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28 August 2018
Author: Sonia Wróbel, Kaja Milanowska
Author: Sonia Wróbel, Kaja Milanowska

“I am large, I contain multitudes“

How is it possible that such a complex and intelligent species exist with a relatively small number of genes? The answer to this question is that a human can no longer be considered as an autonomous unit, because billions of microorganisms live in symbiosis inside each individual.

“I am large, I contain multitudes“ - the realm of our microbes.

One of the most important scientific projects of the 21st century was the Human Genome Project (HGP), which identified all of the genes of the human genome [1].  We learned that a human has over 20,000 genes no more than a mouse and much less than most laboratory plants [2]. How is it possible that such a complex and intelligent species exist with a relatively small number of genes? The answer to this question is brought to us by scientific reports saying that a human can no longer be considered as an autonomous unit, because billions of microorganisms live in symbiosis inside each individual.

Bacteria appeared on Earth about 3.8 billion years ago, as the first and most elementary form of life [3]. They colonized all environments, becoming an indispensable element for the proper functioning of higher organisms, including humans. This ensemble of microorganisms is called a microbiome. The term was introduced in 2001 by Joshua Lederberg, Nobel Prize laureate (the Nobel Prize in Physiology or Medicine 1958 “for his discoveries concerning genetic recombination and the organization of the genetic material of bacteria“) [4-5]. By microbiome, we define all microorganisms that can be found in a given multicellular plant or animal organism.

 

The number of cells in a microbiome of a human is approximately equal to the number of cells that build the body itself [6]. To better visualize this diversity, imagine that there are more bacteria in the human digestive tract than stars in our galaxy [7]! In the gut alone, the genes of these microorganisms outnumber the human ones about 150 times (3.3 million unique genes of intestinal bacteria). The microbiome has thousands of different functions and is treated by many scientists almost as a new, separate organ or even our second genome [8-9]. We are therefore witnesses of a scientific revolution that completely changes modern medicine and the definition of the human being.

One of the most interesting and fastest growing areas of research on the microbiome is immunotherapy. Immunotherapy, used with great success in the treatment of cancer, is one of the most promising achievements of immuno-oncology in recent years. In 2013 Science announced immunotherapy the greatest achievement not only in medicine but also in the whole science and the American Society of Clinical Oncology (ASCO) recognized immunotherapy as the most important oncological achievement in 2016 [10-11]. Unfortunately, not all patients respond well to the treatment. Why?

In 2017, publications, describing studies conducted on animals as well as on humans, showed a direct correlation between the composition of intestinal microflora and the effectiveness of immunotherapy (immune response modulators, which are checkpoint inhibitors eg anti-CTLA-4, anti-PD1) [12-14]. Patients, who responded positively to immunotherapy, had a more diverse intestinal microflora than non-responders [15]. It is also possible to identify specific bacteria that differentiate these two groups [16-18].

This discovery has opened a new segment of the Next Generation Probiotics (NGP) market belonging to the LBP (Live Biotherapeutic Products) product class [19]. Probiotics are defined as “live microorganisms that when given in appropriate amounts bring a health benefit to the host” [19]. Most of the microorganisms that are normally used in the production of probiotics belong to Lactobacillus and Bifidobacterium genus. New Generation Probiotics use bacteria that benefit patients with specific illnesses such as oncological and autoimmune diseases. Bacteria used in the new generation of probiotics may be based on non-standard species that have not been characterized yet. The literature indicates a few species that could be used as elements of the New Generation Probiotic, for example: Faecalibacterium prausnitzii, Akkermansia muciniphila and Eubacterium hallii [19-20]. The strains used for the design of NGP often exhibit features similar to low-molecular or biological drugs. Progress in the development of NGP opens new possibilities for creating effective and safe therapies for patients [21]. One of them is a revolutionary approach, called “personalized next generation probiotics” which uses the properties of live bacterial cultures that are isolated from donors. The concept of a New Generation Probiotic is already operating in the US market and is approved by the Food and Drug Administration (FDA) as “a biological product containing living organisms such as bacteria that can be used to prevent or cure diseases, but which is not a vaccine” [19].

Perhaps personalized probiotics will become a procedure normally used in the treatment of oncological patients in the coming years and research on the microbiome will provide us with new tools to understand what it means to be human. To quote Ed Young, the author of the book “I Contain Multitudes: The Microbes Within Us and a Grander View of Life”:

“When Orson Welles said »We’re born alone, we live alone, we die alone«, he was mistaken. Even when we are alone, we are never alone. We exist in symbiosis (…) None of those lives is lived in isolation; they always exist in a microbial context (…) we see individuals, working their way through life as a bunch of cells in a single body, driven by a single brain, and operating with a single genome. This is a pleasant fiction. In fact, we are legion, each and every one of us. Always a »we« and never a »me«. Forget Orson Welles, and heed Walt Whitman: »I am large, I contain multitudes.«“.

 

[1] “All About The Human Genome Project (HGP).” National Human Genome Research Institute (NHGRI), www.genome.gov/10001772/all-about-the–human-genome-project-hgp/.

[2] “Home – Genome – NCBI.” Advances in Pediatrics., U.S. National Library of Medicine, www.ncbi.nlm.nih.gov/genome.

[3] Delong, Edward F., and Norman R. Pace. “Environmental Diversity of Bacteria and Archaea.” Systematic Biology, vol. 50, no. 4, Jan. 2001, pp. 470–478., doi:10.1080/10635150118513.

[4] “’Ome Sweet ‘Omics– A Genealogical Treasury of Words.” The Scientist, www.the-scientist.com/commentary/ome-sweet-omics—a-genealogical-treasury-of-words-54889.

[5] “The Nobel Prize in Physiology or Medicine 1958.” Nobelprize.org, www.nobelprize.org/nobel_prizes/medicine/laureates/1958/.

[6] Sender, Ron, et al. “Revised Estimates for the Number of Human and Bacteria Cells in the Body.” PLOS Biology, vol. 14, no. 8, 2016, doi:10.1371/journal.pbio.1002533.

[7] I Contain Multitudes: the Microbes within Us and a Grander View of Life. Vintage Books, 2017.

[8] Google Scholar, Google, scholar.google.pl/scholar?hl=pl&as_sdt=0,5&q=microbiome+function.

[9] Zhu, Baoli, et al. “Human Gut Microbiome: the Second Genome of Human Body.” Protein & Cell, vol. 1, no. 8, 2010, pp. 718–725., doi:10.1007/s13238-010-0093-z.

[10] Couzin-Frankel, J. “Cancer Immunotherapy.” Science, vol. 342, no. 6165, 2013, pp. 1432–1433., doi:10.1126/science.342.6165.1432.

[11] “ASCO Names Advance of the Year: Cancer Immunotherapy.” ASCO, 15 Apr. 2017, www.asco.org/about-asco/press-center/news-releases/asco-names-advance-year-cancer-immunotherapy.

[12] Gopalakrishnan, V., et al. “Gut Microbiome Modulates Response to Anti–PD-1 Immunotherapy in Melanoma Patients.” Science, vol. 359, no. 6371, Feb. 2017, pp. 97–103., doi:10.1126/science.aan4236.

[13] Roy, Soumen, and Giorgio Trinchieri. “Microbiota: a Key Orchestrator of Cancer Therapy.” Nature Reviews Cancer, vol. 17, no. 5, 2017, pp. 271–285., doi:10.1038/nrc.2017.13.

[14] Burki, Talha Khan. “Gut Microbiome and Immunotherapy Response.” The Lancet Oncology, vol. 18, no. 12, 2017, doi:10.1016/s1470-2045(17)30841-0.

[15] Matson, Vyara, et al. “The Commensal Microbiome Is Associated with Anti–PD-1 Efficacy in Metastatic Melanoma Patients.” Science, vol. 359, no. 6371, Apr. 2018, pp. 104–108., doi:10.1126/science.aao3290.

[16] Routy, Bertrand, et al. “Gut Microbiome Influences Efficacy of PD-1–Based Immunotherapy against Epithelial Tumors.” Science, vol. 359, no. 6371, Feb. 2017, pp. 91–97., doi:10.1126/science.aan3706.

[17] Patel, Jaymin, and Jason M. Crawford. “Microbiota-Regulated Outcomes of Human Cancer Immunotherapy via the PD-1/PD-L1 Axis.” Biochemistry, vol. 57, no. 6, 2018, pp. 901–903., doi:10.1021/acs.biochem.7b01249.

[18] Gopalakrishnan, Vancheswaran, et al. “The Influence of the Gut Microbiome on Cancer, Immunity, and Cancer Immunotherapy.” Cancer Cell, vol. 33, no. 4, 2018, pp. 570–580., doi:10.1016/j.ccell.2018.03.015.

[19] O’Toole, Paul W., et al. “Next-Generation Probiotics: the Spectrum from Probiotics to Live Biotherapeutics.” Nature Microbiology, vol. 2, no. 5, 2017, doi:10.1038/nmicrobiol.2017.57.

[20] Cani, Patrice D, and Matthias Van Hul. “Novel Opportunities for next-Generation Probiotics Targeting Metabolic Syndrome.” Current Opinion in Biotechnology, vol. 32, 2015, pp. 21–27., doi:10.1016/j.copbio.2014.10.006.

[21] Zitvogel, Laurence, et al. “The Microbiome in Cancer Immunotherapy: Diagnostic Tools and Therapeutic Strategies.” Science, vol. 359, no. 6382, 2018, pp. 1366–1370., doi:10.1126/science.aar6918.

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