The microbiome in precision medicine

Listen to this article on the DDW Podcast: An industry overview of the role of the microbiome in precision medicine, and its interplay with research tools, diagnostics, and therapeutic development. By Katie Gillette, Senior Project Leader, Eliza French, Analyst, and Graham Friedman, Analyst, DeciBio. The human microbiome refers to the vast array of microorganisms that live in and on the human body. With 100-fold the number of genes in the human genome1, this microbial collection is a rich genetic signature of clinical significance that we have only recently gained the tools to explore. Research increasingly demonstrates that within each discrete microbial environment (e.g., the skin, gut, vaginal flora), unique compositions of microbiota correspond to various healthy and diseased states. This leap in understanding, which has been facilitated by the emergence of next generation sequencing (NGS) technologies and bioinformatics tools such as artificial intelligence (AI), has brought forward a new wave of precision medicine resources, diagnostics, and therapeutics specifically aiming to leverage the microbiome. As we continue to learn about our microbial communities, the landscape of next generation technologies aiming to progress this understanding and employ it for the manipulation of our microbiome has become increasingly competitive. These novel tools are facilitating the exploration of the microbiome in diagnostics development and drug discovery. But what advancements are taking place within microbiome-based precision medicine and how is it being used within oncology? Precision medicine tools We classify the next generation tools associated with the microbiome into two applications: (1) diagnostics development and (2) drug discovery. (1) Diagnostics technologies may include a combination of NGS, novel classification algorithms (e.g., high dimensional microbiome profilers), and curated knowledge databases, which can collectively identify signatures of dysbiosis, or the presence of specific microbes indicative of disease. At the heart of these diagnostics is the sequencing process. Microbial NGS methods can range from ribosomal RNA analysis (16S rRNA sequencing), to parallel genomic sequencing or shotgun metagenomic sequencing, to whole genome sequencing, to metatranscriptomics. The vast and diverse set of microbiome genomic data uncovered by NGS requires sophisticated bioinformatic techniques, which come in the form of microbiome community profiling. This requires the identification and categorisation of massive sets of genomic sequences corresponding to a huge diversity of bacteria and other microorganisms – a challenge quite distinct from studying the human genome (e.g., identifying single nucleotide polymorphisms or chromosomal rearrangements). This 'alpha diversity', or microbial diversity within a sample, can include taxonomic assignment. Given the enormous breadth of bacterial diversity, this task may sometimes require de novo genome assembly, the construction of a genome with no prior reference. Furthermore, researchers examine 'beta diversity' (microbial diversity between samples) to establish the significance of an individual’s microbial profile across population-wide references. In addition to developing proprietary algorithms to accomplish such analyses, companies might also rely upon specific knowledge databases that facilitate the identification of a microbiome’s constituents and enable efficient and rigorous pairing of microbial profiles to disease states. To develop a fully functional and useful diagnostic pipeline, the integration of multiple cutting-edge technologies, which may be both chemical and computational, is often required. (2) Drug discovery relies on its own toolkit, albeit one that overlaps significantly with the tools underpinning diagnostic applications. This includes machine learning platforms which use AI to identify microbiome biomarkers associated with specific disease states and to conduct novel pathway analysis, as well as gene engineering assays which leverage sequence editing technologies to develop live biotherapeutics. In addition to relying upon NGS and algorithms built for diversity profiling and association mapping, therapeutic development requires bioinformatic platforms uncovering how microbes operate within biological pathways, and how microbial (im)balances contribute to disease root cause and symptom alleviation. Collectively, these systems biology bioinformatic puzzles often require partnerships to solve. One such example is the Mosaic initiative established between the large pharmaceutical corporation, Janssen, and DNAnexus, a leader in bioinformatics data infrastructure. Genome editing tools such as CRISPR may be employed to create “live biotherapeutics” (drugs composed of living bacteria). Additional approaches include 'culturomics' – pioneered by BaseClear – to cultivate bacterial strains, and explore and employ their metabolism for our needs. In addition to offering stand-alone tools, companies have also emerged with end-to-end pharma service models. Companies such as Microbiome Insights, MR DNA, and Clinical Microbiomics have taken this service model approach with comprehensive R&D solutions that include support for steps from sequencing to regulatory submission. Figure 1: A sample of active microbiome clinical trials (N 700) was analysed to determine top areas of research focus; figure displays proportionate breakdown of studies among the top 5 indications identified (N 301): oncology, GI health, infectious disease, metabolic health, and women’s health. *This figure is not intended to be an exhaustive picture of the microbiome therapeutic and diagnostic market; instead, it represents a selection of a few major players as of April 2023. Additionally, companies may be involved in indications and markets other than those indicated in the figure. Source: Company websites and publicly-available company / product profiles. Indications of focus Research into the microbiome has steadily expanded over the last 10 years, with publications mentioning the microbiome increasing ~10% p.a.2. This has laid the groundwork for a wave of biopharma players to enter. At present, there are over 2,000 active clinical trials investigating the microbiome. Our analysis, which categorised a representative sample of all active microbiome clinical trials into over 25 disease areas, shows that the top five disease areas being targeted compose over 40% of all clinical trials. Within the top five indications being studied, oncology represents ~35%, followed by GI health (~30%), infectious disease (~15%), metabolic health (~10%), and women’s health (~10%). Deeper dive: Oncology Emerging as the most active indication, oncology is ripe with microbiome innovation across diagnostics and drug discovery. The microbiome can carry signatures of cancer, making it well suited across the patient journey from early detection to diagnosis and monitoring. While the early cancer detection market is still immature, a growing number of microbiome diagnostic assays have already achieved FDA breakthrough designation. Some of the most widely publicised products include Metabiomics’ LifeKit Prevent Test for early detection of colorectal cancer, Micronoma’s OncobiotaLUNG for early lung cancer detection, and Viome’s CancerDetect Test for oral and throat cancer. As an early cancer detection tool, the microbiome may even be able to identify disease earlier, and more accurately, than liquid biopsies that use only human genomic material. Cell-free microbial DNA (cf-mbDNA)’s orthogonal position to the human genome offers several advantages. Unlike circulating tumour DNA (ctDNA), the sample concentration of cf-mbDNA does not directly depend on tumour size and cancer stage. This may enable the identification of smaller tumours earlier in disease progression and with higher sensitivity. An additional drawback of working with human genomic material alone is the presence of confounding mutations (e.g., clonal haematopoiesis mutations), which can be avoided by incorporating cf-mbDNA into the testing pool3. Thus, alone or as part of a “multianalyte, multispecies assay,” insights from the microbiome may provide a significant diagnostic edge. Preliminary comparison studies have supported this conclusion as well, showing that mbDNA classification algorithms can successfully identify multiple cancer types, even when the mutational signatures utilised in the Guardant360 and FoundationOne liquid biopsy assays are absent3. Companies such as Micronoma are leveraging these insights to build proprietary “microbiome-driven liquid biopsy” methods. Figure 2: Stages of the development workflow for microbiome-based diagnostics and therapeutics In addition to early detection, the microbiome could serve as a companion diagnostic tool. Due in part to the close relationship between the microbiome and immune function, tests of microbial activity can serve as effective predictors of patient prognosis and ultimately guide therapy selection. One such company, Biome Diagnostics, has launched a gut-microbiome test to forecast a patient’s response to immunotherapy which received CE-IVD status in the EU. Similarly leveraging the connection between the microbiome and the immune system, several companies are approaching cancer care from an immuno- oncology perspective. Going one step beyond using the microbiome to detect disease or predict treatment response, these companies are directly modulating the immune system through microbiome modification. Such microbiome-based treatments often take the form of' live biotherapeutics', whereby the drug itself consists of microbes. The microbial consortia are engineered and clinically proven to restore symbiosis and drive immune function, oftentimes as an adjunct to other treatment methods. One such company, Biomica, designs microbial consortia with anti-tumour immune activity, which can be used as combination therapy with immune checkpoint inhibitors (ICI). MaaT Pharma’s biotherapeutics (named “Microbiome Ecosystem Therapies”) also serve as a combination therapy for ICI, and additionally take on graft vs. host disease in allo-HCT cancer patients. Several other companies (including Seres, 4D Pharma, and Osel) are developing multi- indication pipelines using live biotherapeutics that span the immuno-oncology space. Perhaps even more tellingly, we are beginning to witness not just involvement of emerging players, but also the advent of big pharma’s attention on the microbiome’s role within oncology. For example, in 2022, Johnson & Johnson announced its collaboration with Persephone Biosciences to study microbiome markers for colorectal cancer, and has continued to build upon five years of funding for the Janssen Human Microbiome Institute, which boasts partnerships from academia to biotech. This combination of activity, from diagnostics to drug discovery, across sectors and throughout multiple cancer types, demonstrates the enormous potential of the human microbiome for the detection and care of cancer – and other indications – using next generation technologies. Conclusion The adoption of precision medicine techniques – including NGS, biomarker- informed diagnostics, AI-driven drug discovery, personalised biotherapeutic approaches, and more – has enabled an explosion of research and commercial development in the microbiome space. These tools are facilitating advances across a broad array of application areas, notably including oncology. Thanks to next generation technologies, we are learning that the microbiome may hold the key to better diagnosis and complementary treatment, and ultimately, superior standards of care. DDW Volume 24 – Issue 3, Summer 2023 References Levy M, Thaiss CA, Elinav E. Metagenomic cross-talk: the regulatory interplay between immunogenomics and the microbiome. Genome Med 2015;7:120. PubMed Adams, E, Sepich-Poore, GD, Miller-Montgomery S, Knight R. VIEW. 2022;3:20200118. About the authors: Katie Gillette specialises in pharma diagnostic and research tools across the entire precision medicine spectrum. Through this work, she seeks to drive access to the unique data and strategic insights that facilitate broader adoption of technologies. Gillette has led, global consulting engagements, particularly within spatial biology, next-gen technologies, and bioinformatics. Eliza French is an analyst at DeciBio working across the next-gen technology spectrum, with a focus on research tools and diagnostics. She is particularly interested in leveraging DeciBio insights on next-gen technologies toward the microbiome to encourage the continued exploration of this exciting bio signature. An analyst at DeciBio, Graham Friedman is involved in work relating to oncology biomarker diagnostics, liquid biopsy, and synthetic biology. He has an interest in the microbiome broadly and the ways it can be leveraged to develop innovative, personalised patient care.