Plant saponins

This is the transcript of a talk I gave recently (at the Traditions herb conference in New Mexico), and focuses specifically on a class of plant chemicals: the saponins. However, it is also a great example of how plant chemistry, in general, works: "promiscuous" phytochemicals (as Chatterjee describes them) finding effects in multiple areas of the body, and being affected by the body in turn. This is the beauty of herbal medicine: the context matters as much as the chemical does. No wonder we obsess about "constitutions", "energetics", and other systems-based ways of describing phytohominid interactions.

We are moving away from the idea that isolated, targeted chemicals – be they steroids, antibiotics, or other agents active at specific receptor sites in the human body – are the only way (or even the most efficient way) to achieve health-promoting effects.  This is progress. But herbalism has more to offer to the field of medicine than simple polypharmacy: medicinal plants and their chemical cocktails don’t just act on the system, the way a drug might, they interact with it. This means that, when taken habitually the way most herbal prescriptions are, herbs enmesh themselves into our tissues and processes, and their effects have as much to do with what the body does to the herbs as with what the herbs do to the body. Plant saponins are perhaps the best example of this, acting on every level from the formula to the internal organs and everything in between, changing their conformation and altering their behavior as they move through the physiology and interact with its denizens. If we can understand how a human being and a cocktail of botanical saponins relate to one another, then we don’t just open a door to new formulation tricks and pharmacodynamic mechanisms – we get a visceral sense of how truly non-static herbal chemistry is, how it flows and changes, how different contexts affect it in different ways. And this may be the most important piece.

What is a saponin?
In its simplest form, these chemicals consist of a water-loving (hydrophilic) chunk attached to an oil-loving (hydrophobic) chunk. Often, the hydrophilic piece is a sugar molecule, or perhaps a short chain of sugar molecules, and there can be more than one chain on each saponin. The hydrophobic side is usually a hydrocarbon – either a net of carbon rings (triterpenoid) or a steroid-like structure. But since one piece of the molecule mixes well with water and the other doesn’t, saponins (as the name implies) can have noticeable soap-like effects, forming foams and acting as cleansers (soapwort, Saponaria, has long been prized as an easy and abundant botanical detergent).
The basic test for saponins in a plant is easy. Make a strong infusion (leaves) or decoction (roots/barks) of the plant in question. Strain into a 250ml graduated cylinder, and cool. Shake it vigorously for one minute. If a honeycomb-shaped bubble lattice at least 2cm (a little less than 1 inch) persists in the cylinder for ten minutes, you can be positive that the plant is rich in saponins.
Have you ever tasted soap? You may not have. It is quite bitter, eliciting the typical aversive responses of moderate-to-strong bitter flavors. Saponins, with a few exceptions (like licorice), are generally just as bitter. Their flavor is an important part of their medicinal effects, especially early on in their journey into the human physiology.
It is still a matter of debate as to why plants produce these molecules. Some believe they act as browsing deterrents, because of their bitterness. Others have documented antifungal and antibacterial qualities which may help protect plants from infection. Still others hypothesize that the hydrophobic backbone serves as a sort of “ferry” for the sugar molecules, allowing them to cross barriers they normally couldn’t. I suspect that all these stories are true, at least in some part.

The physics of saponins in water solutions
The foam you see when shaking a cup of licorice tea is only the most macroscopic part of the picture. Inside the cup, the soap-like molecules are arranging themselves into interesting little “bubbles”, known as micelles, with the hydrophilic sugar tails sticking out into the water and the hydrophobic backbones clustering together in the middle of the bubble. This is quite interesting in and of itself, as we will see, but imagine for a moment if there were other molecules in the tea – say, for instance, that you had added some propolis tincture to really help with your client’s bronchial cough – that weren’t very water-soluble. If you’ve ever tried adding a dropper of propolis tincture to a glass of water, you’ll know that the resins it contains immediately separate from the solution, turning the glass cloudy and leaving a ring of sticky material behind. If you add that same dropper to a strong, foamy licorice decoction and shake it up quickly, the effect is much less pronounced: the hydrophobic resins are trapped inside the saponin micelles, mixing with the hydrophobic backbones, and stay in solution much better. This effect is known as emulsification.
These two effects – the foaming, and the emulsification – have numerous practical applications, and you don’t need a lot of saponin to achieve them. For instance, soft drink manufacturers add saponins to their products to improve the quality and persistence of the foam “head” [Ref: A.J. Mitchell, Formulation and Production of Carbonated Soft Drinks]. I favor a combination of hawthorn, gotu kola, and turmeric for chronic ligament and connective tissue injury, and for a long time formulated this tincture blend with two parts hawthorn and turmeric, and one part gotu kola. But the turmeric tincture, extracted at a much higher percentage of alcohol, would always separate, sometimes clogging the dropper, once it got diluted by the other two and all its hydrophobic constituents fell out of solution. The problem was solved by adding horse chestnut tincture, from a saponin-rich seed,  to the mix (one part out of five). The curcuminoids stayed in solution, no more clogging, and horsechestnut’s anti-inflammatory power helped make the formula even more effective.
The British Pharmaceutical Codex recommends a ratio of 1 part Quillaja tincture (the soapbark tree, from Chile) to 8 parts resins or fatty acids to achieve an effective emulsion. This highlights the effectiveness, even at low concentration, of saponins as blending agents.
The emulsifying, blending quality of plant saponins in a multi-constituent herbal formula, especially if it contains high- and low-alcohol tinctures mixed together, is really useful. And it may underlie the traditional wisdom of using plants like licorice as “harmonizers” and “binders” in the formula: not only does the pleasant flavor help in compliance, but the physics of the saponins in solution ensures that all constituents remain equally suspended in the blend – in harmony.

Act I – the gastric phase of digestion
First off, taste. The activity of saponin-rich plants like yucca, fenugreek, and even ginseng begins with their ability to stimulate bitter taste receptors – soap-like, after all. From here you get many of the benefits of bitter tastants, and these actions are reinforced once the saponins reach the stomach and duodenum: secretions increase, movement of smooth muscle in the gut becomes less spasmodic and better synchronized, valves close up. This may be part of the reason why so many saponin-rich plants (again, with the exception of licorice) are good at controlling blood sugar spikes: the food we eat doesn’t get to the intestinal phase as quickly, so it doesn’t flood the bloodstream with glucose.
Another interesting topical effect of saponins relies on the intimate connection between the mucous membrane of the GI tract and the respiratory system. Pick your saponin-rich herb: licorice, Senega snake root, yucca root, Platycodon, fenugreek – almost all have at least some degree of expectorant activity. This is probably due to what Simon Mills calls “acupharmacology” – the fact that our gut lining is connected to other tissues in the body via nerve fibers, particularly the vagus nerve, allows a slight irritation to affect those other tissues by reflex. So saponins encourage the upward movement of material from the lungs by slightly irritating the stomach lining with their soap-like quality.
Yet another effect relies on the physical properties of saponin micelles. When bile, which contains appreciable quantities of cholesterol, is released into the duodenum, some of the hydrophobic cholesterol is trapped in the micelles. It is then excreted at higher levels in the stool, instead of being re-absorbed and circulated in the blood. There has been a lot of animal research confirming this mechanism [Ref: Sautier, C., et al. "Effects of soy protein and saponins on serum, tissue and feces steroids in rat." Atherosclerosis 34.3 (1979): 233-241], but it also helps explain the cholesterol-lowering effect of ginseng saponins [Ref: Kim, Seung-Hwan, and Kyung-Shin Park. "Effects of Panax ginseng extract on lipid metabolism in humans." Pharmacological Research 48.5 (2003): 511-513.]
At this point, the molecules are still very similar to what they were in your tea or tincture. But once they enter the duodenum and start to meet pancreatic amylases (starch-digesting enzymes) and eventually gut flora, things start to get interesting.

Act II – the intestinal phase of digestion
The entire GI tract is a sophisticated chemosensory organ – meaning, it’s really good at tasting, and not just the tongue. While bitter taste receptors persist throughout the gut, you also start to see lots of lymphatic tissue associated with the mucous membrane once you get past the stomach and its high-acid environment. In these areas, immune cells proliferate and sample the contents of the food we eat, all the while interacting with members of the microbiome. It’s a deep and rich conversation down there, and we are just barely beginning to understand the language. One thing that seems clear is that many of the signals that travel back and forth are expressed in sugar chains, or chains of sugar, fat, and protein – because that’s  what is found on the outside of most viruses and bacteria (with some exceptions, like the cyst form of Borrellia, the Lyme disease spirochete, which is naked can thereby evade immune detection). What is so interesting is that the saponin micelle, with its core of hydrophobic molecules and all the little sugars sticking out, looks a lot like a small microbe. Couple this with the fact that it’s never just one kind of saponin, but the sugar chain shapes and sizes vary dramatically (ginseng, for example, has over 100 [Ref: Shin, Byong-Kyu, Sung Won Kwon, and Jeong Hill Park. "Chemical diversity of ginseng saponins from Panax ginseng." Journal of Ginseng Research (2015).]), and you have the potential for a very fascinating little micelle to interact with the microbiome and the immune cells in the gut’s lymphatic tissue. Plant saponins are one of the most powerful ways for the vegetable kingdom to participate in the immunologic conversation that takes place inside the human being.
The interaction with the microbiome continues. Many saponins get broken in half once they meet pancreatic amylases, which can break sugar-to-sugar bonds, or gut flora, which can digest sugar chains for energy. But not all members of the microbiome feel the same way about saponins: probably because they are so ubiquitous in the traditional human diet, our long-term partners (the beneficial flora) aren’t harmed, and can harvest the sugars for energy. But yeasts and pathogenic bacteria that may be overgrowing in the case of dysbiosis can be damaged by saponins, whose soap-like quality melts their outer membranes. Many saponin-rich plants, like chapparal (Larrea) are excellent anti-parasitics and can help correct dysbiosis.
When you stop to think about the recent interest in the microbiome and immune system for modulating our mental health and perception of stress, our inflammatory balance, and our overall relationship with the world, you can begin to see how relevant a cocktail of plant saponins might be. The effects on immunologic tissue in the GI tract and gut flora balance is a big part of the adaptogenic, anti-inflammatory, immunomodulating effects of saponin-rich plants like Panax and Astragalus.
Some [Ref: Robb Wolf, Paleo Solutions] worry that the soap-like quality of plant saponins can “punch a hole in the lining of your gut,” contributing to leaky-gut syndrome and inflammation. In fact, these molecules can be quite toxic to fish and reptiles who lack the ability to metabolize them, and have been used as fish poisons. In these cases they do actually cause a breakdown reaction in tissues and blood cells of the animals. Fortunately, mammals seem immune to these effects (as long as the saponins aren’t injected intravenously), because our digestive enzymes and gut flora separate the hydrophilic sugars from the hydrophobic backbones, thereby destroying the soap-like effect. The hydrophobic metabolites are often absorbed into the blood, sometimes pretty quickly (less than 90 minutes), but they do no damage once they’re separated from the sugars [Ref: Lee, Jayeul, et al. "Studies on absorption, distribution and metabolism of ginseng in humans after oral administration." Journal of ethnopharmacology122.1 (2009): 143-148.]
It is these metabolites that feature prominently in the final act – but what is fascinating is that the metabolites would probably never be absorbed whole into our bloodstream if they didn’t come attached to those sugar chains. In essence, the sugars protect the hydrophobic metabolites from digestion and breakdown in the gastric phase and shield them from microbial metabolism by locking them into those little micelles. A sort of molecular enteric coating. Without it, glycyrretinic acid (the metabolite of glycyrrhizin, a licorice saponin) would never make it into our bloodstream [Ref:  崎谷陽子, et al. "Rapid estimation of glycyrrhizin and glycyrrhetinic acid in plasma by high-speed liquid chromatography." Chemical and Pharmaceutical Bulletin 27.5 (1979): 1125-1129.]

Act III – the blood and tissues
Now stripped of its sugar chains, what was once a saponin is now an aglycone – a sugarless molecule. The first tissue it encounters may be the liver (though being hydrophobic, many aglycones are absorbed into lymphatics and wind their way up to the heart instead. Soon, though, they all will visit the liver). Here, the aglycone travels across the cell membrane and begins to interact with the expression of DNA, affecting the types and quantities of proteins that are produced. Some aglycones from fenugreek saponins, for instance, seem to increase liver cells’ sensitivity to insulin, and decrease cholesterol production – thereby reinforcing the effects the saponin had in act I. Still in the liver, aglycones may interact with enzymes responsible for metabolizing sex and steroid hormones, contributing to a balancing and adaptogenic effect. Sometimes this can be quite powerful: glycyrrhetinic acid, the aglycone from licorice, slows the breakdown of secretions from the adrenal cortex such as cortisol (a stress steroid) and aldosterone (which makes us retain sodium). Taken in large quantities for long periods, it can cause fluid retention and high blood pressure.
Many saponin aglycones have noticeable anti-inflammatory effects, through a wide range of mechanisms. Some inhibit cyclooxygenases – sort of like a gentle aspirin – while others increase the presence of anti-inflammatory hormones, still others (like the aescin aglycones from horse chestnut) tone the tissue of the capillaries and venules, decreasing leakage, swelling, and pain. These actions synergize with the immunological activity exerted in act II, where the saponins talked to lymph tissue and microbiome, to reinforce the overall anti-inflammatory effect.
Because of their fat-soluble nature, a good portion (though not all) of saponin aglycones can cross the blood-brain barrier and affect the production, distribution, and balance of key neurotransmitters, particularly the ones involved in the stress response. Many adaptogens (like licorice, codonopsis, ginseng, eleuthero) rely on this activity. That horse chestnut and fenugreek lack adaptogenic activity speaks to the circulation of their aglycones: they may not be as effective at modulating the relevant hormones because they simply can’t get there.

In conclusion, we can use the example of plant saponins to illustrate the complex and multiple ways that herbal medicines interact with our physiology. They change us, in gentle but profound ways, and yet they are also themselves changed. Without this two-way interaction, none of the activities we reviewed would be possible. But what is even more interesting is that, depending on the context, all or none of these actions may be present: the same root may work differently in different folks. Codonopsis saponins might help correct dysbiosis in one individual, by preferentially feeding beneficial flora and contributing to the destruction of pathogens. This, coupled with the interaction of saponin micelles with immune cells in gut lymph, might help restore emotional and spiritual balance for that specific individual. But for another, it may be the codonopsis aglycone, interacting with the metabolism of stress hormones, that keeps their mood balanced: adrenal spikes flatten out, blood sugar normalizes, emotions stop their roller-coaster ride. The physiology can avail itself of any or all of these actions depending on what is lacking, or out of balance: and unlike single molecules like caffeine or convallotoxin, none are ever strong enough to disrupt a system already in balance. Consider saponins as great harmonizers: first in your formulas, then in your gut, and finally in your blood vessels, liver, and endocrine cells.