The linkage of gut microbiota and the property theory of traditional Chinese medicine (TCM): Cold-natured and sweet-flavored TCMs as an example.

The property theory of traditional Chinese medicine (TCM) is a unique medical theory based on an extensive clinical practice for thousands of years, which guides TCM doctors choosing proper medicines to treat specific diseases. The nature and flavor of TCM are a high generalization of drug's characteristics according to the property theory. Despite intensive investigations, the modern interpretation of TCM property theory still confronts several challenges, which greatly hampers the elucidation of TCM's mechanisms as well as its application. Compelling evidence has proved that gut microbiota may be a potential indicator for TCM's efficacy and mechanism. Nevertheless, at present, the relationship between the gut microbiota and the nature and flavor of TCM has not been fully elucidated. To fill the gap in this field, we developed a comprehensive study to investigate the relationship between gut microbial community and TCM's property. We searched "PubMed" and "China National Knowledge Infrastructure (CNKI)" with the key word "gut microbiota", and screened the published articles related to TCM. In this review, we mainly applied cold-natured and sweet-flavored TCMs as an example to explore the modulation of cold-natured and sweet-flavored TCMs on gut microbiota, and identify the potential relationship between the alterations of gut microbiota and TCM's efficacy. We found cold-natured and sweet-flavored TCMs possess several pharmacological activities and generally enrich beneficial bacteria like Akkermansia, Bacteroides, Lactobacillus and Bifidobacterium, which is in good accordance with their pharmacological effects. Simultaneously, these TCMs reduce the relative abundance of some harmful bacteria belonging to Firmicutes (Streptpcoccus, Enterococcus, Turicibacter, Anaerostipes and Oscillibacter) and Proteobacteria (Helicobacter, Enterobacter, Sutterella, Klebsiella, Desulfovibrio, Escherichia coli and Campylobacter jejuni). These results indicate that there are some intrinsic correlations between gut microbiota and the property of TCM, and gut microbiota may serve as a potential indicator to reflect the property of TCM. This pilot but comprehensive review provides an interesting proposal that the ancient theory of TCM property may be interpreted by the modern biological findings in gut microbiome.

Yang Y ，Wu C 《-》

From ancient wisdom to modern science: Gut microbiota sheds light on property theory of traditional Chinese medicine.

The property theory of traditional Chinese medicine (TCM) has been practiced for thousands of years, playing a pivotal role in the clinical application of TCM. While advancements in energy metabolism, chemical composition analysis, machine learning, ion current modeling, and supercritical fluid technology have provided valuable insight into how aspects of TCM property theory may be measured, these studies only capture specific aspects of TCM property theory in isolation, overlooking the holistic perspective inherent in TCM. To systematically investigate the modern interpretation of the TCM property theory from multidimensional perspectives, we consulted the Chinese Pharmacopoeia (2020 edition) to compile a list of Chinese materia medica (CMM). Then, using the Latin names of each CMM and gut microbiota as keywords, we searched the PubMed database for relevant research on gut microbiota and CMM. The regulatory patterns of different herbs on gut microbiota were then summarized from the perspectives of the four natures, the five flavors and the meridian tropism. In terms of the four natures, we found that warm-natured medicines promoted the colonization of specific beneficial bacteria, while cold-natured medicines boosted populations of some beneficial bacteria while suppressing pathogenic bacteria. Analysis of the five flavors revealed that sweet-flavored and bitter-flavored CMMs positively influenced beneficial bacteria while inhibiting harmful bacteria. CMMs with different meridian tropism exhibited complex modulative patterns on gut microbiota, with Jueyin (Liver) and Taiyin (Lung) meridian CMMs generally exerting a stronger effect. The gut microbiota may be a biological indicator for characterizing the TCM property theory, which not only enhances our understanding of classic TCM theory but also contributes to its scientific advancement and application in healthcare. Please cite this article as: Yang YN, Zhan JG, Cao Y, Wu CM. From ancient wisdom to modern science: Gut microbiota sheds light on property theory of traditional Chinese medicine. J Integr Med 2024; 22(4): 413-445.

Yang YN ，Zhan JG ，Cao Y ，Wu CM ... -  《Journal of Integrative Medicine-JIM》

Traditional Chinese medicines (TCMs) with varied meridians (Gui-Jing) differentially alleviate the adverse impact of Coptis chinensis on gut microbiota.

The meridian (GuiJing) theory is a unique theory of traditional Chinese medicine (TCM) which has been guiding the clinical practice of TCM for thousands of years, but physiological foundation of TCM's meridian remains to be clarified. Recent investigations have marked gut microbiota as a key mediator for the pharmacological effects of various TCMs. However, most studies focus on the response of gut microbes to a single drug or formula, the interactive effects of different drugs on gut microbiota are scarcely investigated. In this work, we evaluated the co-regulatory effects of different TCMs on gut microbiota when they were individually combined with Coptis chinensis (HL), and assessed the relationship between gut microbiota and the GuiJing of TCMs. Normal C57BL/6 mice were gavaged with HL extract for 14 days to disrupt the gut microbial community. Simultaneously, animals were treated with different TCMs which all possess antimicrobial activity but belong to different meridians. The gut microbiota was analyzed by full-length 16S rRNA gene amplicon sequencing to get a thorough bacterial profile at the species level. Administration of HL dramatically disrupted the gut microbiota and decreased the alpha diversity. Co-administration of different TCMs alleviated the adverse impact of HL on gut microbiota in a meridian-dependent manner. TCMs belonging to Shaoyin meridian moderately shifted the gut microbiota, while TCMs belonging to Taiyin and especially Jueyin meridians remarkably recovered the gut microbial community to the normal status. Decreased Firmicutes (Clostridia and Bacilli) and Actinobacteria (Bifidobacteriales) and increased Proteobacteria (Enterobacteriaceae) were main features of HL-induced gut dysbiosis. TCMs belonging to Shaoyin, Taiyin and Jueyin meridians gradually reversed the abundance of these bacteria to their normal levels. Simultaneously, the promoting effect of HL on beneficial bacteria such as Akkermansia muciniphila and Blautia coccoides was substantially preserved when co-administration of these TCMs, suggesting that co-treatment with these TCMs may reduce the toxicity of HL without deteriorating its beneficial effects. Combination of special TCMs may alleviate the adverse effect of HL on gut microbiota while preserving its beneficial actions. Gut microbiota may be a potential biological indicator of the meridian of TCMs.

Yang Y ，Su W ，Zang C ，Tan Y ，Zhang Y ，Zhou Z ，Lu W ，Wu S ，Zhang X ，Wu C ... -  《-》

Traditional Chinese medicines differentially modulate the gut microbiota based on their nature (Yao-Xing).

Property theory is a unique principle guiding traditional Chinese medicine (TCM) that classifies various TCMs into four natures (hot, warm, cool, and cold) to reflect their medical actions on the human body. Despite successful application for thousands of years, characterizing the nature of medical TCMs by modern physiological indicators remains a challenge. In this study, we investigated the potential relationship between the nature of TCMs and their modulation of the gut microbiota. We selected twelve TCMs with hot, warm, cool, or cold natures that possess antidiarrheal effects. Their aqueous extracts were orally administered to C57BL/6 mice at a clinical dose for 4 weeks. The gut microbiota was measured by 16S rRNA-based metagenomics, and the correlation between microbial composition/function and TCM nature was analyzed. Antidiarrheal TCMs with different natures showed distinct impacts on the gut microbiota. Hot-natured TCMs had no influence on the gut microbiota, warm-natured TCMs had a moderate influence, cool-natured TCMs had a strong influence, and cold-natured TCMs substantially changed the structure of the gut microbial community. The abundance of Anaerotruncus, Tyzzerella and Ruminiclostridium steadily increased, while that of Ruminococcaceae_UCG-010, Parasutterella and Bifidobacterium continuously decreased as the herbal nature turned from cold to hot. Microbiome functional prediction for Cluster of Orthologous Groups (COG) of proteins and Kyoto Encyclopedia of Genes and Genomes (KEGG) categories showed that colder TCMs imposed a stronger influence on microbial functional repertoires. Specifically, the abundance of ABC transporters, key bacterial proteins involved in nutrient absorption and drug resistance, was gradually decreased by colder TCMs. Our results demonstrated that the nature of TCMs could be reflected by their modulation of gut microbes. Cold TCMs may exert their antidiarrheal effects, at least partially, by modulating the gut microbiota, while hot TCMs may alleviate dysentery in other ways.

Zhang X ，Yang Y ，Zhang F ，Yu J ，Sun W ，Wang R ，Wu C ... -  《-》

Potential efficacy and mechanism of eight mild-natured and bitter-flavored TCMs based on gut microbiota: A review.

The mild-natured and bitter-flavored traditional Chinese medicines (MB-TCMs) are an important class of TCMs that have been widely used in clinical practice and recognized as safe long-term treatments for chronic diseases. However, as an important class of TCMs, the panorama of pharmacological effects and the mechanisms of MB-TCMs have not been systemically reviewed. Compelling studies have shown that gut microbiota can mediate the therapeutic activity of TCMs and help to elucidate the core principles of TCM medicinal theory. In this systematic review, we found that MB-TCMs commonly participated in the modulation of metabolic syndrome, intestinal inflammation, nervous system disease and cardiovascular system disease in association with promoting the growth of beneficial bacteria Bacteroides, Akkermansia, Lactobacillus, Bifidobacterium, Roseburia as well as inhibiting the proliferation of harmful bacteria Helicobacter, Enterococcus, Desulfovibrio and Escherichia-Shigella. These alterations, correspondingly, enhance the generation of protective metabolites, mainly including short-chain fatty acids (SCFAs), bile acid (BAs), 5-hydroxytryptamine (5-HT), indole and gamma-aminobutyric acid (GABA), and inhibit the generation of harmful metabolites, such as proinflammatory factors trimethylamine oxide (TAMO) and lipopolysaccharide (LPS), to further exert multiplicative effects for the maintenance of human health through several different signaling pathways. Altogether, this present review has attempted to comprehensively summarize the relationship between MB-TCMs and gut microbiota by establishing the TCMs-gut microbiota-metabolite-signaling pathway-diseases axis, which may provide new insight into the study of TCM medicinal theories and their clinical applications.

Su W ，Yang Y ，Zhao X ，Cheng J ，Li Y ，Wu S ，Wu C ... -  《-》