Food Composition and Microstructure on T1R/T2R Activation

Food composition and microstructure significantly influence the availability of flavour and nutrient compounds, as well as the activation of taste receptors—T1Rs (sweet and umami) and T2Rs (bitter) particularly in the gut. This involves a mix of chemical interactions, physical accessibility, and digestion kinetics. The taste receptors are extremely important because they help us select food and they ‘orchestrate that response to all our nutrients. These receptors are part of a group of very distinct receptors called the  G protein-coupled receptors (GPCRs) (Sternini & Rozengurt, 2025).

The Taste Receptors

The taste 1 receptors, called T1Rs (Tas1rs in mice and TAS1Rs in humans) detect two of our taste senses, umami and sweetness. We rely on them for food recognition so that we can assess their nutritive value before we ingest them. The taste 2 receptors, called T2Rs (Tas2rs in mice and TAS2Rs in humans) detect bitterness and are essential for recognising toxic and poisonous foods.  In humans, 26 members of the 291–334 amino acid long G protein-coupled receptor superfamily are involved in the perception of bitter taste (Lossow et al., 2016).

We can reject bitter foods foods before we ingest them. Whilst both these receptor types are found in the mouth (the oral cavity) they are also expressed in the extraoral sites which includes the gastrointestinal mucosa.

For pharmaceutical companies and clinicians, the Tas2rs/TAS2Rs which are the bitter receptors are of great interest because they are drug targets in the prevention, treatment and management of a vast variety of metabolic disorders.

The bitter taste receptors are located in distinct types of gastrointestinal mucosal cells which have an enteroendocrine function. When they are stimulated, the receptors undergo conformational changes that translate this message into a response the across the cell membrane. This triggers the increases in intracellular calcium with subsequent release of different types of signaling molecules such as peptide hormones. All these messages regulate various processes needed for initiating digestion, absorption of nutrients, removing toxins and coordinating overall metabolism.

The Gut Tas2rs/TAS2Rs are potential sites for regulating bile acid production, destroying bacteria and their metabolites, regulating gut homeostasis and especially when it goes wrong, having associations with metabolic syndrome and obesity.

The sweet taste receptors STR (TAS1Rs) cannot be neglected either because they are directly implicated in diabetes including  hyperglycemia, insulin resistance, mild inflammation, and beta cell failure. The perception of sweetness is part of the mechanism for identifying the metabolizable energy-rich nutrients entering the gut. The STRs are G-protein-coupled receptors made up of T1R2/T1R3 heterodimers. These sweet taste receptors are found in all body tissues as well – the liver, pancreas, fat and brain and the digestive system.

The activation of the T1R2/T1R3 receptor then activates the α-gustducin receptor and produces a subunit of Gβγ. This then activates phospholipase-β2 (PLC-β2) and adenylate cyclase (AC), and downstream of it inositol triphosphate (IP3) and cAMP channels. The cAMP channels  upregulate intracellular Ca²⁺ concentrations and activate TRPM5. The activation of TRPM5 channels leads to the production of GLP-1, glucose-dependent insulinotropic peptide (GIP), and tyrosine peptide (PYY) by L cells in the gut, which in turn affects the development of insulin resistance.

When the glucose level is high, the presence of STRs T1R2/T1R3 decreases along with their associated signaling molecules. These sweet taste receptors, T1R2 and T1R3 are not only involved in glucose metabolism but also regulate diet-induced disorders of lipid metabolism.

Now we discuss the various factors and how they are related to each other.

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1. Food Composition

Macronutrients and matrix components (fats, proteins, carbs, fiber) directly affect how compounds are released, solubilized, and perceived. The food matrix refers to how nutrients and bioactive compounds are physically and chemically embedded within the food.

a. Carbohydrates

• Simple sugars (e.g., glucose, sucrose) rapidly dissolve in saliva and are readily available to activate T1R2/T1R3 sweet receptors.

• Complex carbohydrates may delay release of monosaccharides, reducing immediate sweetness perception.

• Dietary fibre can bind or trap flavour molecules, reducing compound diffusion and availability.

b. Fats

• Hydrophobic bitter or aroma compounds often partition into fat phases.

• This reduces their availability in saliva, potentially dampening T2R (bitter) activation.

• Fats may also prolong flavor release, influencing how sustained or delayed taste is perceived.

c. Proteins

• Proteins can bind taste-active molecules (e.g., phenolics or flavonoids) through hydrophobic or ionic interactions.

• This reduces the free concentration of bitter compounds, again modulating T2R activation.

• Some peptides themselves activate umami receptors (T1R1/T1R3).

d. Salt and acids

• Sodium ions enhance sweet and umami tastes and can suppress bitterness via cross-modal interactions.

• Acids (pH) can affect compound ionization and solubility, changing their receptor availability.

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2. Microstructure

The physical arrangement of food components (emulsions, gels, particles, encapsulations) plays a critical role in compound release dynamics and taste receptor activation.

a. Emulsions (fat-in-water or water-in-fat)

• Flavor compounds often partition between oil and aqueous phases.

• Emulsification modulates the release rate of hydrophobic molecules (e.g., bitter alkaloids or lipophilic aroma compounds).

• Controlled release can delay or reduce activation of T2Rs.

b. Encapsulation or Binding

• Encapsulation (e.g., in starch, protein, or lipid shells) can delay release of sweeteners or bitter compounds, affecting when and how strongly T1Rs or T2Rs are activated.

• Useful in functional foods or masking bitter compounds in pharmaceuticals.

c. Gels and Viscosity

• High-viscosity matrices slow diffusion of taste compounds, reducing interaction with receptors.

• This generally blunts taste intensity, especially for sweet and bitter compounds.

d. Particle Size and Surface Area

• Smaller particles or dispersed systems (e.g., powdered flavorings) increase surface area, enhancing solubility and receptor exposure.

• Coarse structures reduce this exposure and modulate the temporal dynamics of taste.

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3. Implications for T1R and T2R Activation

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Summary

• Composition affects chemical availability: how much of a taste compound is free in saliva to bind receptors.

• Microstructure modulates release kinetics: when and how quickly compounds are delivered to receptors.

• These factors together shape taste perception and are critical for designing foods with controlled flavor, improved palatability, or functional benefits.

Yes — several food-specific examples influence the T1R1, T1R2, and T1R3 taste receptors in the gut, not just in the mouth. These receptors are also expressed in the gastrointestinal tract, where they help regulate digestion, nutrient sensing, hormone release, and even appetite.

Summary Chart

Here’s how specific foods and ingredients interact with gut-expressed T1R1/T1R3 (umami) and T1R2/T1R3 (sweet) receptors.

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Overview: T1R1/T1R3 and T1R2/T1R3 in the Gut

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T1R1/T1R3 (Umami) Receptor Activation in the Gut

1. Fermented Soy Products (e.g., Miso, Soy Sauce, Natto)

• Rich in glutamate and small umami-active peptides.

• These compounds activate T1R1/T1R3 in the small intestine, triggering GLP-1 and cholecystokinin (CCK) release, slowing gastric emptying and promoting satiety.

2. Meat Broth and Bone Broth

• Contains free amino acids (glutamate, aspartate) and inosinate (IMP), which act synergistically to strongly stimulate umami taste receptors.

• This gut sensing leads to enhanced protein digestion signaling.

3. Aged Cheeses and Parmesan

• High in free amino acids due to proteolysis.

• Activates umami receptors in the gut, influencing postprandial hormone release (e.g., CCK).

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T1R2/T1R3 (Sweet) Receptor Activation in the Gut

1. Artificial Sweeteners (Sucralose, Acesulfame-K, Aspartame)

• Activate T1R2/T1R3 in the gut, even though they provide no calories.

• This can lead to GLP-1, GIP, and insulin secretion, glucose transporter (SGLT1) upregulation, and changes in microbiota.

• Long-term exposure might desensitize the receptors or alter glucose handling.

2. High-Fructose Corn Syrup & Sucrose

• Fully activate sweet receptors, stimulating gut endocrine responses including insulin and incretins.

• Fructose absorption (via GLUT5) is also modulated by T1R signaling.

3. Stevia and Monk Fruit Extracts

• Natural non-nutritive sweeteners that activate T1R2/T1R3 in the gut.

• Can stimulate GLP-1 secretion and delay gastric emptying, although individual responses vary.

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Functional Effects of Gut T1R Activation

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 Why This Matters

• Nutrient sensing in the gut is not passive — it’s an active process involving taste receptors.

• These receptors help regulate metabolism, gut motility, satiety, and glucose homeostasis.

• Food formulation (e.g., using umami to reduce salt/fat, using sweeteners to manage sugar load) can leverage gut T1R signaling to optimize health outcomes.

What specific dietary interventions interact with these gut taste receptors?

targeting gut taste receptors (T1R1/T1R3 for umami and T1R2/T1R3 for sweet) through dietary interventions can have meaningful impacts on appetite regulation, glucose metabolism, gut hormone secretion, and even microbiota composition.

Here are specific dietary interventions that modulate gut taste receptor activity and the physiological outcomes they drive:

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1. Umami-Rich Diets (T1R1/T1R3 Activation)

 Intervention:

• Increase intake of fermented foods, aged cheeses, mushrooms, meat broths, or use monosodium glutamate (MSG) in cooking.

 Gut Effects:

• Stimulates T1R1/T1R3 in the small intestine, promoting:

  • GLP-1 and CCK secretion → satiety, delayed gastric emptying

  • Improved protein sensing and digestion

  • Potential modulation of the gut-brain axis

 Outcomes:

• Enhanced satiety and reduced overall caloric intake

• Improved postprandial glucose control

• Potential support in weight management

Clinical trials have shown that MSG or umami-enhanced soups can increase satiety and reduce food intake at subsequent meals.

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2. Non-Nutritive Sweetener (NNS) Substitution (T1R2/T1R3 Activation)

Intervention:

• Replace sugars with sucralose, stevia, aspartame, or monk fruit extracts.

 Gut Effects:

• Activates T1R2/T1R3 receptors in the duodenum and jejunum.

• Promotes:

  • GLP-1 and GIP release

  • Upregulation of SGLT1 and GLUT2 (sugar transporters)

  • Insulin secretion, even without caloric sugar

 Outcomes:

• Potentially helps in reducing dietary sugar load

• Mixed evidence on metabolic benefits: may improve or impair glucose homeostasis depending on dose, type, and individual microbiota.

⚠️ Some studies suggest chronic NNS exposure may desensitize sweet receptors or lead to altered glycemic responses via microbiome shifts.

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3. High-Protein Diets (Umami Pathway Activation)

 Intervention:

• Increase dietary intake of easily digestible protein sources: whey, fish, eggs, legumes, fermented soy.

 Gut Effects:

• Liberates L-glutamate, L-alanine, and other umami-active amino acids/peptides during digestion.

• Activates T1R1/T1R3 in gut:

  • Promotes hormonal signals of satiety (CCK, GLP-1, PYY)

  • Enhances nutrient-driven signaling to the hypothalamus

Outcomes:

• Increased fullness, reduced subsequent food intake

• Beneficial for weight loss or type 2 diabetes management

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4. Low-Glycemic Diet with Smart Sweetener Pairing

 Intervention:

• Use of low-glycemic sweeteners (e.g., isomaltulose, tagatose) combined with natural T1R2/T1R3 ligands (e.g., stevia, monk fruit).

Gut Effects:

• Slower digestion and reduced postprandial glucose peaks

• Controlled activation of gut sweet receptors → modulated incretin and insulin responses

Outcomes:

• Helps avoid glycemic spikes

• Supports metabolic flexibility and glycemic control in insulin resistance

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5. Prebiotic or Polyphenol-Rich Diets (Indirect Modulation)

Polyphenols contribute directly to food flavour and to the flavour of plant-based foodstuffs especially.  There are over 8000 different types. They are all compounds of plant secondary metabolism and used in their defence against pathogens and animal ingestion. We associate them with astringency and bitterness in particular.

There are many different classes of polyphenols to deal with when covering their interaction with the bitter taste receptors (TAS2Rs). The most prominent subgroup of polyphenols are the flavonoids, which can, in turn, be divided into subfamilies like flavonols, isoflavones, catechins or tannins

Over many years, half-maximum effective concentrations (EC50) have been established for each type of polyphenol with TAS2Rs but there are still glaring gaps. As with prebiotics, computational methodology is being applied to understand the polyphenol molecular region responsible for receptor activation and to get insights into the type of bonds established in the agonist–TAS2Rs pairs (Soares et al., 2018).

The polyphenols are not very well absorbed in the upper digestive tract and transit to the colon before excretion in faeces. It has been thought in the past that polyphenol interactions meant a negative outcome on diabetes. There was a negative correlation between polyphenol intake and an increasing risk of diabetes. That thinking has been receding because the consumption of polyphenols is positively correlated by the activation of T2R receptors in the gut intestine which improves glucose tolerance and appetite regulation when controlling gut movements (i.e. intestinal motility) (Osakabe et al., 2024). .

Intervention:

• Consumption of foods high in polyphenols (e.g., berries, tea, dark chocolate) or prebiotics (inulin, resistant starch).

Gut Effects:

• Polyphenols and prebiotics modulate gut microbiota, which in turn:

  • Influence expression and sensitivity of T1R1/T1R3 and T1R2/T1R3

  • Affect fermentation products (SCFAs) that can regulate gut hormone secretion

Outcomes:

• Improved GLP-1 and PYY signaling

• Better appetite regulation

• Enhanced insulin sensitivity

There are specific bitter taste receptors in the TAS2Rs class which are activated by polyphenols as is understood on the tongue. TAS2R5 seems to be the only receptor exhibiting a bias toward the activation by condensed tannins, while TAS2R7 seems more tuned for hydrolyzable (ellagi)tannins (Soares et al., 2018). It is not clear if they have similar impact on gut-taste receptors (Tarragon & Moreno, 2020). These authors recognize that potential modification of polyphenols might be  an attractive route into managing various disease conditions.

7. Dietary Fiber

Dietary fiber probably raises GLP-1 levels by some interaction with the taste receptors although it is unclear how. It would explain some of the  effects that have not been attributed to changes in gut size, increases in viscosity etc. GLP-1 amongst other hormones like GLP-2 is produced from a proglucagon peptide that is synthesized in the ileum. It was noted in rat models that the amount of proglucagon rises because of increased ileal proglucagon gene expression in rats as the amount of fibre ingested rises (Reimer & McBurney, 1996). 

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 Summary Table