Traditional Chinese medicine (TCM) is a medicinal system that is thousands of years old and has been widely adopted for treating diseases. The precarious therapeutic approach of Western medicine has limited TCM application to the Chinese people only. To make TCM a good competitor with Western medicine, the Chinese government has established 16 TCM centers to modernize TCM application (Feng et al., 2017). Toward the moderation of TCM, OMICS is one of the imperative fields of research that can search for potential targets on which TCM acts and trigger downstream signaling cascades (Joshi et al., 2010).

Unlike Western drugs, TCM holistically improves body physiology against diseases and, therefore, is prescribed for holistic characterization of the patient’s syndrome by following the yin and yang and five elements theory, visceral meridian theory, etiology and pathogenesis theory, diagnosis, and therapy theory (Huang K. et al., 2021). TCM can be available in the form of decoction, powder, pill, and paste. Interestingly, the same ingredients can compose a prescription; however, different dosages can have distinct functions.

A bigger part of TCM is orally taken, which then passes through physiological changes, mainly, through the enzymatic activities that are secreted by trillions of gut-residing microbes (known as gut microbiota [GM]) and host cells. These activities can remodel the functional constituents of TCM. Importantly, GM display a critical role in host health even in the occurrence of disease. It is estimated that GM constitutes about 43% of the human body by cell count and encodes 100 times more genes than our body genes (Knight et al., 2017). According to the latest statistics, the human microbiome encodes 2-20 million genes, surpassing ∼20,000 human genes (Knight et al., 2017). These microbial genes are presented to hosts for various functions, including digestion, metabolism, and immune system maturation (Cani, 2009). The human GM (approximately 99%) is composed of bacteria. And, among the body parts, the gastrointestinal tract is more densely populated. These commensals inhabit the human gut with a magnitude of about 100 billion to 1 trillion bacterial cells in one gram of human stool (Hugon et al., 2015). A balanced GM is key to host health, and any dysbiosis in gut microbial composition could put the host at a risk for obesity, inflammatory bowel disease, diabetes, autism, rheumatoid arthritis, and colorectal cancer (CRC) (Musso et al., 2010; Stefka et al., 2014; Sun and Kato, 2016; Maeda and Takeda, 2017).

Most importantly, TCM–GM research is updating our understanding of disease prognosis and treatment. A growing trend is developing among TCM researchers to define the pharmacology of orally taken TCM by harnessing the potentials of the GM. TCM interacts with trillions of gut-residing microbes and their enzymes that present massive structural and functional changes. These microbes can affect the bioavailability and efficacy of the herbal therapeutics. Not only herbal medicine, but also the efficacy of Western medicines relies on the GM. For instance, the efficacy of cyclophosphamide, an anticancer immune-suppressant drug, is dependent on two intestinal commensals called Enterococcus hirae and Barnesiella intestinihominis (Viaud et al., 2013). This interaction also unmasks the holistic therapeutic approach of TCM and reveals the vital role of GM. With a growing understanding of TCM–GM, various GM-based therapeutic approaches are developing. However, being a new topic, there are questions that still need to be addressed: (a) How does TCM remodel GM diversity and composition? (b) How can the GM remodel TCM constituents and their function? (c) Does TCM function as a growth substrate for the GM? Nevertheless, the study of GM–TCM interaction has opened an exciting avenue for drug discovery and new drug targeting (El Kaoutari et al., 2013) (Chen F. et al., 2016). This review focuses on highlighting key achievements from TCM–GM research.

TCM–GM interaction employs a comprehensive approach and is making groundbreaking achievements in the field of disease prognosis and treatment. Since targeted intervention for remodeling GM composition has shown encouraging results in the field of disease prevention and treatment, in this regard, TCM has become one of the approaches through which GM composition is targeted and remodeled for predetermined therapeutic outcomes. Various TCM components, such as dietary fiber, phenolic compounds, and undigested carbohydrates, are proven to upregulate the growth of beneficial intestinal microbes, improve gut homeostasis, and alleviate disease symptoms (Makki et al., 2018). For example, several studies show GM remodeling effects of saponins, naturally occurring compounds extracted from a Chinese medicinal herb (known as Gynostemma pentaphyllum). Saponins are reported to facilitate the growth of beneficial bacteria and suppress cachexia-like symptoms in mouse models (Chen L. et al., 2016; Huang et al., 2017).

Not only does TCM affect the GM composition and diversity, but TCM therapeutic efficacy is dependent on the presence of certain bacterial species and their enzymes. For instance, PHY906 (derived from four Chinese herbs) is an anticancer medicine that can reduce irinotecan toxicity in advanced-stage CRC patients. However, the efficacy of PHY906 is dependent on β-glucuronidase, an enzyme produced by intestinal bacteria (Lam et al., 2010). Similarly, curcumin supplements to a Il10^−/− mouse promote the abundance of Lactobacillales and increase bacterial diversity that is concurrently accompanied by a reduced polyp burden (McFadden et al., 2015). Nonetheless, GM also improves the availability of TCM, which is one of the classic limitations of TCM.

Another classic example of the TCM–GM interaction is the ingestion of indigested polysaccharides. Indigestible polysaccharides undergo biochemical processes in the gastrointestinal tract and are converted into short-chain fatty acids (SCFAs) by gut microbes. SCFAs are indispensable in maintaining our health, especially colon health (Figure 1). Nonetheless, SCFAs are the energy sources for colonocytes to guarantee the activity of the colon (Wong et al., 2006). Besides this, through inhibition of histone deacetylases and activation of G-couple protein receptors (GPRs), SCFAs can regulate the immune system and correct metabolic disorders (Sun et al., 2017). In addition, SCFAs can also contribute to the gut barrier construction via enhancement of the expression of the MUC-2 gene, modulation of oxidative stress, and upregulation of tight junction molecules (Wang et al., 2012; van der Beek et al., 2017). Furthermore, SCFAs also help in alleviating metabolic syndrome in a high-fat-diet mouse model by inhibiting the expression of pro-inflammatory cytokines, such as IL-1β and IL-6 as well as toll like receptor 4 (TLR4) in adipose tissue (Zhai et al., 2019). The nexus of TCM–GM is a relatively new concept, and interests have been developing toward this field since 2015. In the following section of the manuscript, we summarize how TCM and GM influence each other directly and/or indirectly.

In TCM classic theories, once TCM is combined, some will increase toxicity and some will reduce others’ efficacy (Zhou et al., 2017), which are the so-called 18 incompatible medicaments (ShiBaFan) and 19 medicaments of mutual restraint (ShiJiuWei) principles. To achieve a better curative effect and avoid side effects, combined TCM should be under the guidance of compatibility theories. Modern pharmacology reveals the rationality of the compatibility of TCM, besides this, from another angle, and GM modulation also explains the compatibility theory.

Even in the case of Western drugs, not all of them work for every patient, and a considerable number of patients are nonresponsive; this observation is known as nonresponse bias. And it is a growing consensus that the nonresponders are missing some important bacterial species in their gut. For instance, the efficacy of cyclophosphamide, an anticancer drug, is dependent on the presence of Barnesiella intestinihominis and Enterococcus hirae in the gut of a patient (Daillère et al., 2016). Not only GM but TCM has also been taken for consideration of enhancing the effectiveness of Western medicine. In one such case, a group of researchers found improved efficacy of the antiprogrammed cell death 1/programmed cell death ligand 1 (anti-PD-1/PD-L1) in the presence of ginseng polysaccharides. It was further confirmed that Parabacteroides distasonis and Bacteroides vulgatus were dominating the gut of the treated patient. Those patients who did not respond to the combinatorial treatment of the anti-PD-1/PD-L1 and ginseng polysaccharides had a depleted abundance of the Parabacteroides distasonis and Bacteroides vulgatus (Huang J. et al., 2021).

Nowadays, with the continuous development of culture, multi-omics combination and gene sequencing technologies, the exploration of TCM and microbiota is making exciting discoveries. The mechanism behind TCM theory about Qi, Xue, Ying, Yang, four properties and five flavors have received much attention. TCM regulates the composition and metabolites of intestinal flora, which can be regarded as one of the mechanisms for expounding the efficacy of TCM. We predict that one of the emerging research areas in TCM–GM research will be the investigation of the GM’s role in TCM’s efficacy. Particularly for those therapeutics that are taken orally. By taking the studies carried out on Western drugs as an example, here we try to explain how much the GM could contribute to the efficacy of the medicine. This could help TCM researchers to orient their research.

(1) As an example, we discuss a therapeutic approach that is based upon the development of antibodies to block CTLA-4, known as the cluster of differentiation 152 (a protein receptor working as an immune checkpoint), for the treatment of cancer. This technique is a current hot topic and has shown promising results in clinical trials. During this process, the body’s T cells are recruited against tumors that pose limited damage to the normal cells (Sivan et al., 2015). Preclinical studies have shown that the efficacy of anti-CTLA-4 therapy is dependent upon the composition of the GM. For instance, it has been discovered that anti-PD-L1 (an antibody that blocks CTLA-4) efficacy improves in the presence of Bifidobacterium. Oral administration of anti-PD-1 and Bifidobacterium has been observed with augmented dendritic cell function and improved CD8⁺ T cell priming in the tumor microenvironment (Sivan et al., 2015). Besides this, anti-CTLA-4 therapies have also shown dependence on the presence of Bacteroides thetaiotaomicron or Bacteroides fragilis. Nonetheless, the anti-CTLA-4 therapy has failed in germ-free mice and those treated with antibiotics (Vétizou et al., 2015). More recently, these preclinical experiments were reproduced in melanoma patients and it was found that patients who responded effectively to anti-CTLA-4 treatments were harboring enriched bacterial diversity belonging to the family Ruminococcaceae (Gopalakrishnan et al., 2018).

(2) As a second example, we discuss the efficacy of cyclophosphamide, an anticancer immune suppressant chemotherapeutic that also remodels the gut microbial composition. During cyclophosphamide treatment, the gram-positive bacteria translocate into the lymphoid organ and mimic the production of pathogenic T helper 17 cells and memory Th1 immune responses C. Especially, cyclophosphamide efficacy is dependent on two intestinal commensals known as Barnesiella intestinihominis and Enterococcus hirae. During cyclophosphamide therapy, Barnesiella intestinihominis accumulates in the colon and infiltrates γδT cells in the cancer lesion, whereas Enterococcus hirae translocates to secondary lymphoid organs and stimulates intratumoral CD8/Treg ratio (Daillère et al., 2016). Similarly, another study reports the interconversion of fluoropyrimidines (the first-line anticancer drug) by gut microbial vitamin B6, B9, and ribonucleotide metabolism (Scott et al., 2017). Microbial influences on the efficacy of chemotherapeutic drugs, 5-fluoro-2′-deoxyuridine, and 5-fluorouracil are also reported (García-González et al., 2017).

It is important to mention that microbiome-based therapies should be tailored to disease types and affected body sites. For example, men with metastatic prostate tumors who responded to checkpoint inhibition have been found to have lower levels of a microbe called Akkermansia muciniphila in their stool than men who did not respond. But the opposite is true of people with lung and kidney cancers: Those with more A. muciniphila in their guts tended to fare better on the therapy (Dolgin, 2020).

TCM has been used in treating neuropsychiatric diseases for thousands of years. Synopsis of Golden Chamber (a classic Chinese medicine book written by Zhang Zhongjing in the Han Dynasty) recorded a disease, Zang Zao, in which the main symptoms are depression of spirit, emotional disturbance, weeping and laughing hysterically. Although this kind of disease cannot be solved thoroughly, it can be alleviated effectively by the TCM formula Ganmai Dazao Decoction. Nowadays, lots of evidence uncovers TCM exerting alteration and restoration function of GM. In addition, the altered microbiome, through repairing the gut barrier, regulates the gut permeability, alleviating the inflammation and other potential mechanisms to cure or relieve the symptoms and disease. A gradual but strong link is establishing the connection of TCM, GM, and mental disease. For instance, it is demonstrated that TCM treatment of chronic unpredictable mild stress (CUMS) rats altered the abundance of Ruminococcus and Roseburia and potentially increased the expression of cysteine [83]. Meanwhile, N-acetylcysteine is considered beneficial for brain disorders [84].

In addition, it is reported that GM diversity has a strong association with insular resting state functional connectivity. A higher fecal bacterial microbiota diversity is linked to a higher resting state insular functional connectivity [78]. Interestingly, the fecal microbiota-derived indole metabolites are found to associate with functional and anatomical connectivity of the amygdala and anterior insular nucleus [79]. For example, Bacteroides, Parabacteroides and Escherichia species can promote production of the γ-aminobutyric acid (GABA). Particularly, a lower abundance of Bacteroides was found in depression patients [80]. A series of human mental diseases (such as posttraumatic stress disorder, bipolar disorder, anxiety, and stress, and so on) are associated with altered GM diversity [81].

Recent research shows that gut bacteria are directly sensed by hypothalamic neurons through bacteria muropeptides to regulate host feeding behavior. In this process, muropeptides are recognized by cytosolic Nod-like receptors, which are expressed by a subset of hypothalamic neurons. This subset also responds to muramyl dipeptide from the intestine, thus regulating food intake and associated behaviors [82]. It is revealed that Nod 2 mutation has a strong association with bipolar disorder, schizophrenia, and Parkinson’s disease [82].

TCM–GM interaction is a fertile research field for identifying the faulted signaling pathways during disease and finding a treatment for them by manipulating GM, and this could provide a modern framework for evaluation and validation of TCM. It is well-known that TCM exerts therapeutic abilities that are holistic in nature, which could be impractical to comprehend with conventional research tools. Therefore, we propose that the integration of TCM with GM research can target the wholeness of a biological system. In a few cases, the integration of GM with TCM and other natural products have already made landmark achievements in the field of diseases prognosis and treatment.

WX and BL wrong a majjor part of the manuscript, ST collected the information, MY revised the manuscript, IK supervised the data and the manuscript. All authors contributed to the article and approved the submitted version.

This project was funded by the Deanship of the Scientific Research (DSR), King Abdulaziz University, Jeddah, KSA, under the grant no. DF-244-141-1441.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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