitter

LCFAs

T1R3

T2R

FFAR4

CaSR

elevated

The calcium-sensing receptor plays a role in the regulation of inflammatory processes. In mice, CaSR regulates NLRP3 inflammasome via intracellular calcium release and cAMP [55]^[47]. In mice with dextran sulfate sodium (DSS)-induced colitis (an animal model of IBD), high protein intake caused an increased expression of inflammatory cytokines through the modulation of CaSR [56]^[48], while L-tryptophan, L-valine, and glutamyl dipeptides inhibited CaSR-dependent pro-inflammatory cytokine secretion in this colitis mouse model [57]^[49]. C57BL/6 intestinal Casr−/− KO mice had decreased expression of C-type lectin-encoding genes (Reg3b and Reg3g), which protects against Gram-negative and Gram-positive bacteria. Moreover, increased inflammatory protein secretion, increased expression of costimulatory molecules in colonic dendritic cells, increased Th1 and Th17 cell polarization, and increased FOXP3+ Treg cell number were observed in a compensatory way. These mice showed intestinal dysbiosis and enhanced susceptibility to DSS-induced colitis. However, the exact role of CaSR in the pathogenesis of human IBD is not known, so it needs further investigation [58]^[50]. Moreover, in colorectal cancer, CaSR expression is reduced and may have a preventative role in colorectal cancer development based on its role in the anti-inflammatory processes [59]^[51].

Interestingly, CaSR is expressed in human monocytes, and the expression level is positively correlated with severe coronary artery calcification in patients suffering from rheumatoid arthritis [60]^[52].

GPRC6A receptor detects L-arginine, L-lysine, and L-ornithine amino acids, but some divalent cations, testosterone, and osteocalcin can be activated in a tissue-specific manner. In an animal model study, Gprc6−/− KO mice had osteopenia, feminization, and metabolic syndrome. After being fed a high-fat diet for 25 weeks, these KO mice demonstrated significantly higher body weight, increased fat mass, and elevated plasma insulin and leptin levels than wild-type mice, but chow-fed KO mice did not show these abnormalities. GPRC6A may have a role in diet-induced obesity and the regulation of energy balance [56]^[48]. In a DSS-induced colitis mouse model, GPRC6A regulates colonic innate lymphoid cell 3 (ILC3) proliferation. ILC3 cells are localized in the lamina propria and play a role in immunomodulation, microbiota balance, and tissue repair to maintain gut homeostasis, as well as secrete IL-22. Stimulation with L-arginine leads to IL-22 production and ILC3 proliferation, and rapamycin inhibits this process [61]^[53].

The other receptor GPR92 is also expressed outside the oral cavity: on G-cells, it detects partially digested proteins and takes part in the secretion of gastrin [62]^[54].

3. Lipid-Sensing Receptors: Free Fatty Acid Receptors 1–4 (FFAR1–4)

Artificial sweeteners affect intestinal sweet taste receptors, intestinal peptide hormone, and insulin secretion, as well as changes in the microbiome. It could drive modified microbial metabolite production such as altered short-chain fatty acid (SCFA) composition. These fatty acids are ligands for other G protein-coupled receptors, including FFAR2 and FFAR3, which are expressed in the intestine, pancreatic β-cells, and innate immune cells (i.e., neutrophils, dendritic cells, macrophages, and mast cells), but not on lymphocytes. FFAR2 has a role in bacterial recognition and infection control, and the expression profile of neutrophils changes during sepsis.

Moreover, FFAR2 may have a pathogenic role in IBD development. Bacteria can produce SCFAs via different metabolic pathways. Acetate and butyrate are primarily produced via acetyl-Coenzyme-A, while propionate is produced via pyruvate or phosphoenolpyruvate through different pathways. Propionate and acetate are the main ligands of FFAR2, while butyrate primarily binds to FFAR3 [63]^[55]. Short-chain fatty acids could modify immune functions and drive GLP-1 and PYY release from enteroendocrine cells of the colon [64]^[56]. SCFAs maintain epithelial integrity and intestinal homeostasis and have antibacterial and anti-inflammatory functions, but they could also play a role in the activation of NLRP3 inflammasomes from colonic epithelial cells and IL-18 production. The role of FFAR3 in the immune response is not exactly known yet. Butyric acid and leucine can be induced via FFAR2/3 alpha-defensin secretion by Paneth cells, and in Crohn’s disease and obesity, alpha-defensin levels are decreased. Alpha-defensins can increase the polarization of FOXP3+ Tr cells [65,66]^[57][58].

Other G protein-coupled receptors, including FFAR1 and FFAR4 (GPR120) receptors, detect medium- and long-chain fatty acids, such as n-6 and n-3 PUFAs. The effects on GLP-1 secretion are controversial. FFAR-4 agonist ligands cause GLP-1 secretion in in vivo mouse models and in vitro human cells [67^[59][60],68], but their major role in GLP-1 secretion cannot be confirmed in rats [69]^[61]. Agonisms of FFAR-4 improve insulin sensitivity and cause anti-inflammatory cytokine secretion in mice, and FFAR-4 interacts with some important signaling pathways. It acts directly on PPARγ to inhibit NF-κB, consequently leading to a decrease in the secretion of inflammatory cytokines such as TNF-α, IL-1, IFN-γ, IL-6, and IL-12 [70,71]^[62][63]. FFAR-4 takes part in the differentiation and activation of dendritic cells and influences the balance of Treg/Th17 and antiviral responses in mice [72]^[64].

Short-chain fatty acids have a receptor-independent effect in the inhibition of histone deacetylation [66]^[58]. FFAR-4 takes part in the pathogenesis of type 2 diabetes mellitus and colorectal cell cancer. It seems that a loss of expression of FFAR-4 is an early event in the progression of CRC [73]^[65].

In short, nutrient-sensing receptors take part in innate immunity, inflammation, regulation of the metabolic process, and feeding behavior. WThe researchers summarized their various functions and health outcomes in a synoptic table (Table 2).

Table 2.

Summary on the role of nutrient sensing receptors.

Receptor	Ligand	Expression	Function	Health Outcome
Sweet taste receptors i.e., T1R3	sugars saccharin sucralose aspartame acesulfame K amino acids Na-glutamate	HGE neurons (brain) solitary chemosensory cells (upper airway system) chemosensory brush cell (urinary system) neutrophil granulocytes T and B lymphocytes Enteroendocrine cells Tuft cells Paneth cells Pancreas ß-cells	glucose metabolism, blood-brain axis regulation host-pathogen interaction cell migration cell activation incretin secretion glucose absorption Th2 immunity regulation antimicrobial peptides secretion insulin secretion	feeding behavior circadian rhythm regulation allergic, infectious diseases, chronic rhinosinusitis innate immunity glucose metabolism, metabolic syndrome IBD, helminth and viral infections, inflammation IBD infections, inflammation diabetes mellitus
G-cells	stomach
Bitter taste receptors i.e., T2R38	drugs i.e., chloroquine saccharin acesulfame K	gastrin	sucralose bacterial peptides: i.e., acyl-homoserine lactones amino acids, sugars peptides	placenta myeloid cells macrophages chemosensory cells (upper airway system) chemosensory brush cell (urinary system) Enteroendocrine cells Goblet cells Paneth cells T1R3 bitter T2R CaSR GPRC6A GPR92 (LPAR5)	elevated
	unknown		migration phagocytosis production of antimicrobial peptides glucose metabolism regulation mucin secretion antimicrobial peptide secretion	unknown innate immunity infection, inflammation chronic rhinosinusitis diabetes mellitus, metabolic syndrome, inflammation inflammation, infections inflammation, infections	P-cells	stomach
CaSR	aromatic L-amino acids	leptin		enteroendocrine cells	calcium homeostasis cytokine secretion N/A
		calcium homeostasis		gut–kidney axis inflammation, IBD? cancer development	Enterochromaffin-like cells	stomach
GPRC6A		histamine		N/A
	amino acids L-arginine, L-lysine and L-ornithine osteocalcin testosterone	enteroendocrine cells ILC-3 cells	bone metabolism IL-22 secretion tissue repair microbiota balance	bone resorption inflammation, IBD	D-cells
GPR92 (LPAR5)	stomach, small intestine	somatostatin		partially digested N/A
	proteins	G cells	gastrin secretion	digestion regulation	I-cells	small intestine
		CCK	FFAR 1, 4 Amino acids	n-6 and n-3 PUFAs, DHA	enteroendocrine cells lymphocytes dendritic cells macrophage sugars, bitter, LCFA T1R1/T1R3 T2R CaSR GPR6C GPR120
K-cells	small intestine	GIP
L-cells	small intestine, colon	GLP-1, GLP-2	Sugars, bitter, SCFAs, LCFAs amino acids T1R2/T1R3, T2R FFAR 1/2/3 GPR120 GPR6C	elevated
Enterochromaffin cells	colon	5-HT		decreased

LCFA: long-chain fatty acid, SCFA: short-chain fatty acid, GIP: glucose-dependent insulinotropic polypeptide; GLP-1: glucagon-like peptide-1; GLP-2: glucagon-like peptide-2, 5-HT: 5-hydroxytryptamine, CaSR: Ca²⁺-sensing receptor, FFAR 1–4: Free fatty acid receptor 1–4, GPRC6A: G protein-coupled receptor class C group 6 member A, GPR92 (LPAR5): lysophosphatidic acid receptor 5, IBD: inflammatory bowel diseases, N/A: not applicable

Chemosensory tuft cells play a key role in parasite and helminth infections in initiating type 2 immunity via IL-25 secretion and innate lymphoid cell type 2 (ILC2) stimulation. T1R3 receptor regulates the homeostasis of tuft cell abundance. In Tas1R3−/− knockout mice, not only was a decreased tuft cell number observed, but this number was only partially compensated by succinate treatment [40,41]^[32][33].

Tuft cells participate in some viral infections as a direct or indirect target of infective agents (e.g., in the case of West Nile virus, they have an immunomodulatory effect in the pathogenesis of this infection) [42]^[34]. Succinate, which is a metabolite of some symbiotic bacteria and helminths, acts as a ligand on succinate receptor 1 (SUCR1) and in the TRPM5-dependent pathway [43]^[35]. Tuft cells have a possible role in the pathogenesis of inflammatory bowel diseases based on a few studies. Decreased tuft cell number was observed in the colonic biopsies of patients suffering from quiescent ulcerative colitis [44]^[36]. Moreover, a reduced tuft cell number was detected in the ileal biopsies of patients with Crohn’s disease, and their number was negatively correlated with the level of inflammation [43]^[35].

Goblet cells are expressed along the small and large intestines and produce mucin to protect the intestinal surface of the epithelium against bacterial invasion. Their number is increased in the distal part of the gut and correlates with the number of bacteria and the expression of T2R131 in mice [45]^[37].

Paneth cells are located in Lieberkühn crypts and secrete antimicrobial peptides and alpha-defensins to control the local microbiome. In ileal Crohn’s disease, Paneth cell number and the secretion of defensins are decreased. T2R43 and T2R10 are detected in the human goblet and Paneth cells, and bitter agonists could cause intracellular Ca²⁺ release in these cells, which means that T2Rs may have a functional role. Moreover, in previous research, treatment with the bitter agonist, denatonium benzoate, induced the expression of antimicrobial peptide and alpha defensin-5 protein in the Paneth cells of patients with obesity. This effect was not seen in healthy controls, while T2R mRNA and protein expression levels were the same in in vitro experiments. The Paneth cells of patients with obesity were more sensitive to bitter-induced degranulation, which altered microbial growth [46,47]^[38][39]. There was also relative goblet cell depletion and defective mucous secretion in these cells in active ulcerative colitis [48]^[40].

According to several in vitro studies, sweet taste receptors are expressed on pancreatic β-cells and take part in the regulation of insulin secretion [49,50]^[41][42]. Interestingly, in animal studies, Tas1R3−/− KO mice had reduced insulin sensitivity and glucose tolerance [51]^[43]. Moreover, reduced size of pancreatic islets and decreased density in the pancreatic tissue were observed [52]^[44]. Interestingly, these mice were characterized by increased cortical bone mass due to reduced osteoclast function [53]^[45].

2. Amino Acid-Sensing Receptors: Calcium-Sensing Receptor (CaSR), GPRC6A and GPR92

There are several other nutrient-sensing receptors outside the oral cavity, which take part in the detection of amino acids. Calcium-sensing receptor (CaSR) is a G protein-coupled receptor expressed on the surface of enteroendocrine cells. It can detect aromatic L-amino acids (phenylalanine, tryptophan, asparagine, and glutamine), and its activation leads to incretin secretion (GLP-1, GIP, and CCK). Divalent cations can activate this receptor. On the surface of absorptive enterocytes, CaSR can regulate intestinal calcium and other divalent absorption and anion secretion. It stimulates Cl⁻ and short-chain fatty acid-dependent HCO₃⁻ secretion but inhibits cAMP-dependent HCO₃⁻ secretion and modulates fibroblast growth factor-23 (FGF-23) production, which has a role in phosphate homeostasis and the gut–kidney–parathyroid gland axis. Moreover, L-amino acids could modulate calcium and other divalent cation homeostasis throughout the activation of CaSR. The calcium-sensing receptor is also expressed on myenteric plexi to modulate gut motility [54]^[46]


antiinflammatory cytokine secretion

Treg/Th17 axis regulation

insulin sensitivity			inflammation	innate immunity antiviral response diabetes mellitus
FFAR 2,3	short-chain fatty acid	enteroendocrine cells innate immune cells: neutrophil granulocytes pancreatic ß cells	epithelial integrity antiinflammatory cytokine secretion NLRP3 inflammasome modulation alpha defensin secretion glucose metabolism	gut permeability microbiome regulation inflammation IBD diabetes mellitus infection diabetes mellitus

HGE neurons: high glucose-excited neurons, IBD: inflammatory bowel diseases, IL-22: interleukin-22, ILC-3: innate lymphoid cells-3, CaSR: Ca²⁺-sensing receptor, FFAR 1-4: Free fatty acid receptor 1–4, GPRC6A: G protein-coupled receptor class C group 6 member A, GPR92 (LPAR5): lysophosphatidic acid receptor 5, PUFA: polyunsaturated fatty acid, DHA: Docosahexaenoic acid, NLRP3: NLR family pyrin domain containing 3, Th2: T helper 2.

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