Research Progress on Licorice Mitigating the Strongly Purging Nature of Rheum-Liaoning Chaohua Pharmaceutical Co., Ltd.

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Research Progress on Licorice Mitigating the Strongly Purging Nature of Rheum

Release Date:

2021-04-28

Research Progress on Licorice Mitigating the Strongly Purging Nature of Rheum

Abstract: The theory of medicinal properties is a core component of the theoretical system of traditional Chinese medicine and serves as an important basis for guiding the clinical use of Chinese herbal medicines and elucidating their mechanisms of action. Licorice, renowned as the “national elder,” is prized for its mild and harmonizing nature, making it the preferred herb for achieving balance and synergy in TCM formulas; by contrast, rhubarb, often referred to as the “general,” possesses a potent and harsh nature, rendering it an excellent purgative agent—yet improper use can inflict harm on the body. The clinical combination of rhubarb and licorice has a history spanning several millennia, during which licorice’s harmonizing properties temper rhubarb’s vigorous purgative effects, thereby not only mitigating its laxative action but also reducing its adverse reactions. Based on the theory of medicinal properties, this review elucidates the traditional understanding that licorice moderates rhubarb’s harsh potency, and summarizes recent advances in modern research on the material basis, drug metabolism, intestinal motility, fluid homeostasis, gut microbiota, and immune modulation resulting from the rhubarb–licorice combination. The aim is to provide a foundation for further investigation into how licorice attenuates rhubarb’s intense purgative effects, while also offering research directions for clarifying the scientific underpinnings of licorice’s “harmonizing” function.

The theory of medicinal properties in traditional Chinese medicine is one of the fundamental theoretical frameworks guiding clinical prescription formulation and drug combination, and it also serves as an important principle for the compatibility of herbs. ^[1] Although individual medicinal substances possess distinctive therapeutic properties, the use of single herbs in treating diseases often entails certain limitations and fails to meet the demands of complex clinical conditions. To address these challenges, traditional Chinese medicines must be appropriately combined and formulated to balance their inherent biases and mitigate their toxicities, thereby minimizing adverse reactions and maximizing therapeutic efficacy. Consequently, research on herbal compatibility based on the theory of medicinal properties is of great significance for deepening our understanding of the scientific principles underlying such combinations, while also providing an essential foundation for more safe and effective guidance of clinical practice in traditional Chinese medicine. ^[2]。

Licorice is the most widely used and frequently prescribed herbal ingredient in clinical practice of traditional Chinese medicine. ^[3] The Shennong’s Classic of Materia Medica classifies licorice as a superior-grade herb, stating: “Licorice has a sweet taste and is neutral in nature.” The Compendium of Materia Medica further notes: “Among all medicinal substances, licorice serves as the sovereign; it can treat seventy-two types of stone-like toxins, neutralize twelve hundred kinds of plant and herb poisons, and harmonize the actions of other herbs—hence its appellation ‘the National Elder.’” ^[4] Tao Hongjing remarked: “This herb is the supreme sovereign among all medicinal substances; few classical formulas do not employ it,” hence the saying, “Nine out of ten prescriptions in the ten directions include licorice.” Licorice alleviates urgency and relieves pain, while harmonizing the other herbs. Its nature is gentle and mild, making it compatible with a wide variety of traditional Chinese medicines. It can reduce the toxicity of certain drugs by exerting a detoxifying effect, and through its harmonizing action, it can be combined with cold- or heat-inducing, tonifying or purgative agents to optimize therapeutic efficacy. ^[5] Rhubarb is a quintessential representative of traditional purgative Chinese medicinal herbs; it has a bitter, cold nature and was first recorded in the Shennong’s Classic of Materia Medica, where it was classified as a lower-grade herb. As stated in the Compendium of Pharmaceutical Formulas: “Rhubarb possesses a heavy, turbid aroma and flavor, descending directly and moving downward without lingering—possessing the power to break through barriers and seize the gateway; hence it is known as the ‘General.’” ^[6] The “Compendium of Herbal Properties Through the Ages” likewise states: “Rhubarb has a profoundly bitter taste and a markedly cold nature… Although it accords with the natural order of heaven and benefits the people in times of dire need, it nonetheless falls short of perfect efficacy… Hence its use is reserved for cases of exogenous febrile diseases.” The “Mengquan Compendium of Materia Medica” further records: “Do not administer in excessive doses; excessive purgation may deplete yin.” Rhubarb’s action is exceedingly potent; improper use can readily damage the fluids of the intestines and bowels and often harms the body’s vital qi. Therefore, in clinical practice it is commonly combined with other herbs.

The clinical use of the rhubarb–licorice combination has a history spanning thousands of years. Licorice, with its sweet and neutral nature, moderates rhubarb’s potent purgative action, enabling rhubarb to promote bowel movements without damaging the body’s vital energy. Modern research also demonstrates that, when combined, licorice not only attenuates rhubarb’s harsh purgative effect but also mitigates the adverse reactions associated with rhubarb’s intense nature. ^[7] Although the combination of rhubarb and licorice has demonstrated clear clinical benefits in purgation and elimination of accumulated pathogenic factors, its underlying mechanisms of action remain incompletely elucidated. Changes occurring before and after the compatibility of traditional Chinese medicines manifest in multiple aspects. Based on the theory of medicinal properties, this article expounds the traditional understanding that licorice moderates rhubarb’s pungent and drastic nature. Furthermore, it reviews recent advances in modern research on how licorice attenuates rhubarb’s potent and abrupt effects, focusing on the changes in the chemical constituents, in vivo pharmacokinetics, and biological activities following their combination, with the aim of providing a scientific basis and reference for further investigation into their mechanisms of action.

1 The Traditional Understanding of Licorice Moderating the Vigorous Nature of Rheum

1.1 The Traditional Understanding of Rhubarb’s Pungent and Potent Nature

The Shennong Ben Cao Jing records of rhubarb: “Its flavor is bitter and its nature cold; it expels stagnant blood, resolves blood stasis, alleviates alternating chills and fever, breaks up accumulations and masses, eliminates retained fluid and lingering food stagnation, purges the intestines and stomach, removes the old to make way for the new, facilitates the smooth passage of water and grain, harmonizes the middle burner and aids digestion, and pacifies and balances the five zang organs.” The Ben Cao Zheng Yi further states: “It moves swiftly and directly to the lower jiao, breaking through any obstruction without exception—its power is like plowing a field and sweeping away every trace…so rapid that once it passes, nothing is left behind.” The Mingyi Bie Lu adds: “This herb is the principal remedy for eliminating excess heat and dryness-induced constipation, as well as for resolving tangible accumulations and stagnation in the lower burner.” All these descriptions underscore that rhubarb is a key herb for purgation and downward movement: under normal circumstances, the food and fluids ingested are distributed throughout the body, nourishing the five zang and six fu organs and enabling their mutual interaction, while turbid, toxic, and putrid substances are expelled from the lower jiao. However, when excess heat and stagnation prevail, such turbid toxins remain in the digestive tract; if allowed to linger, they inevitably transform into harmful toxins, and only forceful, rapid purgation can effectively clear the resulting blockages. Zhang Zhongjing, in the Shanghan Zabing Lun, pioneered the method of峻下 (severe purgation), which involves employing potent purgative herbs to attack and eliminate internal solid conditions, primarily for treating yangming fu-shi syndromes characterized by excess heat and stagnation. ^[8] Rhubarb is bitter, cold, and heavy in nature, with a profound and penetrating aroma; its potency is vigorous and decisive, making it particularly effective in promoting downward movement and evacuation. Consequently, it is indicated for conditions of interior accumulation, excess, heat, and yang excess. Rhubarb expels accumulated stasis and resolves stagnation: it not only clears tangible pathogenic factors, thereby enhancing gastrointestinal motility and facilitating the downward passage of food residues and waste products to swiftly eliminate accumulated intestinal contents, but also unblocks obstructed, intangible pathogenic qi, harmonizes the qi of the six fu organs—including the stomach and intestines—and thus regulates the qi mechanisms of the five zang organs.

The Compendium of Pharmacological Properties records: “Moreover, when rhubarb is employed for purgation, it inevitably damages the qi of the stomach and intestines.” The New Compilation of Materia Medica states: “This herb possesses a swift and vigorous action that boldly advances to eliminate stubborn pathogenic factors and thoroughly dispel accumulated stasis… However, its use must be strictly guided by a very clear diagnosis; only then will it prove highly effective. Otherwise, it may bring about death in an instant.” It is thus evident that rhubarb has a potent and harsh nature: improper use may, at the least, “damage the qi of the stomach and intestines,” and at the worst, “bring about death in an instant.” ^[9] It should be noted that while rhubarb is highly effective in purging and eliminating accumulated pathogenic factors, its potent purgative action can readily give rise to adverse reactions. Rhubarb’s purgative effect is vigorous and rapid, yet its bitter taste and intensely cold nature may dry up dampness, thereby damaging stomach yin, and its cold nature may overpower heat, thus injuring middle-jiao yang, potentially leading to depletion of both yin and yang and consequently weakening the body’s vital energy. Traditional Chinese medicine holds that “bitter-cold herbs damage the stomach.” In ancient medical texts, the term “stomach” refers not only to the anatomical organ but also encompasses multiple digestive organs, including the small intestine, large intestine, and liver. Modern research likewise demonstrates that prolonged or excessive use of rhubarb can indeed cause gastrointestinal irritation—such as abdominal distension, abdominal pain, and diarrhea—and may even result in gastroenteric and hepatorenal toxicity. However, when used in appropriate doses and properly combined with other herbs, rhubarb can exert favorable clinical efficacy.

1.2 The Traditional Understanding of Licorice Moderating the Vigorous Nature of Rheum

Licorice has a sweet taste and neutral nature; it excels at harmonizing all other herbs, mitigating their toxicity and inherent biases, and is typically used as an auxiliary or guiding herb in formulae. ^[10] For example, the “Compendium of Materia Medica” records: “Licorice has an exceedingly sweet taste and embodies the nature of balance and harmony; it possesses the function of tonifying and harmonizing. Thus, when used with toxic herbs, it neutralizes their toxicity; when combined with harsh herbs, it moderates their potency; when paired with exterior-releasing herbs, it enhances their external action; and when employed with purgatives, it tempers their rapid effect.” The “Commentary on the Compendium of Materia Medica” likewise states: “Licorice is neutral in nature… Whenever purely cold or purely hot herbs are used, licorice must be added to temper their force. Even when cold and hot herbs are mixed, licorice is employed to harmonize their properties.” The sweet flavor corresponds to the element Earth in the Five Elements; Earth nourishes and sustains all things and exerts a tonic effect on the human body. Hence, it can “harmonize,” “moderate,” and “tonify”—as the “Record of Integrating Traditional Chinese and Western Medicine” observes: “...with its profoundly sweet taste, licorice fully embodies the essence of Earth. All things originate from Earth and ultimately return to Earth for transformation; therefore, it can counteract all forms of toxicity. Sweetness primarily promotes harmony, thus exerting the function of harmonizing the spleen and stomach; moreover, sweetness tends to moderate, so although it tonifies the spleen and stomach, it does not do so in an overly vigorous manner.” In herbal formulae, licorice therefore exhibits a uniquely harmonizing quality. ^[11] In essence, these functions encompass relieving urgency and tension, moderating the potency of herbs, and neutralizing toxicity. Relieving urgency and tension reflects licorice’s intrinsic pharmacological actions: first, it alleviates physical stiffness and spasm; second, it calms emotional agitation—examples include relieving pain by easing urgency, relaxing muscles and tendons by mitigating urgency, and calming the spirit by soothing urgency. Moderating the potency of herbs refers to harmonizing the properties of medicinal substances, primarily manifested in its compatibility with herbs that are salty, bitter, pungent, or sour in flavor, as well as with those that are cold, hot, warm, or cool in nature. Neutralizing toxicity involves mitigating and eliminating adverse reactions induced by drugs, thereby ensuring their safety and efficacy.

Rhubarb is intensely bitter and extremely cold in nature, with a potent and vigorous therapeutic effect; therefore, its compatibility with other herbs is an effective means of tempering rhubarb’s harsh and penetrating properties. The Rhubarb–Licorice Decoction recorded in the Synopsis of Prescriptions from the Golden Chamber consists solely of rhubarb and licorice. Although this combination is classified as a purgative formula, it does not aim at the forceful evacuation characteristic of rhubarb alone; rather, it seeks to achieve a milder, more gentle purgation. In this formula, rhubarb serves as the principal herb, clearing out turbid qi and accumulated pathogenic factors from the intestines and stomach, thus expelling the old and ushering in the new. However, such a powerful purgative action can easily damage the vital qi; licorice, by harmonizing and moderating the intensity, prevents the harsh purgation from undermining the body’s essential energy, enabling the elimination of pathogenic factors without harming the vital qi, while also clearing heat and promoting the smooth descending movement of stomach qi. Through their complementary interaction, these two herbs work synergistically—one attacking, the other tonifying; one acting swiftly, the other more slowly—thereby not only realizing rhubarb’s laxative effect but also preserving stomach qi. The formula is simple yet potent, directly targeting the site of disease. As stated in the Annotations on Ancient Formulas from Jiangxue Garden: “The purpose of the Harmonizing Stomach and Receiving Qi Formula is for licorice to moderate rhubarb and mirabilite, allowing them to remain in the middle burner to dissipate internal heat; hence the name ‘harmonizing the stomach’… By completely eliminating the formless, stagnant heat in the stomach, yin qi is also enabled to ascend and take its proper place, which is why it is also called ‘receiving qi.’” ^[12] In the formula “Tiaowei Chengqi Tang,” rhubarb and mirabilite are used to purge the interior excess, while licorice is added to harmonize the middle burner, ensuring that the purgative action of rhubarb and mirabilite eliminates pathogenic accumulation in the fu organs without damaging the stomach qi. This formulation thus has the effects of harmonizing the intestines and stomach and gently relieving heat-induced constipation. The “New Compilation of Materia Medica” also records: “Rhubarb has a very rapid nature; it moves swiftly and does not linger… If one wishes it to remain in the body for a short time, the use of licorice can help slow its action.” It is thus evident that in traditional Chinese medicine, rhubarb is often combined with licorice to better enhance its purgative efficacy. Chen Jiaqian et al. ^[13] A statistical analysis of the common herbal combinations in the TCM formula database that utilize rhubarb for its purgative effect revealed that licorice is the most frequently paired herb, accounting for 26.21% of all such combinations. This finding provides empirical support for scientific research on the rhubarb–licorice purgative pair. In ancient times, physicians combined rhubarb with licorice to balance the bitter-cold nature of rhubarb with the sweet-and-mild character of licorice, thereby moderating rhubarb’s potent purgative action and maximizing the synergistic benefits of this pairing.

2 Modern Research on Licorice Mitigating the Potent Nature of Rheum

2.1 Current Research Status on the Strong Cathartic Effects and Adverse Reactions of Rhubarb

Rhubarb is a plant of the Polygonaceae family, specifically Rheum palmatum. Rheum palmatum L., Rheum tanguticum R. tanguticum Maxim. ex Balf., or medicinal rhubarb R. officinale The dried roots and rhizomes of Baill. contain major chemical constituents such as anthraquinones, anthrones, stilbenes, phenylbutanones, chromones, tannins, and polysaccharides. ^[14] The primary active constituents responsible for the purgative effect of rhubarb are anthraquinones and their derivatives. Among these, bound anthraquinones (such as sennoside A) exhibit a stronger laxative potency, whereas free anthrones (such as sennoside aglycone A) are less potent, and free anthraquinones (including emodin, rhein, chrysophanol, aloe-emodin, and physcion) display even weaker activity. ^[15] Conjugated anthraquinones are poorly absorbed in the small intestine and readily reach the colon, thus being regarded as the principal active constituents responsible for the laxative effect; in contrast, free anthraquinones are readily absorbed in the small intestine, undergo enterohepatic circulation to enter the bloodstream, and fail to reach the colon, hence their relatively low laxative activity. However, modern research has demonstrated that sennoside A and rhein glycoside in rhubarb are inactive glycosides that do not exert a direct laxative effect; within the colon, they are metabolized by β-glucosidase produced by bifidobacteria into the true active laxative components—rhein anthrone and rhein. ^[16] These free anthraquinones are the ultimate active constituents responsible for the laxative effect of rhubarb, and their metabolic pathway is illustrated in Figure 1.

Rhubarb primarily exerts its laxative effect by acting on the colon, with the mechanism involving increased colonic tone, accelerated intestinal peristalsis, stimulation of the colonic mucosa, and promotion of the secretion of water and electrolytes into the colonic lumen, thereby facilitating bowel movement. ^[17] Free anthraquinones are readily absorbed in the small intestine and do not reach the large intestine to exert their effects; however, they can inhibit sodium–potassium adenosine triphosphatase (Na ⁺ , K ⁺ -adenosinetriphosphatase, Na ⁺ , K ⁺ –ATPase), increasing intraluminal water content and thereby promoting peristalsis and bowel movement; meanwhile, the glycosides in bound anthraquinones can protect the aglycone from hydrolysis and oxidation in the small intestine, playing an important role in intestinal stimulation and laxative action. ^[14] In addition, rhubarb induces alterations in the expression of aquaporins (AQPs) in the colon, which is also one of the key mechanisms underlying its laxative effect.

Modern research indicates that, while rhubarb exerts its purgative effect, it also strongly irritates the gastrointestinal mucosa, leading to symptoms such as nausea, vomiting, abdominal pain, and bloating. This irritation can result in impaired intestinal motility, dysbiosis of the gut microbiota, disruption of the intestinal barrier function, and suppression of systemic immunity. It may also cause disturbances in water and electrolyte metabolism, precipitating severe diarrhea. Moreover, prolonged use can induce drug resistance, thereby reducing therapeutic efficacy and potentially being associated with a range of adverse intestinal outcomes, including the development of colonic melanosis and an increased risk of colorectal cancer. ^[18] Notably, rhubarb also exhibits a bidirectional regulatory effect on intestinal peristalsis—both inhibiting and stimulating it—thereby manifesting dual therapeutic effects of purgation and antidiarrheal action. ^[19] Its tannin constituents exert an astringent and antidiarrheal effect by inhibiting gastrointestinal motility; however, long-term low-dose administration may paradoxically lead to secondary constipation upon discontinuation. In addition to its impact on gastrointestinal function, the hepatorenal toxicity of rhubarb has also attracted considerable attention, with research primarily focusing on anthraquinone compounds. The metabolic accumulation of rhein in the intestine is associated with the development of colonic melanosis, and the cell apoptosis and autophagy it induces may underlie the toxic mechanisms of rhein. ^[20] The toxic mechanism of aloe-emodin involves the induction of apoptosis through death receptor-mediated signaling, mitochondrial stress, and endoplasmic reticulum stress. ^[21] Emodin exerts hepatorenal toxicity by inducing apoptosis via caspase-3–dependent and mitochondrial pathways; moreover, it also involves glutathione metabolism and fatty acid metabolism pathways. ^[22] There are also reports on the genotoxicity, reproductive toxicity, carcinogenicity, and embryotoxicity of rhubarb. It is evident that, while rhubarb exerts therapeutic effects, it can also cause adverse reactions, thereby affecting its clinical use.

2.2 Licorice mitigates the harsh purgative nature of rhubarb and its adverse effects.

The combination of rhubarb and licorice demonstrates significant clinical benefits in promoting bowel evacuation and eliminating accumulated pathogenic factors. In modern clinical practice, the use of Rhubarb–Licorice Decoction for treating constipation has shown good therapeutic efficacy, as reported by Shao Jingxian. ^[23] A total of 113 cases of constipation induced by antipsychotic medications were treated with Dahuang-Gancao Decoction, achieving an overall effective rate of 90%. The therapeutic effect was significant and the action was mild; apart from a few patients who experienced mild abdominal pain, no other adverse reactions were observed. Liu Baozhong et al. ^[24] A total of 163 psychiatric patients with constipation were treated with Dahuang-Gancao Decoction, achieving an overall effective rate of 85.27%. The therapeutic effect was reliable, with only 18 cases experiencing mild abdominal pain. Due to the potent and rapid action of Dahuang, caution is advised when using it in elderly patients or those with deficiency syndromes and weak spleen-stomach function. Dong Suqin ^[25] The use of Dahuang-Gancao Decoction for treating constipation in the elderly has demonstrated good therapeutic efficacy. This suggests that, in clinical practice, the combined use of Dahuang and Gancao can enhance Dahuang’s purgative effect while mitigating its adverse reactions.

Licorice is a leguminous plant. Glycyrrhiza uralensis Fish.、Swollen-fruited Licorice G. inflata Bat., or Glycyrrhiza glabra G. glabra The dried roots and rhizomes of L. Its main chemical constituents include triterpenoid saponins, flavonoids, coumarins, alkaloids, and carbohydrates, among others. ^[26] Among them, the active constituents of licorice that harmonize other herbs include triterpenoid saponins (glycyrrhizic acid and glycyrrhetinic acid) and flavonoids (glycyrrhizin and liquiritin), which are primarily associated with changes in in vitro chemical composition before and after compatibility, in vivo metabolism, and the pharmacological actions of licorice itself: (1) co-decoction with other drugs may lead to precipitation or complexation reactions, resulting in alterations in the bioactive components or reductions in the content of toxic constituents. ^[27-28] (2) The adrenocortical hormone–like effects of licorice can enhance the body’s tolerance to toxic substances; (3) it modulates the hepatic cytochrome P450 (CYP450) enzyme system, particularly CYP3A, upregulating the expression and function of efflux transporters, primarily P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), and multidrug resistance proteins, thereby delaying the absorption and distribution of toxic constituents, promoting their metabolism and excretion, and ultimately reducing toxicity. ^[29-30] (4) Increasing the abundance and diversity of beneficial gut microbes, such as lactic acid bacteria and bifidobacteria, and modulating gut microbial metabolism to exert their regulatory effects. ^[31] (5) Alleviating adverse drug reactions through its pharmacological actions, including spasmolysis, antiarrhythmic effects, and neuroprotection; (6) The macromolecular glycoproteins in licorice can self-assemble into nanoparticles, which are associated with its detoxification activity. ^[32] (7) Licorice and its active constituents exhibit anti-inflammatory and anti-allergic activities, primarily mediated by immune molecules such as interleukin-10 and interleukin-12, thereby suppressing immune-mediated tissue damage. ^[33] Licorice can effectively mitigate the harsh purgative effect of rhubarb and reduce its adverse reactions. ^[34] Clinically, rhubarb is often combined with licorice to mitigate adverse reactions such as vomiting, nausea, abdominal pain, and diarrhea, as well as to reduce hepatobiliary toxicity. ^[35] This article primarily discusses the changes in chemical constituents, intestinal motility, fluid metabolism, and gut microbiota before and after compatibility, as illustrated in Figure 2.

2.2.1 Effects of Rhubarb–Licorice Compatibility on Chemical Constituents Numerous studies have been reported on the changes in chemical constituents of rhubarb–licorice before and after compatibility; however, to date there have been no reports of the formation of new chemical constituents upon such compatibility, with research primarily focusing on alterations in the relative contents of existing constituents. ^[36] Most literature reviews indicate that, when combined, licorice can increase the extraction yield of free anthraquinones from rhubarb while reducing the extraction yield of bound anthraquinones. ^[37] Comparing the changes in glycyrrhizic acid content between the combined decoction of rhubarb and licorice and the single-decoction of licorice, it was found that the glycyrrhizic acid content in the combined decoction was significantly higher than that in the single-decoction, indicating that co-decocting the two herbs promotes the leaching of glycyrrhizic acid. ^[38] Glycyrrhizic acid is the principal bioactive constituent of licorice and functions as a natural surfactant, which may account for the increased dissolution of free anthraquinones. After combination of rhubarb and licorice, the dissolution rate of anthraquinoid compounds is lower than that observed with rhubarb alone, likely reflecting the attenuated pharmacological effects resulting from this formulation. It is hypothesized that the combination increases the content of glycyrrhizic acid, which can complex with alkaloids, anthraquinones, metal ions, and other constituents to form precipitates or high-molecular-weight complexes with greater polarity that are poorly absorbed by the gastrointestinal tract; by exerting its precipitation effect, glycyrrhizic acid thereby reduces the amount of bound anthraquinones.

2.2.2 Effects of Rhubarb Combined with Licorice on Drug Metabolism Rhein is the principal free anthraquinone constituent in rhubarb and also the major metabolite of conjugated anthraquinones. After being absorbed in the small intestine, rhein is predominantly metabolized in the liver; it is then excreted via bile into the enterohepatic circulation, thereby increasing its bioavailability and enabling rapid absorption into the bloodstream. ^[39] Pharmacokinetic studies of anthraquinone compounds in rhubarb have demonstrated a “double-peak” pattern in plasma concentrations of rhein following oral administration, attributable to the sequential processes of: (1) minimal absorption of rhein glycosides in the small intestine, which are subsequently hydrolyzed by intestinal microbiota into rhein; and (2) in vivo metabolism of emodin, chrysophanol, and aloe-emodin into rhein. Moreover, the plasma level of rhein is positively correlated with the extent of liver injury; therefore, rhein is regarded as both the principal active constituent and the primary toxic component of rhubarb. ^[40]。

When licorice is combined with other drugs, it can influence the metabolism of the concomitant medications, thereby delaying and reducing their absorption. The higher plasma concentrations of rhein and glycyrrhizic acid compared with other constituents indicate that these two compounds play a major role in drug metabolism. ^[41] Glycyrrhizic acid can induce CYP450 activity, accelerating the metabolism of drugs in the body and thereby reducing the plasma concentrations of their active components. ^[42] Following intragastric administration of rhubarb and rhubarb–licorice decoction to rats, the plasma concentration–time profiles of rhein conformed to a two-compartment model. Significant differences were observed in the pharmacokinetic parameters of rhein between single-dose administration of rhubarb and co-administration with the rhubarb–licorice decoction; the combination with licorice reduced the plasma concentration of rhein in rats, increased its clearance rate, and accelerated its metabolic processes. ^[43] The reduction in plasma concentrations of rhein may account for the attenuation of its adverse effects; the underlying mechanism likely involves glycyrrhizic acid, which can induce the expression of CYP3A enzymes responsible for rhein metabolism, thereby accelerating rhein clearance and mitigating hepatic injury. ^[44] The transporter protein BCRP is an efficient efflux transporter that primarily mediates the efflux transport of rhein. In vitro cell experiments have demonstrated that licorice can reduce the uptake of rhein in Caco-2 colon adenocarcinoma cells and increase its efflux rate by enhancing BCRP activity and upregulating BCRP-mediated transport. ^[45] P-gp is widely expressed on the apical membrane of intestinal epithelial cells, where it facilitates the efflux of drugs and toxins from these cells into the intestinal lumen while limiting the passive transport of drugs from the lumen into the bloodstream. The combination of rhubarb and licorice can significantly inhibit ATPase activity; however, the extent of this inhibition is less pronounced than that observed with rhubarb alone. ^[46] This may be because the inhibitory effect of rhubarb–licorice is primarily mediated by rhubarb, while licorice and its major constituent glycyrrhizic acid can enhance P-gp function and expression. ^[47] Glycyrrhiza can reduce drug absorption and alter drug distribution, thereby decreasing the drug concentration at non-target sites and mitigating adverse drug reactions.

2.2.3 Effects of Rhubarb Combined with Licorice on Intestinal Motility Rhubarb exerts its purgative effect by enhancing intestinal motility; the underlying mechanism involves a marked reduction in the frequency of intestinal contractions and an increase in both high-amplitude and low-amplitude contractions. ^[48] Sennoside A significantly promotes proximal colonic transit. ^[49] Its metabolite, rhein anthrone, exhibits cholinergic activity, acting on M receptors in intestinal smooth muscle to stimulate gastric wall nerves and the submucosal nerve plexus, thereby promoting intestinal peristalsis and enhancing gastrointestinal motility and facilitating fecal evacuation. ^[50] Furthermore, rhubarb can modulate gastrointestinal motility by mediating various gastrointestinal neurotransmitters, including acetylcholine, serotonin, substance P, nitric oxide, and vasoactive intestinal peptide. ^[51] Acetylcholine and serotonin markedly stimulate gastrointestinal smooth muscle, increasing its contractile amplitude, tone, and peristaltic activity, and also promote gastrointestinal secretion. ^[52-53] ; In contrast, vasoactive intestinal peptide and nitric oxide are inhibitory neurotransmitters that suppress the contraction of the intestinal circular muscle, thereby maintaining a prolonged state of intestinal relaxation. ^[54] Rhubarb accelerates intestinal transit and promotes defecation by enhancing the release of acetylcholine and serotonin while inhibiting the release of vasoactive intestinal peptide and nitric oxide. ^[55]。

Rhubarb has a potent pharmacological effect; prolonged use can damage the enteric nervous system, impairing the synthesis and transmission of neurotransmitters, thereby injuring the myenteric plexus and muscular layer of the colonic wall, disrupting intestinal transit, and leading to colonic motility disorders. ^[56] Moreover, rapid gastrointestinal peristalsis can irritate the intestinal mucosa, leading to damage of the colonic wall, resulting in loose stools or even diarrhea, and concurrently causing adverse reactions such as nausea and abdominal pain. Licorice has the effect of inhibiting gastric emptying and intestinal smooth muscle motility; when combined with rhubarb, its contractile activity is reduced compared with rhubarb used alone, thereby decreasing both the amplitude and frequency of intestinal peristalsis. ^[49] Glycyrrhiza can inhibit gastrointestinal motility by modulating the secretion of serotonin, substance P, and vasoactive intestinal peptide in the gastric mucosa and the myenteric plexus, suggesting that it exerts its effect by regulating neurotransmitters to restore intestinal motility. ^[57] Licorice also inhibits gastric acid secretion, relieves spasm of gastrointestinal smooth muscle, and exerts analgesic effects. Moreover, the anti-inflammatory properties of glycyrrhizic acid can mitigate colonic inflammatory responses induced by rhubarb, such as defecation-related pain or abdominal pain. ^[58] Moreover, glycyrrhizic acid and glycyrrhizin can synergistically inhibit the strong stimulatory effect of rhubarb on the colonic circular muscle. ^[57] This reduces irritation to the intestinal mucosa and alleviates the severe abdominal pain caused by rhubarb-induced diarrhea, which is consistent with licorice’s “spasmolytic and qi‑regulating” effects. Therefore, it is believed that rhubarb exerts an overstimulatory effect on gastrointestinal motility, whereas licorice has an inhibitory effect; when the two are combined, the dosage of rhubarb can be relatively reduced, resulting in a milder stimulation of intestinal motility.

2.2.4 The Effects of Rhubarb Combined with Licorice on Water and Fluid Metabolism. Colonic water absorption represents the final stage of intestinal fluid absorption in the body, and rhubarb’s purgative action is closely linked to water transport in the colon. Traditional research holds that rhubarb exerts its effect by inhibiting Na+ transport across the apical membrane of intestinal epithelial cells. ⁺ , K ⁺ -ATPase activity, inhibits Na ⁺ It promotes intestinal transit by increasing luminal osmotic pressure, thereby inhibiting the reabsorption of water and electrolytes in the intestine, which leads to fluid retention in the lumen and facilitates bowel movements. ^[59] The Complete Works of Jingyue records that rhubarb “unblocks the water channels,” while modern research indicates that water molecules enter and exit cells through the aquaporin (AQP) water pores, enabling rapid and substantial water transport across cell membranes. This suggests that AQP-mediated transcellular water absorption may be closely linked to intestinal fluid transport. During rhubarb-induced laxation, AQPs play a crucial role in intestinal absorption, secretion, and the regulation of water–electrolyte metabolism. Kon et al. ^[60] Studies have confirmed that sennoside A is metabolized in the colon to form rhein anthrone, which then increases prostaglandin E by activating macrophages in the colon. ₂ (prostaglandin E ₂ , PGE ₂ ) secretion, PGE ₂ Acting as a paracrine factor, it downregulates the expression of AQP3, thereby reducing intestinal water absorption and exerting a laxative effect. Rhubarb and its active constituents can also downregulate the expression of AQP4 in the colonic mucosal layer of constipation models, thus modulating water transport and absorption in the intestine and increasing fecal water content. ^[61-62] The colon contains a large number of goblet cells, which secrete a certain amount of mucus to lubricate and protect the intestinal tract and facilitate the passage of feces. Rhubarb also promotes the excessive secretion of intestinal mucin, thereby enhancing intestinal lubrication and exerting a laxative effect. ^[63]。

Rhubarb exerts its purgative effect by regulating water and fluid metabolism in the intestine; however, its action is very rapid and tends to disperse rather than to remain localized. Excessive purgation can easily disrupt intestinal fluid balance, and the massive flushing of fluids during diarrhea can thin the intestinal mucus layer, compromise the intestinal barrier, and impair normal intestinal physiological functions. Dufour et al. ^[64] It has been confirmed that long-term use of anthraquinone-containing drugs can damage the intestinal mucosa, and injury to the myenteric plexus may impair the coordinated peristaltic activity of the intestine, thereby delaying the transit of intestinal contents and reducing the laxative efficacy of these drugs. Licorice, with its property of “stabilizing without promoting movement,” when combined with rhubarb, achieves a balance between “static” and “dynamic” actions, modulating water–electrolyte metabolism and thus attenuating the purgative effect. Furthermore, licorice may exert regulatory effects on the abnormal expression and distribution of AQP genes and proteins, thereby restoring normal water–electrolyte homeostasis. ^[65] Studies have demonstrated that glycyrrhizic acid can inhibit the activation of macrophages induced by rhein anthrone, thereby reducing AQP3 expression; the combined use of the two can attenuate the laxative effect of rhubarb and alleviate inflammatory responses. ^[31] Therefore, licorice may repair intestinal mucosal injury induced by the potent purgative effect of rhubarb by modulating intestinal AQP expression; however, its underlying mechanisms remain to be further investigated.

2.2.5 Effects of Rhubarb Combined with Licorice on the Gut Microbiota The gut microbial community can convert the unabsorbed sennoside A in rhubarb into its true cathartic active metabolite—rhein anthrone—thereby exerting a laxative effect. A healthy gut microbiota is conducive to maintaining normal intestinal function and regulating systemic metabolism; however, following antibiotic-induced disruption of the gut microbiota, oral administration of sennoside A in mice fails to produce any laxative effect. ^[66] Thus, it is evident that the gut microbiota plays a crucial role in the bioavailability of sennoside A from rhubarb. However, rhubarb’s potent and abrupt effects may also lead to quantitative changes in the intestinal bacterial population. Bifidobacteria and lactobacilli are the dominant members of the normal intestinal flora; they can adhere to intestinal epithelial cells to form a biofilm, thereby maintaining intestinal microecological balance. Members of the Lachnospiraceae family can enhance resistance to colonization by intestinal pathogens, thereby influencing host health. ^[67] Continuous intragastric administration of rhubarb to rats for 7 days reduces the relative abundance of Lactobacillaceae, Bifidobacteriaceae, and Bacteroidaceae in the gut microbiota, while increasing the abundance of Spirochaetaceae. ^[31] . Akkermansia Akkermansia muciniphila Intestinal bacteria closely associated with the mucus layer can be preferentially enriched by long-term administration of sennoside A, thereby compromising the integrity of the mucus barrier. ^[68] While rhubarb exerts its laxative effect, it readily induces gut microbiota dysbiosis, which disrupts intestinal barrier homeostasis, facilitates the invasion and colonization of potential pathogens in the gut, exacerbates inflammatory responses, and ultimately leads to a cascade of adverse reactions.

Maintaining the vitality of the intestinal microbiota is an indispensable step in exerting the purgative effect of rhubarb; however, rhubarb-induced disruption of the intestinal microbiota can, in turn, impair its own purgative activity. When rhubarb is combined with licorice, the enhanced activity of bifidobacteria promotes the metabolism of sennoside A within the intestinal microbiota, and the levels of sennoside A, glycyrrhizin, and liquiritin exhibit a dose-dependent correlation. In contrast, glycyrrhizic acid does not affect the metabolic rate of sennoside A. ^[69] Following 7 days of continuous intragastric administration of rhubarb in rats, the abundance of the family Lachnospiraceae increased significantly, while that of the family Lactobacillaceae decreased significantly; however, no such changes were observed after administration of rhubarb–licorice decoction. ^[31] This may be attributable to licorice inhibiting rhubarb’s ability to increase the abundance of Lachnospiraceae and decrease that of Lactobacillaceae. In addition, emodin, rhein, and aloe-emodin exhibit a certain inhibitory effect on intestinal bacteria. ^[70] The combination of rhubarb and licorice can mitigate rhubarb’s potent purgative effect, possibly due to the increased dissolution of free anthraquinones from both herbs. Moreover, this herbal pairing helps maintain the dynamic balance of the intestinal microbiota. ^[31] By modulating the gut microbiota dysbiosis induced by rhubarb with licorice, the purgative effect of rhubarb can be better realized while its toxicity is reduced.

2.2.6 The Immunomodulatory Effects of Combined Administration of Rhubarb and Licorice The potent purgative action of rhubarb can stimulate the synthesis and secretion of inflammatory cytokines, thereby eliciting an inflammatory response in the organism. Kon et al. ^[60] Studies have shown that rhubarb, while exerting a laxative effect, can also induce colonic inflammation. The underlying mechanism involves the intestinal microbiota metabolizing sennoside A into rhein anthrone, which in turn activates colonic macrophages and triggers an inflammatory response. The upregulation of pro-inflammatory cytokines such as tumor necrosis factor-α and interleukin-8 is associated with tissue damage and can mediate cellular immune responses. Long-term use of rhubarb may lead to melanosis coli, as reported by Chen et al. ^[71] Investigation of the underlying molecular mechanisms revealed that rhubarb can disrupt the intestinal mucosal barrier, increase the release of tumor necrosis factor-α, and induce apoptosis of colonic epithelial cells. Macrophages recognize and phagocytose these apoptotic cells, leading to the formation of brown pigmentation in the lamina propria of the colon and ultimately resulting in melanosis coli. Licorice and its active constituents exert regulatory effects on inflammatory and immune mediators. ^[72] Glycyrrhiza can alleviate gastrointestinal inflammation by increasing the secretion of serotonin and prostaglandins. ^[73] The combined use of rhubarb and licorice can reduce the expression levels of tumor necrosis factor-α and interleukins-6 and -8 in a rat model of intestinal failure, thereby enhancing anti-inflammatory effects. ^[74] Licorice can effectively suppress inflammatory responses and enhance immune function, which may be one of the mechanisms by which the combination of rhubarb and licorice alleviates intestinal inflammation.

3 Conclusion and Outlook

Research on the compatibility of licorice with rhubarb to mitigate rhubarb’s harsh and potent properties has primarily focused on the following aspects: Chemically, licorice can alter the content of anthraquinone compounds in rhubarb, as evidenced by increased dissolution of free anthraquinones and decreased dissolution of bound anthraquinones. However, the changes in both free and bound anthraquinones are rather complex, and findings regarding the alterations in chemical constituent levels before and after the licorice–rhubarb combination remain inconsistent, warranting further investigation. In vivo studies have revealed the following: (1) Licorice can accelerate the clearance rate of anthraquinone constituents from various tissues and reduce the absorption of toxic components, thereby alleviating the adverse effects of rhubarb. More in-depth mechanistic studies are needed to fully elucidate licorice’s mitigating effects; additional research is still required to clarify the pharmacokinetic and metabolic underpinnings of this combination. (2) Licorice can modulate neurotransmitter levels to restore intestinal motility disturbances induced by rhubarb, thus relieving the severe abdominal pain associated with rhubarb-induced diarrhea. While its mitigating effect is well established, the underlying molecular basis remains poorly understood. (3) Licorice regulates fluid metabolism and attenuates inflammatory responses by inhibiting the expression of aquaporin-3 (AQP3). Although AQPs are widely distributed in the intestine, most current research centers on AQP3; it remains unclear whether other types of AQPs also play a role in regulating rhubarb-induced fluid metabolism. (4) Licorice can increase the abundance of beneficial bacteria such as Bifidobacteria and Lactobacilli while reducing the abundance of Spirochaetes, thereby restoring gut microbiota dysbiosis and maintaining microbial homeostasis. However, the precise mechanisms by which licorice modulates gut microbiota abundance and composition require further elucidation. (5) Licorice can alleviate rhubarb-induced intestinal inflammation and enhance immune function by modulating pro-inflammatory and immunoregulatory cytokines; yet the specific mechanisms underlying the immunomodulatory effects of this combination remain to be explored.

Rhubarb–licorice is a classic purgative herbal pair: rhubarb is bitter and cold, clearing the intestines and stomach while expelling old accumulations and promoting renewal; licorice is sweet and neutral, relieving urgency and alleviating pain, and harmonizing all other herbs. Together, these two herbs both promote evacuation and facilitate passage, detoxifying without harming the body’s vital energy. Licorice moderates rhubarb’s potency by altering the dissolution of its chemical constituents, influencing the metabolism of its active components, attenuating rhubarb’s excessive stimulation of gastrointestinal motility, correcting the fluid–electrolyte imbalance induced by rhubarb’s purgative action, restoring the intestinal microbiota disrupted by rhubarb, and suppressing the inflammatory response triggered by rhubarb. The multi-component, multi-target, and multi-pathway nature of traditional Chinese medicine further underscores the complexity of compatibility studies. In summary, rhubarb’s purgative effect is closely linked to changes in its chemical composition, drug metabolism, intestinal motility, fluid–electrolyte balance, gut microbiota, and immune regulation before and after compatibility with licorice; yet many aspects remain unexplored. It is therefore impossible to draw definitive conclusions about the mechanism of action solely by examining individual components; more in-depth research on the mutual interactions following compatibility with licorice is required. Given the still widespread clinical use of the rhubarb–licorice combination, understanding the essence of how licorice mitigates rhubarb’s harsh purgative properties from the perspective of pharmacological theory, and investigating the specific effects and mechanisms underlying this moderation, is of great significance. Such research can also provide valuable insights into the scientific underpinning of licorice’s reputed “harmonizing” function.

Analysis of the Patterns and Mechanisms of Physicochemical Property Changes During the Drying Process of Traditional Chinese Medicinal Materials

The Most Comprehensive Collection of Traditional Chinese Medicine Mnemonics in History—All Here!

Analysis of the Patterns and Mechanisms of Physicochemical Property Changes During the Drying Process of Traditional Chinese Medicinal Materials

The Most Comprehensive Collection of Traditional Chinese Medicine Mnemonics in History—All Here!

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