The Impact of Intestinal Flora on the Effective Components of Traditional Chinese Medicine

The intestinal flora can produce a variety of enzymes, mainly including α-rhamnosidase, β-glucosidase, β-galactosidase, nitroreductase, 7α-hydroxylase, proteases, and multiple carbohydrate-active enzymes (CAZymes). Components of traditional Chinese medicine can undergo biotransformation through these enzymes, resulting in the production of more bioavailable active metabolites.

The human intestine harbors approximately 100 trillion bacteria, with over 99% belonging to the phyla of Firmicutes, Bacteroidetes, Actinobacteria, and Proteobacteria. Among them, Firmicutes and Bacteroidetes are particularly abundant, accounting for approximately 64% and 23% respectively. Other bacteria such as Archaea, Deferribacteres, Fusobacteria, Spirochaetes, Verrucomicrobia, Melainabacteria, etc., make up less than 1%. Based on the relationship between intestinal bacteria and the host, the vast number of bacteria can be broadly classified into three categories: ① Beneficial bacteria: such as the genera of Bifidobacterium, Lactobacillus, and Akkermansia; ② Pathogenic bacteria: such as the genera of Desulfovibrio, the Clostridium species including Clostridium difficile and Clostridium perfringens, as well as the Staphylococcus species including Staphylococcus aureus; ③ Opportunistic pathogens: such as the Escherichia species including Escherichia coli, the Enterococcus genus, the Bacteroides species including Bacteroides fragilis, and the Acinetobacter species including Acinetobacter baumannii.

The intestinal flora can produce a diverse range of enzymes, primarily including α-rhamnosidase, β-glucosidase, β-galactosidase, nitroreductase, 7α-hydroxylase, proteases, and various carbohydrate-active enzymes (CAZymes). The components of traditional Chinese medicine (TCM) can undergo biotransformation through these enzymes, resulting in the production of more bioavailable and active metabolites. Furthermore, the intestinal flora can also alter the properties of toxic components found in natural products, thereby exerting various effects on the host's health.

1.The intestinal flora metabolizes the active ingredients of traditional Chinese medicine, enhancing absorption and improving efficacy.

Under the influence of intestinal flora, the components of traditional Chinese medicine undergo hydrolysis, oxidation, and reduction reactions, making them easier to absorb, metabolize, and even produce new active substances. This results in an enhanced activity of the traditional Chinese medicine.

① Alkaloids. Berberine, which is poorly soluble in water, can be converted into dihydroberberine by the nitroreductase produced by 14 intestinal bacteria such as Staphylococcus aureus, Enterococcus faecium, and Acinetobacter baumannii. This conversion increases its absorption by five times. After being absorbed by the gastrointestinal tract, dihydroberberine can be oxidized back into berberine and enter the bloodstream, thus enhancing the bioavailability of berberine. Additionally, studies have found that Lactobacillus acidophilus and Escherichia coli can convert berberine into oxo-berberine, which also exhibits good anti-inflammatory, anti-arrhythmic, and antifungal activities.

② Flavonoids. Most flavonoid compounds undergo reactions such as hydrolysis, reduction, dehydroxylation, and other transformations under the influence of intestinal flora, converting them into simpler phenolic acids that are easily absorbed by the body and exert significant therapeutic effects. Catechin, a flavonoid with strong antioxidant activity, has low bioavailability. Under the action of intestinal bacteria and Eggerthella species, catechin is metabolized into γ-valerolactone. Compared to catechin, γ-valerolactone produced through intestinal flora metabolism exhibits significant antioxidant activity. Baicalin cannot be directly absorbed and can only enter the bloodstream and increase its bioavailability after being converted into baicalein through the action of intestinal flora. Research has found that Escherichia coli and Lactobacillus brevis can hydrolyze baicalin into baicalein and oroxylin A, and the active products after microbiota metabolism have anti-tumor and intestinal inflammation-suppressing effects. Apigenin can be metabolized by Bacillus globigii into small molecule acidic substances, exhibiting antiviral effects that are superior to the original form. Flavonoid compounds from citrus fruits are converted into active aglycones by intestinal flora, such as hesperidin being converted into hesperetin by Bifidobacterium pseudolongum. Due to the lack of glycoside moieties, hesperetin is more easily absorbed by the intestine, thus exerting neuroprotective effects.

③Saponins. Natural saponins generally have strong polarity and low bioavailability, making them difficult to be absorbed by the intestine. Modern pharmacokinetic studies have shown that under the action of intestinal flora, most saponins can be metabolized into secondary glucosides and aglycones, increasing their fat solubility and promoting the absorption and utilization of saponins. For example, in an experiment on the biotransformation of saponins in the host intestine using Bifidobacterium adolescentis and Lactobacillus rhamnosus, four metabolites, namely ginsenoside F1, ginsenoside Rh2, ginsenoside CK, and protopanaxatriol, were detected in the plasma of normal rats, but not in the plasma of pseudo-germ-free rats, indicating that intestinal flora plays an important role in the biotransformation process of saponins from Panax notoginseng.

④ Polysaccharides. Most polysaccharides cannot be directly digested and absorbed by the human body, but they can be degraded by various CAZymes produced by intestinal flora into short-chain fatty acids and lactic acid, thus exerting biological activities. There are differences in the number and composition ratio of CAZymes carried by different intestinal flora, and polysaccharides tend to enrich specific flora during the fermentation process, such as Bacteroides and Clostridium. Research has shown that after long-term administration of ginseng polysaccharides to rats, the content of short-chain fatty acids such as acetic acid, isobutyric acid, and butyric acid in the colon content significantly increased, indicating that ginseng polysaccharides can produce secondary metabolites under the action of intestinal flora, thus exerting a similar effect to prebiotics. Fungal polysaccharides can be digested by intestinal flora to produce short-chain fatty acids that can induce intestinal cells to secrete glucagon-like peptide-1 (GLP-1), which can coordinate the regulation of the functions of skeletal muscle, adipose tissue, and liver tissue, delay gastric emptying, improve blood glucose homeostasis and insulin sensitivity, and thus have therapeutic effects on obesity. Glycyrrhizic acid undergoes hydrolysis and esterification by intestinal flora to produce 18α-glycyrrhetic acid and 18β-glycyrrhetic acid, the latter inhibiting the growth of gastric epithelial mucosa in K19-C2mE transgenic mice by inhibiting the expression of COX-2 enzyme and improving the inflammatory microenvironment.

⑤ Others. Traditional Chinese medicine ingredients such as arctigenin, lariciresinol, matairesinol, and linseed lignans require a series of reactions such as glycoside hydrolysis, demethylation, and dehydroxylation under the action of intestinal bacteria like Mucispirillum schaedleri and Eggerthella lenta to metabolize into enterolactone and enterodiol before exhibiting pharmacological activities. The active component that enables rhubarb to exert its purgative effect is anthraquinone glycoside, of which the main active ingredient is sennoside. However, sennoside itself does not have a purgative effect; it can only exert its efficacy after being hydrolyzed by β-D-glucosidase secreted by intestinal Bifidobacteria to produce rhein anthrone and rhein. This demonstrates that intestinal flora plays a crucial role in the process of sennoside exerting its purgative effect. Sulfoglucosides can be converted into sulforaphane under the action of intestinal flora, further reducing intestinal mucosal damage caused by indomethacin. With the assistance of intestinal flora, the metabolite urolithin A produced by the metabolism of ellagitannins and ellagic acid can improve cognitive impairment in APP/PS1 mice by reducing the levels of IL-6, IL-1β, and TNF-α in the cerebral cortex and hippocampus, exhibiting more significant neuroprotective effects.

2、The Impact of Intestinal Flora on the Toxicity of Traditional Chinese Medicines

Under the action of intestinal flora, traditional Chinese medicines undergo a series of biological transformations, leading to changes in their composition, which may result in a reduction or enhancement of their original toxicity.

①Reduction of toxicity. Aconitine, a major toxic component found in medicinal plants such as Aconitum carmichaeli, Aconitum kusnezoffii, and Radix Aconiti Lateralis Preparata, has pharmacological effects such as anti-inflammatory, analgesic, and anti-tumor properties. However, it also has significant toxic side effects on the central nervous system and cardiovascular system. Research has shown that under the metabolic action of intestinal bacteria, aconitine undergoes deacylation, demethylation, dehydroxylation, and esterification reactions to produce various metabolites with weaker toxicity, including new monoester, diester, and lipid alkaloids. Notably, these lipid alkaloids possess similar pharmacological activities to aconitine but have significantly lower toxicity.

②Toxicity enhancement. The metabolism of certain ingredients in traditional Chinese medicines by intestinal flora may also increase their toxicity. For example, geniposide, a component of Gardenia jasminoides, is not hepatotoxic in itself. However, after being metabolized into its aglycone genipin in the body, it exhibits significant hepatotoxicity. Strychnine and brucine are highly toxic components of Strychnos nux-vomica, a poisonous traditional Chinese medicine. After processing, the content of these highly toxic components decreases, while the content of less toxic nitrogen oxides of strychnine and brucine increases. Under the action of intestinal flora, the less toxic nitrogen oxides of strychnine and brucine are reduced back to the highly toxic strychnine and brucine, resulting in an increase in toxicity. Amygdalin, an active ingredient in the traditional Chinese medicine bitter almond, is now widely used in the treatment of asthma, bronchitis, emphysema, constipation, and as an adjuvant anticancer drug. Animal experiments have shown that compared to the normal oral administration group, there were no significant toxic reactions in the intravenous injection group and the antibiotic-treated oral administration group, and the plasma cyanide concentration in both groups was lower than that in the normal oral administration group. Furthermore, amygdalin injected into rats is mainly distributed and excreted in its original form, while amygdalin administered orally is distributed in the form of its metabolite prunasin, which is further deglycosylated to produce phenylacetonitrile. Phenylacetonitrile decomposes to produce the toxic substance hydrogen cyanide (HCN), causing toxic reactions. This indicates that intestinal flora is a key factor in the toxicity of amygdalin.

References

[1] Ding Jinwen, Lin Yuan, Jiang Jiandong. Research progress on the interaction between intestinal flora and natural products [J]. Chinese Medical Biotechnology, 2024,19(01):52-56.

[2] Zu Xianpeng, Lin Zhang, Xie Haisheng, et al. Research progress on the interaction between effective components of traditional Chinese medicine and intestinal flora [J]. China Journal of Chinese Materia Medica, 2016,41(10):1766-1772.

[3] Sun Jian, Li Jing, Peng Xingwu. Research progress on the interaction between traditional Chinese medicine and intestinal flora [J]. Shandong Animal Science and Veterinary Medicine, 2021,42(05):74-76.