Secondary Logo

Journal Logo

Human microbiome brings new insights to traditional Chinese medicine

Wang, Rui-Rui, PhDa; Zhang, Lei, MDa; Xu, Jing-Juan, PhDa; Gu, Zhan, PhDa; Zhang, Li, MSa; Ji, Guang, MDa,b,*; Liu, Bao-Cheng, PhDa,*

doi: 10.1097/JBR.0000000000000007
Articles
Open

The human microbiome has become a new frontier of life sciences and plays a crucial role in determining individual and population health. Over thousands of years of medical practice, practitioners of traditional Chinese medicine (TCM) developed an understanding of the importance and activity of commensal microorganisms without access to modern technology. In this review, we examine the theoretical similarities between modern studies of the human microbiome and TCM, and propose feasible strategies to integrate the 2 fields. Advances in our understanding of the human microbiome will also help to modernize the practice of TCM, thereby providing a basis for bridging the gap between modern medicine and TCM.

aShanghai Innovation Center of TCM Health Service

bInstitute of Digestive Diseases, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China

Corresponding author: Guang Ji (jiliver@vip.sina.com) and Bao-Cheng Liu (baochliu@shutcm.edu.cn), Shanghai Innovation Center of TCM Health Service, Shanghai University of Traditional Chinese Medicine, Shanghai, China.

Received 15 May, 2018

Accepted 15 May, 2018

This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. http://creativecommons.org/licenses/by-nc-nd/4.0

Back to Top | Article Outline

Introduction

In recent years, the human microbiota, which is mainly resident in the digestive tract, has been recognized as a crucial contributor to human health.[1] The collective genome of the resident microbes contains more than 100 times as many genes as our own,[2] 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[3] and Metagenomics of the Human Intestinal Tract,[4] 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.[5] 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.

Back to Top | Article Outline

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.[6] 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)[7] 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,[9] protecting against pathogens,[10] digesting and metabolizing molecules from food and human cells,[11] and regulating host development[12]and immunity (Fig. 1).[13]

Figure 1

Figure 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.[2] These studies have revealed that a dysbiotic human microbiota is correlated with many inflammatory and metabolic diseases such as inflammatory bowel disease,[14] obesity,[15] liver disease,[16] diabetes,[17] and cancer.[18] 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.

Back to Top | Article Outline

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.[23] 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.[30]

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.”[31] 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.[31] 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.[32] Using a real-time quantitative polymerase chain reaction assay, patients with “spleen-deficient” syndrome showed a lower bifidobacteria/enterobacteria ratio than the healthy controls.[33] Denaturing gradient gel electrophoresis-based analysis of the profiles of the gut microbiota also showed that the “spleen-deficient” patients had different community signatures.[34] 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.[35] 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,[36] while both oral and gastric microbiota can induce halitosis.[37,38] The intestinal microbiota determines fecal characteristics.[39] 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.

Back to Top | Article Outline

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.[33] 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.

Back to Top | Article Outline

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.[35] 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.

Back to Top | Article Outline

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.[41] The training of professional staff, establishment of the research platform, and interdisciplinary communication and cooperation are urgently needed.

Back to Top | Article Outline

Application of multi-omics techniques

Multi-omics techniques have been widely applied in the study of modern medicine as well as in TCM.[5] Human microbiome studies are also closely related to genomic,[42] metabolomic,[43] transcriptomic,[44] and epigenomic analyses.[45] In addition, >10% of the metabolites found in mammalian blood are microbially produced or modified.[46] 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.

Back to Top | Article Outline

Conclusion

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.

Back to Top | Article Outline

Acknowledgments

None.

Back to Top | Article Outline

Author contributions

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.

Back to Top | Article Outline

Financial support

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.

Back to Top | Article Outline

Conflicts of interest

The authors declare that they have no conflicts of interest.

Back to Top | Article Outline

References

1. Cani PD. Gut microbiota—at the intersection of everything? Nat Rev Gastroenterol Hepatol 2017; 14:321–322.
2. Qin J, Li R, Raes J, et al. A human gut microbial gene catalogue established by metagenomic sequencing. Nature 2010; 464:59–65.
3. Turnbaugh PJ, Ley RE, Hamady M, et al. The human microbiome project. Nature 2007; 449:804–810.
4. Dusko Ehrlich S. MetaHIT ConsortiumMetagenomics of the intestinal microbiota: potential applications. Gastroenterol Clin Biol 2010; 34 (suppl 1):S23–S28.
5. Buriani A, Garcia-Bermejo ML, Bosisio E, et al. Omic techniques in systems biology approaches to traditional Chinese medicine research: present and future. J Ethnopharmacol 2012; 140:535–544.
6. Human Microbiome Project ConsortiumStructure, function and diversity of the healthy human microbiome. Nature 2012; 486:207–214.
7. Savage DC. Microbial ecology of the gastrointestinal tract. Annu Rev Microbiol 1977; 31:107–133.
8. Gill SR, Pop M, Deboy RT, et al. Metagenomic analysis of the human distal gut microbiome. Science 2006; 312:1355–1359.
9. Natividad JM, Verdu EF. Modulation of intestinal barrier by intestinal microbiota: pathological and therapeutic implications. Pharmacol Res 2013; 69:42–51.
10. Bäumler AJ, Sperandio V. Interactions between the microbiota and pathogenic bacteria in the gut. Nature 2016; 535:85–93.
11. Tremaroli V, Bäckhed F. Functional interactions between the gut microbiota and host metabolism. Nature 2012; 489:242–249.
12. Josefsdottir KS, Baldridge MT, Kadmon CS, et al. Antibiotics impair murine hematopoiesis by depleting the intestinal microbiota. Blood 2017; 129:729–739.
13. Gensollen T, Iyer SS, Kasper DL, et al. How colonization by microbiota in early life shapes the immune system. Science 2016; 352:539–544.
14. Nagao-Kitamoto H, Shreiner AB, Gillilland MG, et al. Functional characterization of inflammatory bowel disease-associated gut dysbiosis in gnotobiotic mice. Cell Mol Gastroenterol Hepatol 2016; 2:468–481.
15. Turnbaugh PJ, Hamady M, Yatsunenko T, et al. A core gut microbiome in obese and lean twins. Nature 2009; 457:480–484.
16. Boursier J, Mueller O, Barret M, et al. The severity of nonalcoholic fatty liver disease is associated with gut dysbiosis and shift in the metabolic function of the gut microbiota. Hepatology 2016; 63:764–775.
17. Qin J1, Li Y, Cai Z, et al. A metagenome-wide association study of gut microbiota in type 2 diabetes. Nature 2012; 490:55–60.
18. David R. Microbiome: a bacterial trigger for liver cancer. Nat Rev Microbiol 2013; 11:509.
19. Bäckhed F, Ding H, Wang T, et al. The gut microbiota as an environmental factor that regulates fat storage. Proc Natl Acad Sci U S A 2004; 101:15718–15723.
20. Bäckhed F, Manchester JK, Semenkovich CF, et al. Mechanisms underlying the resistance to diet-induced obesity in germ-free mice. Proc Natl Acad Sci U S A 2007; 104:979–984.
21. Duca FA, Sakar Y, Lepage P, et al. Replication of obesity and associated signaling pathways through transfer of microbiota from obese-prone rats. Diabetes 2014; 63:1624–1636.
22. Le Roy T, Llopis M, Lepage P, et al. Intestinal microbiota determines development of non-alcoholic fatty liver disease in mice. Gut 2012; 62:1787–1794.
23. Wang B. The Yellow Emperor's Inner Classic, Essential Questions. Beijing, China:People's Medical Publishing House; 1956.
24. Zhao L. Genomics: the tale of our other genome. Nature 2010; 465:879–880.
25. Brandl K, Kumar V, Eckmann L. Gut-liver axis at the frontier of host-microbial interactions. Am J Physiol Gastrointest Liver Physiol 2017; 312:G413–G419.
26. Royall D, Wolever TM, Jeejeebhoy KN. Clinical significance of colonic fermentation. Am J Gastroenterol 1990; 85:1307–1312.
27. Canfora EE, Jocken JW, Blaak EE. Short-chain fatty acids in control of body weight and insulin sensitivity. Nat Rev Endocrinol 2015; 11:577–591.
28. Samuel BS, Shaito A, Motoike T, et al. Effects of the gut microbiota on host adiposity are modulated by the short-chain fatty-acid binding G protein-coupled receptor, Gpr41. Proc Natl Acad Sci U S A 2008; 105:16767–16772.
29. Kimura I, Ozawa K, Inoue D, et al. The gut microbiota suppresses insulin-mediated fat accumulation via the short-chain fatty acid receptor GPR43. Nat Commun 2013; 4:1829.
30. Koeth RA, Wang Z, Levison BS, et al. Intestinal microbiota metabolism of L-carnitine, a nutrient in red meat, promotes atherosclerosis. Nat Med 2013; 19:576–585.
31. Wu XN. Current concept of Spleen-Stomach theory and Spleen deficiency syndrome in TCM. World J Gastroenterol 1998; 4:2–6.
32. Yan MZ. Influence of the sijunzi decotion on the intestinal flora in a mice model with “spleen deficiency”. Zhongguo Weishengtai Xue Zazhi 1987; 1:203–243.
33. Wu SM, Zhang WD. Microecological study on patients with diarrhea due to asthenis of the spleen. Zhongguo Zhongxiyi Jiehe Xiaohua Zazhi 1996; 4:203–204.
34. Liu J, Peng Y, Zhang SY, et al. Investigation on intestinal microflora of elderly patients with spleen deficiency by 16S rDNA DGGE analysis. Zhonghua Zhongyiyao Zazhi 2010; 25:1566–1569.
35. Jiang M, Lu C, Zhang C, et al. Syndrome differentiation in modern research of traditional Chinese medicine. J Ethnopharmacol 2012; 140:634–642.
36. Mantilla Gómez S, Danser MM, Sipos PM, et al. Tongue coating and salivary bacterial counts in healthy/gingivitis subjects and periodontitis patients. J Clin Periodontol 2001; 28:970–978.
37. Kazor CE, Mitchell PM, Lee AM, et al. Diversity of bacterial populations on the tongue dorsa of patients with halitosis and healthy patients. J Clin Microbiol 2003; 41:558–563.
38. Kinberg S, Stein M, Zion N, et al. The gastrointestinal aspects of halitosis. Can J Gastroenterol 2010; 24:552–556.
39. Carroll IM, Ringel-Kulka T, Siddle JP, et al. Alterations in composition and diversity of the intestinal microbiota in patients with diarrhea-predominant irritable bowel syndrome. Neurogastroenterol Motil 2012; 24:521–530. e248.
40. Lozupone CA, Stombaugh JI, Gordon JI, et al. Diversity, stability and resilience of the human gut microbiota. Nature 2012; 489:220–230.
41. Xu Q, Bauer R, Hendry BM, et al. The quest for modernisation of traditional Chinese medicine. BMC Complement Altern Med 2013; 13:132.
42. Lim MY, You HJ, Yoon HS, et al. The effect of heritability and host genetics on the gut microbiota and metabolic syndrome. Gut 2017; 66:1031–1038.
43. Mardinoglu A, Shoaie S, Bergentall M, et al. The gut microbiota modulates host amino acid and glutathione metabolism in mice. Mol Syst Biol 2015; 11:834.
44. Murakami M, Tognini P, Liu Y, et al. Gut microbiota directs PPARgamma-driven reprogramming of the liver circadian clock by nutritional challenge. EMBO Rep 2016; 17:1292–1303.
45. Qin Y, Wade PA. Crosstalk between the microbiome and epigenome: messages from bugs. J Biochem 2018; 163:105–112.
46. Wikoff WR, Anfora AT, Liu J, et al. Metabolomics analysis reveals large effects of gut microflora on mammalian blood metabolites. Proc Natl Acad Sci U S A 2009; 106:3698–3703.
Keywords:

human microbiome; integrated medicine; traditional Chinese medicine

Copyright © 2018 The Chinese Medical Association. Published by Wolters Kluwer Health, Inc.