Science Update: Bitters—A Taste for Immunity by Guido Masé; March 13th, 2016

dandelionI think we would all agree that bitters are, first and foremost, classic digestive remedies. The herbs and recipes, though widely variable, always feature strong, bitter-tasting molecules (like the lactones in dandelion, angelica, gentian or Andrographis) that activate gut secretions, modulate the transit time of the food we eat, and reduce a range of gut symptoms. The consensus is that receptors for bitter taste probably serve as a protection against poisons, and trigger digestion and detoxification processes in many different animal species, from caterpillars to human beings1. These are old, evolutionarily-conserved detectors that activate self-protection mechanisms, ensuring that we consume less of any potential poisons, and that if we do, we neutralize them quickly. But what if bitter taste receptors protect us from more than just poisonous substances?

 

enteroendocrine cellNew trends in research have also continued to build the case for bitters as regulators of appetite, with potential effects on metabolism and obesity. In a recent study, physicians in Naples, Italy noticed a 20% decrease in caloric consumption in patients who had been given a capsule containing quinine (a strong bitter alkaloid) 60 minutes before eating2. Partly by triggering the release of “fullness” hormones such as cholecystokinin and decreasing “hunger” hormones such as ghrelin, the bitter-sensitive cells in the lining of our intestines act as an interface between the contents of the gut and endocrine signals that affect the rest of the body3. In fact, scientists such as Slavo Komarnytsky, from the department of plants and human health at North Carolina State University, have described these cells, rich in bitter taste receptors, as a type of “enteroendocrine” cells. When stimulated by bitter tasting molecules, these cells also seem to modulate the production of hormones such as insulin, GLP-1, and PYY (all involved in appetite regulation and control of blood sugar levels)4. The case is compelling: bitters can have an important role in the management of obesity and diabetes5. But what if there’s more to this effect than just the secretion of “fullness” and insulin-sensitizing hormones?

 

Researchers including Catia Sternini, who has for years been pursuing how the GI tract detects signals from its contents and transmits these signals to the rest of the body, just published a series of interesting observations about the enteroendocrine cells of obese versus lean subjects. It turns out that obese individuals have a larger number of a particular kind of bitter taste receptor, T2R38, on the cells lining their guts. While these cells were trying to produce hormones to control appetite and blood sugar, Sternini’s team uncovered the fact that the cells were also secreting pro-inflammatory compounds, kicking up an immune response in the gut lining. This was linked to an increase in bitter-tasting compounds secreted by a population of gut bacteria very different from those found in the lean individuals. The gut flora of obese individuals has a marked effect on metabolism, making it difficult to lose weight and control blood sugar6. But this type of gut flora also secretes an abundance of bitter-tasting molecules. And the gut, in turn, triggers an immune response to try to clear them out. The bitter taste receptor seems to play a role in managing our body’s reaction to disease-causing microorganisms: in short, it may be a part of our immune system, protecting us from pathogens as well as poisons.

 

Bitter taste receptors have been found throughout the body: in the airway, the skin, the brain, throughout the gut, in reproductive organs. While their role in the gut has seemed fairly clear, researchers puzzled as to why they would be found in so many other places, too. Now we are starting to understand: in the opinion of Noam Cohen, surgeon at the University of Pennsylvania, bitter taste receptors are part of an ancient, fast-acting immune response7. Others agree: the stimulation of bitter taste receptors enhances immune function in the mouth, for example, helping to fight off bacteria involved in periodontal disease8. Dr. Cohen has described how this works in the nose and sinus passages, too9, and shown how this bitters-based immunity boost can help in chronic sinusitis.

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Figure 1

Dr. Cohen discovered that harmful bacteria, including antibiotic-resistant bacteria, secrete a group of molecules called acyl-homoserine lactones (Figure 1) in order to coordinate their process of growth and colonization (an effect called “quorum-sensing”). These lactones taste quite bitter, and trigger the bitter taste receptors found in the upper airway. In response, tiny hairs clear out debris more quickly, secretions increase, and the bitter-sensitive cells release compounds that neutralize the bacteria (such as nitric oxide and immune proteins called defensins)10. Work is underway to find out how we might use this mechanism to help those with chronic, antibiotic-resistant sinus infections. But perhaps the answer has been on our dining room tables this whole time: lactones found in plants (such as angelica, Figure 2, dandelion, Figure 3, and Andrographis, Figure 4), which universally taste quite bitter, have powerful effects on these taste receptors and can participate in strengthening this new facet of our immune response. Some of these plants have a long history of helping with infections – though until now, their mechanism of action has been unclear.

 

angelica lactone

Figure 2: Angelica lactone 

So add another layer to the protective power of bitters: they guard against poison, protect us from the effects of sugar and carbohydrate overexposure, guard against imbalances in our gut flora, but also stimulate a very old, pervasive part of our immune response. And, thankfully, the bitter plants we love contain molecules very similar to those secreted by dangerous microorganisms: consumed regularly, they support gentle daily detoxification and healthy innate immunity. No wonder bitter taste receptors are found everywhere in the body. And no wonder we feel better when we gently stimulate them with bitter plants.

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Figure 3: taraxinic acid lactone

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Figure 4: andrographolide lactone

 

 

 

 

 

 

 

 

 

 

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  1. Glendinning, John I., Marci Tarre, and Kiyoshi Asaoka. “Contribution of different bitter-sensitive taste cells to feeding inhibition in a caterpillar (Manduca sexta).” Behavioral neuroscience 113.4 (1999): 840.
  2. Andreozzi, Paolo, et al. “The bitter taste receptor agonist quinine reduces calorie intake and increases the postprandial release of cholecystokinin in healthy subjects.” Journal of neurogastroenterology and motility 21.4 (2015): 511-519.
  3. Wu, S. Vincent, et al. “Expression of bitter taste receptors of the T2R family in the gastrointestinal tract and enteroendocrine STC-1 cells.” Proceedings of the National Academy of Sciences 99.4 (2002): 2392-2397.
  4. Palatini, Kimberly, et al. “Diverse Classes of Bitter Phytochemicals Modulate Carbohydrate Metabolism and Immune Responses through Gastrointestinal Bitter Taste Receptors.” The FASEB Journal 29.1 Supplement (2015): 405-5.
  5. Posovszky, Carsten, and Martin Wabitsch. “Regulation of Appetite, Satiation, and Body Weight by Enteroendocrine Cells. Part 2: Therapeutic Potential of Enteroendocrine Cells in the Treatment of Obesity.” Hormone Research in Paediatrics 83.1 (2015): 11-18.
  6. Tilg, Herbert, and A. Kaser. “Gut microbiome, obesity and metabolic syndrome.” J Clin Invest 121.6 (2011): 2126-32.
  7.  Lee, Robert J., and Noam A. Cohen. “Bitter Taste Bodyguards.” Scientific American 314.2 (2016): 38-43.
  8. Gil, Sucheol, et al. “Genotype-specific regulation of oral innate immunity by T2R38 taste receptor.” Molecular immunology 68.2 (2015): 663-670.
  9. 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): 1-8.
  10. Lee, Robert J., and Noam A. Cohen. “Role of the bitter taste receptor T2R38 in upper respiratory infection and chronic rhinosinusitis.” Current opinion in allergy and clinical immunology 15.1 (2015): 14-20.

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