Over the last two decades we have seen interest in digestive bitters continue to grow. This is fantastic, and we’re hoping it indicates an increasing appreciation for the important role of the bitter flavor. Seemingly hand-in-hand, research on the structure and function of our bitter taste receptors (T2Rs) has proceeded apace. We already know a lot about these interesting receptors:1
they can trigger reflexes in our autonomic nervous system (mostly relayed via the vagus nerve) to help coordinate the secretion of digestive juices, including enzymes and bile. They also are found on enteroendocrine cells, lining our intestinal mucous membrane, where they trigger the release of hormones involved in appetite regulation (making us feel more full) and insulin sensitivity.2 Stimulating T2Rs protects us from a range of potential issues: by activating efflux pumps, bitter taste receptors ensure that harmful substances are kept in the GI tract, not absorbed, and excreted before they can do damage;3 additionally, T2Rs in our airways seem to be part of an important immune mechanism that safely helps us handle microbial threats.4 It is interesting to note that bitter taste receptors are abundant on the heart, where their activation may contribute to regulating blood flow, especially after a meal.5
But over the the last two years, researchers are uncovering even more fascinating detail on bitter taste receptors. Let’s take a look: recent science further describes the shape and structure of T2Rs, tracks their role in managing bacteria inside our gut and respiratory system, uncovers new locations where they are found, and helps explain how T2Rs regulate smooth muscle contraction.
I’ve always wondered how our chemosensing systems (which include T2Rs) can detect both an overall “bitterness load” in foods (how much radicchio is in this salad?) with a wide range of tolerance, while also being exquisitely sensitive to particular, dangerous, poisonous bitter compounds like strychnine or atropine. As it turns out, T2Rs have a “two-sided” structure, where one binding area is broadly tuned to a range of different bitter-tasting molecules, while the other binding area is sensitive to a few key toxins.6 This gives our bitter taste receptors both great sensitivity, and also the power to present an effective overview of the overall exposure to bitter compounds. Among the types of molecules able to activate the more generic side of a T2R’s binding pocket are botanical glycosides (molecules attached to one or more sugars), such as salicin, flavo-glycosides, or saponins – all of which are compounds, or families of compounds, known to trigger the perception of bitterness.
One of the reasons we have T2Rs, particularly those T2Rs found in our respiratory system, is to monitor the bacteria in our tissues and stimulate an innate immune response if pathogenic species start to gain a foothold. Previous research has shown how homoserine lactones (similar to compounds found in bitter plants like angelica or dandelion), which are bacterial quorum-sensing molecules, trigger T2R activation7 (they taste bitter!). The result is a release of antibacterial compounds that are ready and waiting inside epithelial cells, part of an ancient immune response that began in single-celled organisms.
sweetness relaxes and suppresses the immune response, but as bacteria consume sugar and increase the production of metabolites, we see T2Rs respond and activate the same immune responses triggered by quorum-sensing molecules.8 This response is elicited by a fairly wide array of bitter-tasting bacterial metabolites: perhaps the broadly-sensitive binding region of the T2Rs allows for this effect.
T2Rs are turning up almost everywhere we look in the human body. Recently-uncovered locations include two areas rich in smooth muscle (they type of muscle responsible for controlling tension and contraction in most areas that are under involuntary control):
the uterus and arteries in the brain, abdomen, and GI tract. In both areas, stimulating T2Rs seems to lead to relaxation: in the uterus, bitter-tasting molecules almost completely counteract the stimulating effect of oxytocin, and so researchers are exploring T2Rs as a target for agents that could stop pre-term labor and prevent miscarriage.9 In the arteries (remember, we’ve already seen that the heart has many bitter taste receptors), we find T2Rs contribute to vasodilation, relaxation and elasticity: quinine, for example, causes 100% relaxation of arterial smooth muscle at concentrations of 300mg/L (about 300ppm), and even 50% relaxation at concentrations as low as 10mg/L.10 For reference, typical tonic water contains about 80mg/L. Tonic water can’t deliver that same concentration to your arteries, so don’t look for vasodilative gin and tonics anytime soon, but
Just how this antispasmodic effect works is still unclear, though in the last two years we’re learning a lot more. One intermediate that seems to be involved is the paracrine gas, nitric oxide (NO). We know that NO induces vasodilation, and that it is secreted in part as a response to inflammation. In the context of bitter taste receptors, bacterial infection can lead to an increase in NO through T2R-dependent mechanisms.11 But bitter-tasting compounds have this effect even without bacteria being present: for example, part of the relaxing effect on intestinal tissue maycome from the increased production of NO in response to intestinal T2R stimulation.12 This may seem a bit surprising: after all, we’ve seen that stimulating T2Rs on the tongue and in the stomach usually increases the level of muscle contraction, particularly in the valves at the bottom of the esophagus and at the end of the stomach–this is how bitters can help with occasional heartburn and reflux, and also to making us feel more full more quickly.13 So how does this square with the recent research showing antispasmodic effects?
The answer appears to be twofold: first, T2Rs in the mouth and stomach elicit different responses than those further down in the
intestines, with less NO produced and more contraction; second, there appears to be a dose-dependency with bitter compounds wherein low concentrations cause contraction of smooth muscle, and higher concentrations lead to relaxation.14 This is reflected in traditional use patterns: in Italy, for example, large doses (up to one fluid ounce) of bitter amaro is taken after meals to relax the stomach and intestines and relieve feelings of over-fullness.
The implication for handling occasional heartburn is that lower doses, tasted on the tongue, might be the most effective: just a taste of bitters leads to contraction of the valve at the bottom of the throat, and keeps the acid where it belongs.
Clinically, we can think about bitters as useful allies for our immune system, our heart and blood vessels, and of course the level of tension in our guts. Many of these effects seem tied to T2R receptors on cell surfaces in our airway, GI tract, and blood vessels. But even though the effects are local, the consequences can be wide-ranging, especially with habitual use.
1. Rozengurt, Enrique, and Catia Sternini. “Taste receptor signaling in the mammalian gut.” Current opinion in pharmacology 7.6 (2007): 557-562.
2. Sternini, Catia, Laura Anselmi, and Enrique Rozengurt. “Enteroendocrine cells: a site of ‘taste’in gastrointestinal chemosensing.” Current opinion in endocrinology, diabetes, and obesity 15.1 (2008): 73.
3. Jeon, Tae-Il, Young-Kyo Seo, and Timothy F. Osborne. “Gut bitter taste receptor signalling induces ABCB1 through a mechanism involving CCK.” Biochemical Journal 438.1 (2011): 33-37.
4. Workman, Alan D., et al. “The role of bitter and sweet taste receptors in upper airway immunity.” Current allergy and asthma reports 15.12 (2015): 72.
5. McMullen, Michael K., Julie M. Whitehouse, and Anthony Towell. “Bitters: time for a new paradigm.” Evidence-Based Complementary and Alternative Medicine 2015 (2015).
6. Thomas, Anu, et al. “The Bitter Taste Receptor TAS2R16 Achieves High Specificity and Accommodates Diverse Glycoside Ligands by using a Two-faced Binding Pocket.” Scientific Reports7.1 (2017): 7753.
7. Carey, Ryan M., et al. “Taste receptors: regulators of sinonasal innate immunity.” Laryngoscope investigative otolaryngology 1.4 (2016): 88-95.
8. Verbeurgt, Christophe, et al. “The human bitter taste receptor T2R38 is broadly tuned for bacterial compounds.” PloS one 12.9 (2017): e0181302.
9. Zheng, Kaizhi, et al. “Bitter taste receptors as targets for tocolytics in preterm labor therapy.” The FASEB Journal (2017): fj-201601323RR.
10. Chen, Jing-Guo, et al. “The expression of bitter taste receptors in mesenteric, cerebral and omental arteries.” Life sciences 170 (2017): 16-24.
11. Carey, Ryan M., et al. “Sinonasal T2R-mediated nitric oxide production in response to Bacillus cereus.” American journal of rhinology & allergy 31.4 (2017): 211.
12. Jing, Fangmiao, et al. “Relaxant effect of chloroquine in rat ileum: possible involvement of nitric oxide and BKCa.” Journal of Pharmacy and Pharmacology 65.6 (2013): 847-854.
13. “Bitter taste receptors and a-gustducin regulate the secretion of ghrelin with functional effects on food intake and gastric emptying,” PNAS, 108:2094-99, 2011.
14. Avau, Bert, et al. “Targeting extra-oral bitter taste receptors modulates gastrointestinal motility with effects on satiation.” Scientific reports 5 (2015).
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