Effect of Intestinal Flora on Active Ingredients in Traditional Chinese Medicine

There are about 100 trillion bacteria in the human gut, of which more than 99% belong to Firmicutes, Bacteroides, Actinomycetes and Proteobacteria, especially Firmicutes and Bacteroidetes, accounting for about 64% each and 23%. Other bacteria such as Archaea, Ferrobacterium, Clostridium, Spirochet, Verrucous Microbacteria, and Black Narcissus accounted for less than 1%. According to the relationship between intestinal bacteria and hosts, the large number of bacteria can be roughly divided into three categories: (1) beneficial bacteria, such as Bifidobacteria, Lactobacillus and Ackermansi; (2) Pathogens: such as Vibrio desulfurization, Clostridium difficile in Clostridium spp., Clostridium perfringens and Staphylococcus aureus in Staphylococcus spp.; (3) Conditionally pathogenic bacteria: such as Escherichia coli in Escherichia spp., Enterococci spp., Bacteroides fragilis in Bacteroides spp., and Acinetobacter baumannii in Acinetobacter spp. 

The gut microbiota can produce a variety of enzymes, mainly α-rhamnosidase, β-glucosidase, β-galactosidase, nitroreductase, 7α-hydroxylase, protease, and a variety of carbohydrate-active enzymes，CAZymes. TCM components can be biotransformed through the various enzymes mentioned above to produce active metabolites with higher bioavailability. In addition, the gut microbiota can also alter the properties of the toxic components of natural products, which in turn can have different effects on host health. 

1. The intestinal flora metabolizes the active ingredients of traditional Chinese medicine, enhances absorption, and improves drug efficacy

Under the action of intestinal flora, the components of traditional Chinese medicine will undergo hydrolysis, oxidation and reduction reactions, so that the components of traditional Chinese medicine are easier to absorb, metabolize and even produce new active substances, and the efficacy of traditional Chinese medicine will be enhanced by activity. 

(1) Alkaloids. Berberine is insoluble in water, and can be converted into dihydroberberine by nitroreductase produced by 14 kinds of intestinal bacteria such as Staphylococcus aureus, Enterococcus faecium, and Acinetobacter baumannii, and the absorption can be increased by 5 times. Dihydroberberine is absorbed by the gastrointestinal tract and can be oxidized into berberine into the bloodstream, thereby enhancing the bioavailability of berberine. In addition, studies have also found that Lactobacillus acidophilus and Escherichia coli can convert berberine to oxyberberine, which also exhibits good anti-inflammatory, antiarrhythmic, and antifungal activities.

(2) Flavonoids. Most flavonoids undergo hydrolysis, reduction, dehydroxylation and other reactions through the action of intestinal flora and are converted into simple phenolic acids, which are easily absorbed by the body and thus exert significant efficacy. Catechins are a class of flavonoids with strong antioxidant activity, but the bioavailability is not high, and catechins are metabolized to γ-penterolactone under the action of intestinal bacteria and Eggertella. Compared with catechins, γ-penterolactone, which is metabolized by the gut microbiota, exhibits significant antioxidant activity. Baicalin cannot be absorbed directly, and can only be converted into baicalin through the action of intestinal flora to enter the blood circulation and improve bioavailability. Studies have found that Escherichia coli and Lactobacillus breve can hydrolyze baicalin into baicalein and melaleucin A, and the active products metabolized by the microflora have anti-tumor and intestinal inflammation effects. Apigenin can be metabolized by Bacillus circularis into small molecule acidic substances and exhibits superior antiviral effects than the prototype. Citrus flavonoids are converted into active aglycones by the intestinal flora, such as hesperidin by Pseudosmall-chain Bifidobacterium to hesperetin, which is more easily absorbed by the intestine due to the lack of glycoside moiety and thus exerts neuroprotective effects. 

(3) Saponins. Natural products of saponins are generally highly polar and have low bioavailability, so they are not easily absorbed by the intestine. Modern pharmacokinetic studies have shown that most saponins can be metabolized into secondary glycosides and aglycones under the action of intestinal flora, increasing fat solubility, and then promoting the absorption and utilization of saponins. For example, Bifidobacterium adolescent and Lactobacillus rhamnosus were used in the biotransformation experiment of saponins in the host intestine and found that four metabolites, ginsenoside  F1, ginsenoside Rh2, ginsenoside CK and proginsenotriol, could be detected in the plasma of normal rats, but could not be detected in the plasma of pseudo-sterile rats. These results indicated that the intestinal microbiota plays an important role in the biotransformation of notoginseng saponins. 

(4) Polysaccharides. Most polysaccharides cannot be directly digested and absorbed by the body, but they can be degraded by a variety of CAZymes produced by the intestinal flora and converted into short-chain fatty acids and lactic acid, which exert biological activity. There are differences in the number and proportion of CAZymes carried by different intestinal microbiota, and polysaccharides will enrich specific microflora during fermentation, such as Bacteroides and Clostridium. Studies have shown that the content of short-chain fatty acids such as acetic acid, isobutyric acid, and butyric acid in colon contents increased significantly after long-term administration of ginseng polysaccharides in rats, indicating that ginseng polysaccharides can generate secondary metabolites under the action of intestinal flora, thereby playing a prebiotic-like role. Fungal polysaccharides can be digested by the intestinal flora to produce glucagon-like peptide-1 (GLP-1) that induces intestinal cells to secrete glucagon-like peptide-1) can synergistically regulate the function of skeletal muscle, adipose tissue and liver tissue, delay gastric emptying, improve blood glucose homeostasis and insulin sensitivity, and thus have a therapeutic effect on obesity. Glycyrrhizic acid is hydrolyzed and esterified by intestinal microbiota to produce 18α-glycyrrhetinic acid and 18β-glycyrrhetinic acid, the latter of which inhibits the growth of gastric epithelial mucosa in K19-C2mE transgenic mice by inhibiting the expression of COX-2 enzyme and improves the inflammatory microenvironment. 

(5) Miscellaneous. Traditional Chinese medicine ingredients such as burdock glycosides, larch resins, podocarpins, and flaxseed lignans need to undergo a series of reactions such as glycoside hydrolysis, demethylation, and dehydroxyl under the action of intestinal bacteria such as Eubacterium mucosinoides and Eggertella tardiforma to metabolize and generate intestinal lipid and enterodiol in order to produce pharmacological activity. The active ingredient of rhubarb that exerts a laxative effect is anthraquinone glycosides, where the main active ingredient is sennoside. However, sennoside itself has no laxative effect, and can only be effective after being hydrolyzed by  β-D-glucosidase secreted by Bifidobacterium intestinal to produce anthone and rhein rhein, indicating that the intestinal flora plays a key role in the process of laxative effect of sennoside. Glucosinolates can be converted to sulforaphane under the action of intestinal flora, which further reduces indomethacin-induced intestinal mucosal damage. Urolithin A produced by ellagitannin and ellagic acid metabolism in response to gut microbiota  improves  APP/PS1  by decreasing levels of IL-6, IL-1β, and TNF-α in the cerebral cortex and hippocampusCognitive impairment in mice, with more significant neuroprotective effects. 

2. The effect of intestinal flora on the toxicity of traditional Chinese medicine

Under the action of intestinal flora, the composition of traditional Chinese medicine has undergone a series of biotransformations, which may reduce the toxicity of the original traditional Chinese medicine or enhance the toxicity of traditional Chinese medicine.

(1) Attenuation. Aconitine is the main toxic component in medicinal plants such as Chuanwu, Caowu, and Aconite, which has anti-inflammatory, analgesic and anti-tumor pharmacological effects, but has obvious toxic side effects on the central nervous system and cardiovascular system. Studies have shown that aconitine is deacylated, methyl, hydroxyl and esterified under the action of intestinal bacterial metabolism to produce new monoesters, diaesters and lipid alkaloids and other less toxic metabolites, and lipid alkaloids have the same pharmacological activity as aconitine but its toxicity is significantly lower than that of aconitine.

(2) Toxicity. The intestinal microbiota metabolizes certain components of traditional Chinese medicine and may also increase its toxicity. For example, the ingredient gardeniside in gardenia itself has no hepatotoxicity, and gardeniside has significant hepatotoxicity after being metabolized into its aglycone genipine in vivo. Nux nux and strychnine are highly toxic components of the toxic Chinese medicine Nux nux nux, and the content of strychnine and strychnine in the highly toxic components of strychnine will be reduced after processing, and the nitrogen oxide content of strychnine and strychnine will be increased after processing. Under the action of intestinal flora, the nitrogen oxides of low-toxicity strychnine and strychnine will be reduced to high-toxicity strychnine and strychnine, thus showing enhanced toxicity. Amygdalin is an active ingredient in traditional Chinese medicine bitter almond, which has been widely used in the treatment of asthma, bronchitis, emphysema, constipation, etc., and is also used as an adjuvant anti-cancer drug. Animal experiments showed that compared with the normal oral gavage group, the intravenous group and the antibiotic-treated gavage group had no significant toxicity, and the plasma cyanide concentration was lower than that of the normal oral gavage group. In addition, amygdalin was mainly distributed and excreted in rats after injection and administration, and was distributed in the form of the metabolite wild amygdalin after intragastric administration, which was further deglycosylated and converted into phenylacetonitrile, which decomposed to form the toxic substance HCN hydrocyanate, causing toxic reactions, indicating that the intestinal flora is the key factor leading to the toxicity of amygdalin. 

References:

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[2]祖先鹏,林璋,谢海胜,等.中药有效成分与肠道菌群相互作用的研究进展[J].中国中药杂志,2016,41(10):1766-1772.

[3]孙健,李璟,彭兴武.中药与肠道菌群的相互作用研究进展[J].山东畜牧兽医,2021,42(05):74-76.

About the Author:

Xiaomichong

Xiaomichong is a researcher in drug quality, who has long been committed to the research of drug quality and the validation of drug analysis methods. Currently, Xiaomichong is employed by a large Chinese pharmaceutical research and development company, engaging in drug inspection and analysis as well as validation of analytical methods.