“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).

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