“Our bodies are spaceships for microbes” is Dr. Allen-Vercoe’s microbiology lab motto at the University of Guelph. Amusing, yet completely on point. If earth is a rock hurtling through space harboring an extensive network of ecosystems, we can think of ourselves as a microcosm of the same phenomena. A single human body carries 39 trillion microbial cells, outnumbering human cells at a ratio of 10:1. Microbial communities inhabit the deserts of our skin, the wetlands of our mucosal surfaces, and the rainforests of our gut. Collectively, these communities constitute the human microbiome – with which we live in symbiosis. Our microbiome helps us digest food, regulate our immune system, and protects us from pathogens.
Most of the bacteria in our microbiome are unculturable and thus it took until the invention of DNA sequencing in 1977 for us to begin to understand the vastness and complexity of these microbial communities. The last two decades have seen an explosion of microbiome research. Sequencing has become cheaper and computers exponentially more powerful, thereby increasing our knowledge of the symbiotic relationship between humans and microbes radically. While sequencing the first human genome in 2001 took upwards of $2.7 billion and 15 years to complete, today sequencing a human genome costs around $1400 and takes less than a week.
We can look at which bacteria are present in the microbiome by sequencing the 16S ribosomal gene which is only present in bacteria. This method is quick and inexpensive but lacks information relating to other microbes (Archaea and Eukaryotes) and the functional capacity of the microbiome. To study this, scientists apply “omics” style analyses like metagenomics, metatranscriptomics, and metabolomics. Metagenomics tells us the collection of genes present, metatranscriptomics reveals the genes being expressed and metabolomics identifies metabolites produced by microbes. By combining these omics analyses, multiomics approaches can help us to discover associations between the presence of specific bacteria, gene expression, and the production of certain bacterial by-products. When combined with human disease data, we can use this data to uncover patterns between the functional capacity of the microbiome and disease states. These findings generate hypotheses which must be validated using biologically-relevant models.
An altered microbiota has been implicated in a range of disorders including metabolic diseases, irritable bowel syndrome, and neurological disorders. To assess a causal link between the gut microbiota and disease, germfree mouse models are commonly used where the mice are transplanted with feces from human donors. In a study conducted by Gérard et al. fecal microbiota transplant from donors with non-alcoholic fatty liver disease (NAFLD) into mice caused them to gain more weight and have increased fatty liver deposits when compared to mice transplanted with healthy donor feces. These results confirm that the gut microbiota plays a role in the development of NAFLD and can inform the creation of therapeutic strategies that target the microbiome.
In some cases, the complete replacement of the microbiota has been shown to be curative against disease. The standard of care for recurrent C. difficile infection is now fecal microbiota transplant, with a success rate between 80-90%. However, the need for healthy fecal donors and the inherent variation of the microbiome from person-to-person highlights the need for standardized microbiome therapeutics. One company, NuBiyota, which spun out from Dr. Allen-Vercoe’s lab, is working to address this issue. The team at NuBiyota is working to create defined Microbial Ecosystem Therapeutics (METs) constructed from healthy donor isolates. NuBiyota uses “Roboguts” – bioreactors that mimic the human colon, to culture defined communities of microbes. These communities are processed and can then be administered orally in capsule form. In the future, microbial therapeutics have the potential to treat disorders ranging from diabetes to generalized anxiety.
Since the coining of the term “microbiome” in 2001, scientists have only scratched the surface of our relationship with microbes. Yet, ongoing research in this field is continuing to show a deep interconnectedness between humans and the natural world. Future advances in omics technologies will allow a deeper understanding of how microbes influence us, and we will be able to harness their power to help treat a plethora of diseases. It’s an exciting time to be a microbiologist.
References
1. NIH Human Microbiome Project – Home. Available at: https://hmpdacc.org/. (Accessed: 14th June 2022)
2. Burz, S. D. et al. Fecal Microbiota Transplant from Human to Mice Gives Insights into the Role of the Gut Microbiota in Non-Alcoholic Fatty Liver Disease (NAFLD). Microorganisms 9, 1–27 (2021).
3. Stool transplants are now standard of care for recurrent C. difficile infections – Harvard Health. Available at: https://www.health.harvard.edu/blog/stool-transplants-are-now-standard-of-care-for-recurrent-c-difficile-infections-2019050916576. (Accessed: 13th June 2022)
4. Kao, D. et al. Division of Gastroenterology The effect of a microbial ecosystem therapeutic (MET-2) on recurrent Clostridioides difficile infection: a phase 1, open-label, single-group trial. Artic. Lancet Gastroenterol Hepatol 6, 282–91 (2021).
Marie-Christine Perry
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