What is microbiome? Why is it important?

The human body is home to a variety of microorganism, including eukaryotes, archaea, bacteria and viruses. These microbiota communities, together with their genes are referred to as the microbiome. The human body is composed of approximately 10 trillion human cells, while it harbors 10–100 trillion microbiome cells. On the genetic level, the number of genes in human microbiome is about 15 times the number of genes in human genome¹. Undoubtably, these microbes can wield strong power over human health.

Microbes inhabit almost every part of the human body, living on the skin, in the gut, and up the nose and mouth. Most of them are not only beneficial, but also essential for maintaining health. They support and regulate basic biological processes, including metabolism, innate immunity, infection protection and mental health. On the other hand, they are influenced by the host and environmental factors such as diet, antibiotics, stress. Overall,the human microbiome is a complex and dynamic systems with huge intrapersonal diversity.

Along with the development of advanced sequencing techniques and the initiation of several large-scale microbiome projects such as the Human Microbiome Project (HMP)² and the MetaHIT (Metagenomics of the Human Intestinal Tract)³, there has been an explosion in our understanding of the human microbiome. It’s found that microbiota disequilibrium (dysbiosis) is associated with a wide variety of diseases, from metabolic, inflammatory, cardiovascular diseases to cancer, and even neurodegenerative diseases like Parkinson’s disease.

The emerging research in this field unravel the great potential of microbiome-based therapeutics. For example, Faecal microbiota transplants (FMT) therapy which aims at re-balancing the gut microbiota has shown extremely efficacious against Clostridium difficile infection (CDI) 4. Other strategies such as probiotics, prebiotics, synbiotics, postbiotics and phage therapy are also under investigation. Though no microbiome therapeutics have been approved by FDA for human use yet.

The new microbiome industry

Given the exciting research progress achieved in this field, there have been lots of microbiome start-up companies emerging in recent years. A part of them are gene sequencing companies, providing technique service and support for microbiome research. The rest of them focus on therapeutics and/or diagnostics. A small number of them target the skin microbiome (e.g. Pendulum, Evolve BioSystems), while the majority concentrate on the gut microbiome, whose development and regulatory pathway is much more stringent than products for the consumer market (nutritional supplements/probiotics).

Gut microbiome: the next chapter of precision medicine

The gut microbiome has always been the major focus of human microbiome research. It’s the largest and most diverse community in the human microbiome, and also referred to as our ‘second brain’ or ‘second genome’. The gut microbiome participates in regulation metabolism, immunity, and even central nervous system through gut-brain axis.

In addition, the gut microbiome is considered as an ‘orchestrator’ of cancer immunotherapy as it’s able to affect the patient’s response to cancer treatment with checkpoint inhibitor immunotherapies. For instance, patients with favorable gut microbiome show improved response to anti-PD1 treatment⁵.

The variation and individuality of the gut microbiome make it a perfect target of precision medicine. According to multiple large-scale studies, perturbations of normal gut microbial profiles are certainly linked with clinical outcomes. With the advanced sequencing techniques, a patient’s microbiome can be easily de-composited, which can be treated as a patient-specific fingerprint/barcode. Transitioning from observational association studies to deeper mechanistic investigation with help of big data analysis and modeling, the gut microbiome is shedding new light on personalized therapeutic approaches.

Many microbiome companies like Seres Therapeutics, Second Genome and Enterome are building their own biomarker platform for personalized therapy and precision drug discovery. Some other firms focused on food/diet use microbiome to develop personalized nutrition plan. DayTwo combines microbiome analysis, data science and digital health together for its personalized nutrition programs, diabetes management as well as gut microbiome testing.

Microbiome research is becoming a huge data science

With the advanced next-generation sequencing and multi-omics technologies, the microbiome field has accumulated large reference data sets. These vast amount of data presents new challenges and opportunities. One of the key challenges is that microbiome genomes themselves are not that useful, and they need to be analyzed in conjunction with other data types, such as patient demographic info, clinical data and epigenome data. Another challenge is to apply state-of-the-art methods, like machine learning and cloud computing to large and complex microbiome data sets.

Recently, Eagle Genomics announces collaboration with Cargill to harness AI to microbiome research. It’s also partnering with Microsoft to scale up its AI platform.

Future directions

Although the microbiome research has shown positive results, there are still plenty of development and commercialization challenges in this new field, including proper clinical trial design, unclear regulatory frameworks, manufacturing and technology considerations.

Here, we identify several promising directions in the future:

• Explore different microbiome therapeutics strategies and their combination: FMT, small-molecule therapy, genetically modified bacteria, defined consortia, and phage cocktail.
• Integrate the microbiome into precision medicine, for example, use patients’ gut microbiome profile to determine their potential response to treatment.
• Apply advanced biocomputational approaches, such as machine learning and system‐level modeling into multidimensional‐omics data analysis.

References

1. Turnbaugh, P.J. et al. The human microbiome project. Nature 449, 804–810 (2007).
2. The Human Microbiome Project Consortium et al. Structure, function and diversity of the healthy human microbiome. Nature 486, 207–214 (2012).
3. Qin, J. et al. A human gut microbial gene catalogue established by metagenomic sequencing. Nature 464, 59–65 (2010).
4. Kelly, C.R. et al. Update on FMT 2015: indications, methodologies, mechanisms and outlook. Gastroenterology 149, 223–237 (2015).
5. Routy, B. et al. Gut microbiome influences efficacy of PD‐1‐based immunotherapy against epithelial tumors. Science 359, 91–97 (2018).
6. Zmora, Niv et al. “Transforming medicine with the microbiome.” Science translational medicine vol. 11,477 (2019)
7. Petrosino, Joseph F. “The microbiome in precision medicine: the way forward.” Genome medicine vol. 10,1 12. 22 Feb. 2018

‍