The human microbiome is a diverse collection of microbes, including bacteria, fungi, viruses, and protozoa. When people hear words like bacteria or viruses, they think of the diseases caused by infections with pathogens. However, there is no one-to-one correspondence between microbes and diseases. Emerging evidence indicates that the majority of microbes play a crucial role in the maintenance of human health, including regulating the immune system, nourishing human cells, and resisting invading pathogens. (1)
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The understanding of the intimate relationship between human health and microbiota motivated the development of microbiome-base therapies to link diseases to complex microbial communities. (3) Over the past decades, the development of high-throughput DNA sequencing techniques opened up new horizons and revealed the answer to how we can take advantage of the close associations. With a clearer understanding of the microbiome characteristics of a healthy person (2), scientists designed different strategies to alter microbiota composition back to a healthy equilibrium. The microbiome-based therapeutics can be classified as chemical modifiers, cellular modifiers, or phage-based modifiers. (4) Among the three contemporary microbiome manipulation methods, the clinical relevance of cellular-based methods is discussed in detail below.
Cellular Methods for Microbiome Manipulation
In the first place, live bacteria strains can be added to the host to recover the microbiome. Probiotics are live bacteria that can prevent pathogenic colonization and are beneficial to human health. Applications of probiotics such as Lactobacillus spp., Escherichia coli, and Bifidobacterium spp. have shown positive effects on disease treatments. (3) Compared with the regular probiotics, engineered probiotic bacteria have enhanced functions with the extra ability to target specific pathogens in one particular site of disease. For example, E. coli Nissle 1917 was engineered to express CAI-1 (Nissle-cqsA) and inhibit the Vibrio cholerae virulence gene expression and colonization (6). The effectiveness of the engineered microbiota has been proven through an experiment on infant mice. In the treatment group, mice that are pretreated with cells of Nissle-cqsA 8 hours before the Vibrio cholerae attackachieved a 92% survival rate. In contrast, in the two control groups, all mice solely treated with pretreatment survived, and all mice ingested Vibrio cholerae without pretreatment of Nissle-cqsA died (6).
In the second place, microbe communities can be introduced to the host as a whole to realize the manipulation. Fecal microbiota transplant is an effective treatment for people who suffered from recurrent Clostridium difficile infections. Fecal transplant is the infusion of liquid feces from a healthy donor into the gastrointestinal tract of the recipient individual to cure the disease. Introducing good bacteria to restore balanced microbiome communities is the fundamental concept of this therapy. Studies have shown that over 90% of patients treated with fecal microbiota transplantation were cured with no significant side effects. (5)
Challenges in Microbiome-based Therapeutics
While expecting effective treatment of various diseases that further researches on microbiome would bring us, we have to recognize the challenges and side effects associated with microbiome-based therapeutics.
Firstly, with the rapid development of microbiome-based therapeutics, building, and perfect the corresponding regulation is extremely necessary. Probiotics have been widely used in the food and drugs industry, but as long as the product did not market with health claims, it is out of the U.S Food and Drug Administration's control (7). It is a threat to the society if engineered probiotics, which have a more powerful impact on the human microbiome, can be utilized in food without proof of safety and effectiveness through extensive clinical trials.
Secondly, though the human microbiome of different individuals performs the same core functions, the overall microbiota of the individual is unique. The human microbiome is distinct due to the intrinsic factors such as genetics and extrinsic factors like the environment and personal lifestyle. One of the significant difficulties in advancing microbiota-based therapeutics to human disease treatment is the identification and customization of microbe communities (3). The core of cellular-based methods is to introduce foreign bacteria strains or communities into the host. The consequences of colonization, similar to the rejection reactions of organ transplants, are out of control. It is challenging to have generalized microbiome manipulation solutions that can address complex human diseases with the uniqueness of human microbiota characteristics.
Hope of the Microbiome Manipulation Application in Human Health
We envisioned that proven microbiota techniques could be used to categorize patients based on the similarities and differences of their microbiome characteristics and predict the customized treatment. Moreover, through identifying an individual with a specific pattern of microbiome perturbation and high risk of some diseases, we expect proven microbiota techniques to provide early intervention to diminish the risk of illness.
The microbiome-based therapeutics are the gift from modern science. Emerging evidence indicated that we could take advantage of the characteristics of the human microbiome and use the chemical, cellular, or phage-based modifiers to recover human microbiota back to a healthy equilibrium. Besides the benefit of curing complex diseases, we should also be aware of the challenges in immature microbiome-based therapeutics regulation and difficulties in therapy generalization. In summary, opportunities and challenges coexist in future microbiome researches, and we are looking forward to seeing the processes and achievements in microbiomebased therapeutics.
(1) Davis N. The human microbiome: why our microbes could be key to our health [Internet]. The Guardian. Guardian News and Media; 2018 [cited 2019 Nov 9]. Available from: https://www.theguardian.com/news/2018/mar/26/the-human-microbiome-why-our-microbescould-be-key-to-our-health
(2) Surveying the Immune System [Internet]. Surveying the Immune System | Top Hat. [cited 2019 Nov 9]. Available from: https://tophat.com/marketplace/science-&math/biology/textbooks/surveying-the-immune-system-wendy-tamminen-lilianaclemenza/3190
(3) National Academies of Sciences, Engineering and Medicine, Studies, Division on Earth and Life, Technology, Board on Chemical Sciences and, Roundtable CS. The Chemistry of Microbiomes Proceedings of a Seminar Series. Washington, D.C: National Academies Press; 2017.
(4) Sheth RU, Cabral V, Chen SP, Wang HH. Manipulating Bacterial Communities by in situ Microbiome Engineering. Trends in Genetics. 2016;32(4):189–200.
(5) Choi HH, Cho Y-S. Fecal Microbiota Transplantation: Current Applications, Effectiveness, and Future Perspectives [Internet]. Clinical endoscopy. The Korean Society of Gastrointestinal Endoscopy; 2016 [cited 2019 Nov 9]. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4895930/
(6) Duan F, March JC. Engineered bacterial communication prevents Vibrio cholerae virulence in an infant mouse model [Internet]. Proceedings of the National Academy of Sciences of the United States of America. National Academy of Sciences; 2010 [cited 2019 Nov 9]. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2895089/
(7) NCCIH [Internet]. National Center for Complementary and Integrative Health. U.S. Department of Health and Human Services; 2019 [cited 2019Nov10]. Available from: https://nccih.nih.gov/health/probiotics/introduction.htm
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