In recent years, the human microbiota, which is mainly resident in the digestive tract, has been recognized as a crucial contributor to human health. The collective genome of the resident microbes contains more than 100 times as many genes as our own, and is referred to as the human microbiome or metagenome. Since the launch of several international metagenomic studies 10 years ago, including the Human Microbiome Project and Metagenomics of the Human Intestinal Tract, the human microbiome has become one of the hottest topics in life sciences and is considered a promising target for disease prevention and therapy.
There is a long history of recognition and application of commensal bacteria in the practice of traditional Chinese medicine (TCM) in China. In the context of global systems biology, the “omics” technologies provide new strategies and powerful tools for the scientific renewal of TCM. However, there is still a big gap between modern human microbiome studies and TCM, which may obstruct further studies in this area. Herein, we provide a brief introduction to the human microbiome, summarize the theoretical background of both TCM and current research pertaining to the human microbiome, and propose a potential strategy for combining this new scientific discipline with TCM, which may promote a more comprehensive and scientific understanding of TCM.
Brief introduction to the human microbiome
The human microbiota refers to the collective group of microbes that is mainly resident on the external and internal surfaces of the human body, including the oral cavity, gut, skin, and vagina. Containing >1.5 kg of bacterial biomass, the human gastrointestinal tract is the most active site of bacterial fermentation and human–microbe interactions. The human gut microbiota contains ten times as many cells (around 1014 cells) and over 150 times as many genes (around 3.3 million genes)[2,8] as the human body. Thus, the gut microbiota has been recognized as a “microbial organ,” with various functions such as maintaining the intestinal barrier, protecting against pathogens, digesting and metabolizing molecules from food and human cells, and regulating host developmentand immunity (Fig. 1).
Over the past 2 decades, the development of next-generation sequencing techniques has helped scientists to gain a broader and deeper perspective into the world of microorganisms. Microbiome-wide association studies make it possible to discover links between gut microbiota and disease. These studies have revealed that a dysbiotic human microbiota is correlated with many inflammatory and metabolic diseases such as inflammatory bowel disease, obesity, liver disease, diabetes, and cancer. Furthermore, the application of germ-free mice, which are raised in the absence of microorganisms in sterile isolators, provides opportunities to move from correlation to causality in human microbiome studies.[19,20] Through the transplantation of gut microbiota from donors with specific diseases such as obesity and non-alcoholic fatty liver disease,[21,22] metabolic phenotypes can be transferred to germ-free mice, providing valid evidence of the role of the gut microbiota in the development of the disease.
Connections between human microbiome studies and TCM
TCM is characterized by its holistic approach to human health, emphasizing the integrity of the human body and the interactions between humans and their environment. The emerging concept of superorganisms, which considers the human body and commensal bacteria as a whole, could be deemed a new holistic view. The human microbiota is indispensable for human health and participates in various biological functions, including digestion, nourishment, and immunity.[2,8,11,24] The human body and gut microbiota actively exchange their respective metabolic products via enterohepatic circulation, the intestinal barrier, and other physiological and anatomic connections.[11,25] For example, short-chain fatty acids, the main products of the fermentation of dietary fibers by anaerobic bacteria, could serve as an energy source for the intestinal epithelium and liver.[26,27] In addition, short-chain fatty acids can act as signaling molecules in the regulation of host metabolism by inhibiting histone deacetylases and activating G-protein-coupled receptor 41 and 43.[28,29] In contrast, trimethylamine-N-oxide, a host–microbe co-metabolism product, has been associated with atherosclerosis.
Spleen–Stomach theory is well known as one of the basic principles of TCM, considering the health foundation of acquired disposition and the source of “Qi” and “Blood.” The Spleen–Stomach theory emphasizes functional integration rather than the individual anatomical organs. Notably, these organs are mainly involved in digestion, as well as immunity, hematopoiesis, and metabolism, which is functionally consistent with the roles of the gut microbiota. Interestingly, dysbiosis of the gut microbiota can result in poor appetite, diarrhea, or constipation, which coincides with the symptoms of spleen and stomach diseases in TCM. The gut microbiota in “spleen-deficient” mouse models showed a significant decrease in the abundance of Lactobacillus and Bifidobacterium species, which could be restored by a TCM herbal formula known as Sijunzi decoction. Using a real-time quantitative polymerase chain reaction assay, patients with “spleen-deficient” syndrome showed a lower bifidobacteria/enterobacteria ratio than the healthy controls. Denaturing gradient gel electrophoresis-based analysis of the profiles of the gut microbiota also showed that the “spleen-deficient” patients had different community signatures. Therefore, we propose that the Spleen-Stomach theory in TCM should be recognized as a functional complex incorporating the related human organs and gut microbiota.
Syndrome differentiation (Bian Zheng) is the core principle of TCM practice and is based on comprehensive clinical information acquired via 4 diagnostic methods: observation, auscultation and olfaction, inquiry, and pulse feeling and palpation. The appearance of the tongue coating and feces, which is mainly affected by bacterial activity, is an essential basis of syndrome differentiation in TCM. Microbial community studies have shown that the oral microbiota affects the color and thickness of the tongue coating, while both oral and gastric microbiota can induce halitosis.[37,38] The intestinal microbiota determines fecal characteristics. The finding that the gut microbiome varies among individuals and different conditions[6,40] is consistent with the recognition of individual differences and the dynamic variation within TCM pattern theory.
Future implementation of TCM syndrome differentiation-associated microbiome studies
The contribution of the human microbiota to syndrome differentiation in TCM has been recognized but lacks sufficient evidence-based support. As mentioned above, specific diseases are associated with specific microbiota signatures, such as decreased abundance of Lactobacillus and Bifidobacterium species. However, these results are only considered preliminary because of suboptimal study design (eg, small sample size) and the use of outdated techniques.
To effectively conduct a combination study of human microbiota and syndrome differentiation, the research design should follow some common guidelines. Here, we provide some suggestions for future TCM syndrome differentiation-associated microbiome studies.
Select a representative subtype of the syndrome (Zheng) as a target of the research
One of the major obstacles to the modernization of TCM is the lack of standardization of the diagnostic criteria and syndrome differentiation procedures. We would be better to start from 1 typical subtype of Zheng. Furthermore, syndromes with a consensus standard, such as “spleen-deficient,” should be the priority.
Conduct population-scale studies
Considering the differences between individuals recognized by both TCM pattern theory and human microbiome analyses, large-scale cohort studies should be conducted to provide a comprehensive and authentic profile. Moreover, the design and application of the cohort study should follow strict and well-established guidelines, with all staff being appropriately trained. The training of professional staff, establishment of the research platform, and interdisciplinary communication and cooperation are urgently needed.
Application of multi-omics techniques
Multi-omics techniques have been widely applied in the study of modern medicine as well as in TCM. Human microbiome studies are also closely related to genomic, metabolomic, transcriptomic, and epigenomic analyses. In addition, >10% of the metabolites found in mammalian blood are microbially produced or modified. Therefore, the use of multi-omics techniques is indispensable for developing a comprehensive profile of human health status, which is crucial for understanding and interpreting TCM.
An integrative research approach into the human body as a whole, along with its commensal bacterial community, will be beneficial for a more comprehensive and precise understanding of TCM theory and will aid in the modernization of TCM.
RRW, GJ, and BCL conceived the idea and wrote the manuscript. LZ and JJX gave suggestions about the Traditional Chinese Medicine part. ZG and LZ contributed to data collection and integration. All authors approved the final version of the paper.
This work was supported by the National Natural Science Foundation of China (No. 816220108030, No. 81603411, No. 81573814) and China Postdoctoral Science Foundation No. 2018M630465.
Conflicts of interest
The authors declare that they have no conflicts of interest.
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