Where from and where to in gut microbiome research

Author: Dr Alena Pribyl, Microba Senior Scientist.

26 June 2020

 

 

The beginning

Until only a few decades ago, our knowledge of the human microbiome was based on what could be grown in the laboratory. The first example of this was in the early 1880s when Robert Koch and Fannie Hesse isolated and grew the bacterial pathogen that causes tuberculosis1. A couple of years later, Theodor Escherich discovered that microbes could be part of the normal gut environment when he isolated Escherichia coli from the stools of both healthy and sick children2.

However, it was not until the development of DNA sequencing in the 1970s and 16S rRNA gene sequencing shortly after, that we started to glimpse the extent of the microbial diversity present in the world around and inside us. And it was not until the early 2000s when sequencing technology became cost effective enough for widespread use that we started to realise the microorganisms in the human body are an essential part of us and intricately linked with our health.

 

Recent advancements

Three big advances that have been made in the area of the gut microbiome over the last couple decades, include the discovery of greater microbial richness in the gut than ever suspected, the association of the gut microbiome with a wide range of diseases, and the identification of various factors that can influence the makeup of the gut microbiome.

 

Metagenomics gut microbiome

What is metagenomics? Find out more.

 

Microbial richness

Microbial richness is the number of different types of microorganisms that are present in a sample.

As mentioned above, it was not until the early 2000s that we got our first glimpse of the incredible number of microorganisms that call the human gut home. Later, as sequencing costs dropped further, a high-resolution type of sequencing called shotgun metagenomics, that could look at the entire genome of microorganisms, started being used more frequently. With shotgun metagenomics, scientists started discovering thousands of new bacterial species and strains along with their functional genes4.

Being able to classify the functional genes present in gut bacteria also showed us that the microbes inhabiting our gut have a far larger catalogue of genes they can use to produce various proteins compared to our human cells – in terms of numbers, we have between 20,000-25,000 genes in the human body compared to about 22 million genes in our gut microbiome5. This means our gut bacteria can break down a much wider range of compounds and produce a far broader range of substances than our human cells can.

Links with disease

A fascinating development over the last couple decades has been the correlation between numerous disease states and the gut microbiome. The diseases are wide ranging, including diseases that occur inside the gut such as inflammatory bowel disease and colon cancer to diseases outside the gut such as diabetes, cardiovascular disease, arthritis, neurodegenerative diseases and even mental disorders6.

There is still one question we’re trying to answer for most diseases, and that’s whether the disease causes the change in the gut microbiome, or if the change in the gut microbiome causes the disease? For the majority of diseases correlated to the gut microbiome, this question of causality is still up in the air.

However, we are starting to see more mechanistic studies coming out – these are studies in animal models or in the laboratory that show how specific substances produced by the gut microbiome interact with our immune, metabolic, and nervous system pathways to influence or trigger the onset of a disease7-11. There are also compelling studies appearing about how alterations in the gut microbiome during the first 1000 days of life can influence the development of the immune system. For example, numerous studies have shown differences in the infant gut microbiome of children who later grow up to develop allergies, asthma and obesity compared to children who do not have these conditions12-14.

We are truly only seeing the tip of the iceberg right now when it comes to understanding how the gut microbiome is involved with our health, but this small glimpse thus far is very compelling. It suggests that in the future, we may be able to prevent and maybe even treat some diseases, simply by changing our gut microbiome.

Influencing factors

Research into the gut microbiome has also identified numerous factors that can influence the makeup of our gut microbiome. Some of these factors are out of our control such as genetics, age, geography, and ethnicity, however many of the most influential factors are lifestyle factors that are within our control to change.

These include things like diet, medication use, stress, exercise, and smoking15. This suggests that simple changes to our lifestyle to promote a healthy gut microbiome may help contribute to disease prevention.


Where is it going?

All this research is opening the possibility for developing new diagnostics and therapeutics using the gut microbiome. If the gut microbiome is different in people with a disease state, can we use those differences to predict if someone has that disease or may be at a high risk of developing it? And if we can identify what is different in the gut microbiome in someone who is sick compared to someone who is healthy, would changing that part of the microbiome help alleviate symptoms or change progression of the disease?

Trying to translate this existing research into real world solutions will be the direction for the next couple decades.

Diagnostics

As we continue to build increasingly larger datasets of high-resolution gut microbiome information for specific diseases, we can start to use this data to determine if we can predict disease, using only someone’s gut microbiome profile.

These types of predictive models have already been published for several disease states including colon cancer16, inflammatory bowel disease17, irritable bowel syndrome18, non-alcoholic fatty liver disease19, cardiovascular disease20, ankylosing spondylitis21, and even schizophrenia22. At Microba, we have also developed in-house classifiers that can accurately predict whether someone has IBD with an accuracy of over 90%. However, all these microbiome-based classifiers still need to be tested with larger and more diverse groups of people and no microbiome-based classifier has undergone clinical validation yet.

Likely the first type of microbiome-based diagnostic that will be made commercially available, though, will be companion diagnostics23 – or using the gut microbiome to predict how well someone will respond to a treatment. For example, at Microba, we are in the process of developing companion diagnostics that will predict how someone with IBD will respond to different biological treatments and how cancer patients will respond to different types of immunotherapy.

If validation studies are successful, this could transform how we approach disease diagnosis and determining the appropriate treatment for several diseases.

Therapeutics

This is probably the area that has generated the most excitement – can we change the gut microbiome to improve symptoms or even treat a disease?  There are  hundreds of clinical trials currently underway for microbiome-based therapeutics, racing to answer this question. Three main strategies are being used:

  1. One strategy is to develop clinical bacterial strains that can be used as drugs, often referred to as “live biotherapeutics.” Unlike probiotics, these are bacterial strains that would be regulated and classified as drugs for the treatment of a specific disease or symptom. Probably the most advanced of these live biotherapeutics is the development of what are often referred to as “poo pills” or “crapsules” to treat Clostridium difficile infections24. These consist of communities of bacteria derived from healthy donors that have been well characterised and placed in a pill for oral ingestion.

  2. Another strategy is to identify and isolate the bioactive component of a bacterial strain – this is the bacterially produced substance responsible for interacting with the body and providing a benefit – such as suppressing inflammation or beneficially activating the immune system25. These bioactives can be extracted from the specific bacterial strains and placed into pill form.

  3. And the third strategy being explored is using drugs to target specific bacteria or the substances they produce – for example using bacteriophages to remove harmful bacterial species26 or blocking the production of a harmful substance by bacteria27.

Most of these treatments are still in early stage clinical trials, so it will be a while before we start to see any becoming available. However, some live biotherapeutics, such as the poo pills for treating C. difficile infections are in late stage clinical trials, so these are what will likely hit the market first.

 

Microba is leading the way in IBD for the future. Read the article.

 

The future

If the clinical trials and validation studies for developing microbiome-based diagnostics and therapeutics are successful, in the next couple decades we will likely start seeing a shift in how we approach and treat several diseases. For some diseases, the gut microbiome may be one of the missing pieces to the puzzle. There is much work to do to get to this “next frontier in medicine”, but some of the best minds in the world are working on it, and there is good reason to be optimistic about the potential of the gut microbiome to improve healthcare.

About the Author

 

Dr Alena Pribyl

Alena is a Senior Scientist at Microba with a passion for science outreach and communication. Alena’s work at the University of Queensland developing the science content to present metagenomic gut microbiome profiles later became the basis for Microba’s Insight Report.

References

    1. Koch, R. Die Ätiologie der Tuberkulose (1882). in Robert Koch : Zentrale Texte (ed. Gradmann, C.) 113–131 (Springer Berlin Heidelberg, 2018). doi:10.1007/978-3-662-56454-7_4.
    2. Escherich, T. Die darmbakterien des säuglings und ihre beziehungen zur physiologie der Verdauung. (F. Enke, 1886).
    3. Proctor, L. et al. A review of 10 years of human microbiome research activities at the US National Institutes of Health, Fiscal Years 2007-2016. Microbiome 7, 31 (2019).
    4. Ranjan, R., Rani, A., Metwally, A., McGee, H. S. & Perkins, D. L. Analysis of the microbiome: Advantages of whole genome shotgun versus 16S amplicon sequencing. Biochem Biophys Res Commun 469, 967–977 (2016).
    5. Tierney, B. T. et al. The Landscape of Genetic Content in the Gut and Oral Human Microbiome. Cell Host & Microbe 26, 283-295.e8 (2019).
    6. Wang, B., Yao, M., Lv, L., Ling, Z. & Li, L. The Human Microbiota in Health and Disease. Engineering 3, 71–82 (2017).
    7. Chen, S. et al. Trimethylamine N-Oxide Binds and Activates PERK to Promote Metabolic Dysfunction. Cell Metabolism 30, 1141-1151.e5 (2019).
    8. Zhao, J. et al. Neuroinflammation induced by lipopolysaccharide causes cognitive impairment in mice. Scientific Reports 9, 5790 (2019).
    9. Alexeev, E. E. et al. Microbiota-Derived Indole Metabolites Promote Human and Murine Intestinal Homeostasis through Regulation of Interleukin-10 Receptor. The American Journal of Pathology 188, 1183–1194 (2018).
    10. Kaisar, M. M. M., Pelgrom, L. R., van der Ham, A. J., Yazdanbakhsh, M. & Everts, B. Butyrate Conditions Human Dendritic Cells to Prime Type 1 Regulatory T Cells via both Histone Deacetylase Inhibition and G Protein-Coupled Receptor 109A Signaling. Frontiers in Immunology 8, 1429 (2017).
    11. Pedersen, H. K. et al. Human gut microbes impact host serum metabolome and insulin sensitivity. Nature 535, 376 (2016).
    12. Ruohtula, T. et al. Maturation of Gut Microbiota and Circulating Regulatory T Cells and Development of IgE Sensitization in Early Life. Front Immunol 10, 2494–2494 (2019).
    13. Robertson, R. C., Manges, A. R., Finlay, B. B. & Prendergast, A. J. The Human Microbiome and Child Growth – First 1000 Days and Beyond. Trends in Microbiology 27, 131–147 (2019).
    14. Dominguez-Bello, M. G., Godoy-Vitorino, F., Knight, R. & Blaser, M. J. Role of the microbiome in human development. Gut 68, 1108 (2019).
    15. Rothschild, D. et al. Environment dominates over host genetics in shaping human gut microbiota. Nature 555, 210–215 (2018).
    16. Zeller, G. et al. Potential of fecal microbiota for early-stage detection of colorectal cancer. Molecular systems biology 10, 766–766 (2014).
    17. Vich Vila, A. et al. Gut microbiota composition and functional changes in inflammatory bowel disease and irritable bowel syndrome. Science Translational Medicine 10, eaap8914 (2018).
    18. Tap, J. et al. Identification of an Intestinal Microbiota Signature Associated With Severity of Irritable Bowel Syndrome. Gastroenterology 152, 111-123.e8 (2017).
    19. Loomba, R. et al. Gut Microbiome-Based Metagenomic Signature for Non-invasive Detection of Advanced Fibrosis in Human Nonalcoholic Fatty Liver Disease. Cell Metabolism 25, 1054-1062.e5 (2017).
    20. Jie, Z. et al. The gut microbiome in atherosclerotic cardiovascular disease. Nature Communications 8, 845 (2017).
    21. Wen, C. et al. Quantitative metagenomics reveals unique gut microbiome biomarkers in ankylosing spondylitis. Genome Biology 18, 142 (2017).
    22. Zhu, F. et al. Metagenome-wide association of gut microbiome features for schizophrenia. Nature Communications 11, 1612 (2020).
    23. Raes, J. Microbiome-based companion diagnostics: no longer science fiction? Gut 65, 896 (2016).
    24. Kao, D. et al. Effect of Oral Capsule– vs Colonoscopy-Delivered Fecal Microbiota Transplantation on Recurrent Clostridium difficile Infection: A Randomized Clinical Trial. JAMA 318, 1985–1993 (2017).
    25. Milshteyn, A., Colosimo, D. A. & Brady, S. F. Accessing Bioactive Natural Products from the Human Microbiome. Cell Host & Microbe 23, 725–736 (2018).
    26. Dong, X. et al. Bioinorganic hybrid bacteriophage for modulation of intestinal microbiota to remodel tumor-immune microenvironment against colorectal cancer. Sci Adv 6, eaba1590 (2020).
    27. Roberts, A. B. et al. Development of a gut microbe–targeted nonlethal therapeutic to inhibit thrombosis potential. Nature Medicine 24, 1407–1417 (2018).