The Regulatory Effects of Natural Products on Intestinal Flora

The intestinal flora is an important component of the intestinal microecosystem, and humans have formed a mutually beneficial symbiotic relationship with the intestinal flora during the long process of evolution. Once affected by changes in the host's own or external environment, the balance between the host and the flora will be disrupted, leading to the imbalance of the intestinal microecosystem and dysfunction of various functions of the body, which may further lead to diseases.

Natural products have been identified for treating diseases related to intestinal flora disorders, such as diarrhea, obesity, colorectal cancer, and others. A large number of studies have shown that natural products exert their influence on host health by directly inhibiting or promoting the growth of certain bacteria, altering the structure and composition of intestinal flora, and restoring the balance of imbalanced flora. Natural products can also exert pharmacological effects by changing the content of metabolites produced by the flora. These metabolites mainly include short-chain fatty acids, tryptophan, indoles and their derivatives, bile acids, and trimethylamine oxide (TMAO), which play an important role in maintaining the normal immune function of the host's intestine. Additionally, natural products can regulate the secretions of intestinal flora, maintain the structural integrity of the intestinal mucosal barrier, and indirectly change the composition and diversity of intestinal flora. For example, natural products stimulate intestinal mucus secretion, providing nutrients for bacteria such as Lactobacillus and Akkermansia, thereby maintaining intestinal homeostasis.

1. Regulation of intestinal flora composition

Research has found that the extract of Ganoderma lucidum (Lingzhi) not only reduces the elevated ratio of Firmicutes to Bacteroidetes induced by a high-fat diet and the level of endotoxin-producing Proteobacteria, but also maintains the integrity of the intestinal barrier and reduces the occurrence of endotoxemia. When the treated mouse feces were transplanted to other obese mice, the beneficial metabolic effects caused by the Ganoderma lucidum extract were reproduced.

The extracts of red ginseng and coix seed both promote the growth of probiotics such as Lactobacillus and Bifidobacterium in vitro, while inhibiting the growth of pathogens like Escherichia coli, Staphylococcus, and Salmonella. A pharmacodynamic evaluation using a model of ulcerative colitis induced by trinitrobenzene sulfonic acid (TNBS) showed that both the extracts of red ginseng and coix seed can improve intestinal flora imbalance and colitis symptoms, with the extract of red ginseng exhibiting a better effect.

Berberine can reduce the abundance of pathogenic Desulfovibrio species and increase the abundance of beneficial bacteria, Mucispirillum schaedleri, thereby alleviating ulcerative colitis (UC) symptoms in mice. Berberine can also increase the abundance of Firmicutes strains and decrease the abundance of Bacteroidetes strains, leading to changes in short-chain fatty acid content. Specifically, it down-regulates the levels of acetic acid and propionic acid among the short-chain fatty acids while increasing the content of isovaleric acid.

The polymethoxyflavones in citrus fruits can significantly increase the abundance of bacteria such as Lactobacillus and Akkermansia, thus enriching the composition of intestinal flora. Additionally, polymethoxyflavones can also promote the growth of Bacteroides ovatus and lower the ratio of Firmicutes to Bacteroidetes, indicating that they can regulate intestinal beneficial bacteria and increase their number, thereby reducing lipid accumulation in mice fed a high-fat diet and alleviating metabolic syndrome.

Guava polysaccharides can restore the ratio of Firmicutes to Bacteroidetes, promote the growth of beneficial bacteria such as Clostridium XIVa, and inhibit the growth of inflammation-related bacteria. Research results have shown that guava polysaccharides improve the metabolic level of obese mice induced by a high-fat diet through modulating intestinal flora composition.

The extracts of Pogostemon cablin (Blanco) Benth. (patchouli alcohol, patchouli ketone, and β-patchoulene) can significantly increase the abundance of beneficial bacteria such as Butyrivibrio fibrisolvens, Clostridium jejuni, and Eubacterium uniforme, demonstrating that Pogostemon cablin can improve intestinal flora and produce effects similar to prebiotics.

The extract of Penthorum chinense Pursh (Ganhuangcao) can reduce the relative abundance of intestinal bacteria that produce bile salt hydrolase enzymes, such as Clostridium IV, Lactobacillus, and Clostridium XIVa. The reduction of these bacteria can inhibit the dissociation of taurocholic acid, thus improving the symptoms of non-alcoholic fatty liver disease in mice induced by a high-fat diet.

In addition, saponins extracted from the Chinese medicinal herb Gynostemma pentaphyllum (Jiaogulan) can promote the colonization of beneficial intestinal bacteria, reduce the abundance of sulfate-reducing bacteria, and inhibit cachexia-like symptoms in ApcMin/+ mice. Extracts from Dangshen (Codonopsis pilosula), Yunmuxiang (Saussurea costus), Dabaimao (Imperata cylindrica), and Chuanlianzi (Melia toosendan) can also increase the content of antibacterial peptides in the intestine, significantly affecting the composition of intestinal flora.

2.Protecting the intestinal mucosal barrier function and preventing bacterial translocation

In addition to influencing the composition and number of intestinal bacteria, natural products can also indirectly affect the positioning of the flora by protecting the intestinal mucosal barrier. The normal intestinal mucosal barrier can effectively prevent intestinal bacteria and endotoxins from crossing the intestinal mucosa, avoiding intestinal-derived infections. It has been discovered that traditional Chinese medicine and its compounds and preparations, which are the main sources of natural products, have a significant protective effect on the intestinal mucosal barrier.

In a study examining the protective effects of rhubarb on intestinal barriers in septic piglets, it was found that the apoptosis of intestinal epithelial cells in the rhubarb treatment group was significantly reduced. The expression of tight junction proteins ZO-1 and Occludin mRNA was significantly increased compared to the model group. Electron microscopy showed that the tight junctions were relatively intact. Furthermore, the expression of TNF-α mRNA was reduced, while the expression of IL-10 mRNA was enhanced. Malondialdehyde content was reduced, and superoxide dismutase activity increased. This indicates that rhubarb exerts a protective effect on the intestinal mucosal barrier in septic piglets by reducing intestinal epithelial cell apoptosis and increasing tight junction protein expression through its anti-inflammatory and anti-oxidative damage properties.

Matrine has been found to promote the expression of tight junction proteins such as Zonula Occludens-1 (ZO-1) and Occludin, increase the number of mucin-producing cells, and enhance the expression of Mucin-2. This, in turn, strengthens the defense function of the intestinal lamina propria mucosa, prevents the invasion of pathogenic bacteria, and remodels the composition of intestinal flora, effectively improving the symptoms of dextran sulfate sodium (DSS)-induced ulcerative colitis (UC) in mice.

On the other hand, ginsenoside Rg1 can increase the abundance of Lactobacillus and other beneficial bacteria, regulate tryptophan (Trp) metabolism, and increase the levels of nicotinamide, indole-3-carbaldehyde, and 3-indolepropionic acid metabolites. These effects enhance the protective function of the intestinal barrier and reduce the inflammatory level in mice with ulcerative colitis.

Polysaccharides extracted from Undaria pinnatifida, a type of seaweed, have been shown to improve metabolic syndrome and intestinal inflammation by maintaining the structural integrity of mucins, reducing lipopolysaccharide levels, reducing the degree of colonic tissue damage, and reshaping the gut microbiota in mice with a high-fat diet.

In an experiment investigating the effects of the traditional Chinese medicine compound Qingchangshuan on colonic mucosal permeability in rats with ulcerative colitis induced by trinitrobenzenesulfonic acid (TNBS), it was found that Qingchangshuan effectively inhibited the increase in colonic permeability, improved intestinal mucosal barrier function, and promoted ulcer healing in colitis rats.

The traditional Chinese medicine preparation Shenfu Injection can inhibit the expression of nuclear factor-κB in intestinal tissue, reduce the production of tumor necrosis factor-α, intercellular adhesion molecule-1, and inducible nitric oxide synthase, thus protecting the intestinal mucosal barrier in rats with acute necrotizing pancreatitis.

3.Regulation of Gut Microbiota Metabolites

The metabolites produced by gut microbiota, such as amino acids, vitamins, bile acids, short-chain fatty acids, indoles, and their derivatives, play a regulatory role in the pathological state of the body and are crucial for improving disease progression and prognosis through gut microbiota. Multiple research results have shown that the regulation of gut microbiota metabolites by natural medicines is closely related to the physiological and pathological processes of the body. Therefore, maintaining the balance of gut microbiota and regulating the production of microbial functional metabolites have become new approaches and hotspots in the research of natural product mechanisms.

① Vitamins and Amino Acids

Beneficial intestinal bacteria in the body, such as Bifidobacterium, can produce various vitamins that are essential for the body's metabolism but cannot be synthesized by the body itself, including B vitamins, vitamin K, pantothenic acid, and niacin. Some intestinal microorganisms can also synthesize amino acids that the body cannot produce, such as phenylalanine, aspartic acid, and valine. The Qiwei Baishu Powder, a reformulated traditional Chinese medicine prescription based on the Four Gentlemen Decoction with additional herbs like Patchouli, has shown good therapeutic effects on pediatric enteritis and diarrhea caused by spleen deficiency and dampness. Research has indicated that Qiwei Baishu Powder can promote the growth of beneficial bacteria such as Bifidobacterium, yeast, and lactic acid bacteria, increase the expression of amino acids and B vitamins in yeast, enhance the catalytic activity of yeast enzymes, and improve intestinal digestion and absorption functions.

② Short-Chain Fatty Acids

Short-chain fatty acids (SCFAs), produced by the metabolism of intestinal lactic acid bacteria and Bifidobacterium, can maintain electrolyte balance, have anti-inflammatory effects, regulate the immune system, and fight cancer. Puerarin can increase the total content of SCFAs in the intestine of postmenopausal osteoporotic rats, regulate the functions of various immune cells in intestinal epithelial cells and intestinal mucosal tissue, thus maintaining the integrity of the intestinal mucosa, reducing the incidence of inflammation, and improving the symptoms of postmenopausal osteoporosis. The Four Gentlemen Decoction, a traditional Chinese medicine prescription for tonifying qi and strengthening the spleen, can effectively inhibit harmful bacteria in the intestine, promote the growth of probiotics, restore the intestinal flora homeostasis of rats with inflammation, and indirectly increase the metabolism of SCFAs. Traditional Chinese medicine compounds like Huanglian Jiedu Tang (Coptis Decoction), Jinqi Jiangtang Pian (Golden Millet and Astragalus Tablet), and Xiexin Tang (Purgative Decoction) are commonly used for preventing and treating metabolic diseases. They can improve glucose and lipid metabolism and regulate various physiological and pathological reactions by modulating intestinal bacteria and the production of SCFAs.

③ Trimethylamine Oxide (TMAO) and Bile Acids

Trimethylamine oxide (TMAO) is formed by the oxidation of trimethylamine, a metabolite of intestinal bacteria, by flavin monooxygenase in the liver. Studies have shown that TMAO can significantly weaken the enzyme's metabolic effect on cholesterol, and excessive accumulation of cholesterol can easily lead to cardiovascular diseases. Research indicates that resveratrol can optimize the structure of intestinal microbiota, reduce the production of TMAO and the reabsorption of bile salts, upregulate the activity of bile salt hydrolase, promote cholesterol metabolism, and lower the risk of disease in the body.

References

[1] Ding Jinwen, Lin Yuan, Jiang Jiandong. Research Progress on the Interaction between Gut Microbiota and Natural Products [J]. Chinese Journal of Medical Biotechnology, 2024, 19(01): 52-56.

[2] Zu Xianpeng, Lin Zhang, Xie Haisheng, et al. Research Progress on the Interaction between Active Ingredients of Traditional Chinese Medicine and Gut Microbiota [J]. China Journal of Chinese Materia Medica, 2016, 41(10): 1766-1772.

[3] Yuan Fuwei, Yong Yan, Zhang Guijun, et al. Research Progress on the Interaction between Traditional Chinese Medicine and Animal Gut Microbiota in Intervening Body Functions [J]. Progress in Veterinary Medicine, 2023, 44(03): 89-93.

About the Author

Xiaomichong, a pharmaceutical quality researcher, has long been committed to the research of drug quality and the validation of drug analysis methods. Currently, she works in a large domestic pharmaceutical research and development company, engaged in drug inspection, analysis, and analytical method validation.