Paul Denslow, CEO, Intus Bio, discusses how a new approach to tracking gut bacteria can revolutionse our understanding of the microbiome and bring about new discoveries for therapeutics.
It’s a long-held doctrine that there’s no effective method to track the microbiome during drug research and development. This doctrine no longer holds.
For many years, an essential yet elusive variable in drug research and development has been the role of bacteria. As the most prevalent cell type in mammals, bacteria dramatically outnumber human cells. While the human genome boasts around 23,000 genes, the average human gut encompasses approximately 2,000,000 genes. Unravelling the influence of these gut bacteria—commonly referred to as the bacterial gut microbiome—on drug response and immune response will bring fundamental changes to how we approach drug discovery and development, as well as patient care.
Despite the growing understanding of the role of bacteria in drug response, the microbiome’s influence has typically been considered a ‘known unknown’ and sidestepped due to technological constraints. However, as technology advances, the situation is changing. By using new tools which exploit the power of next-generation sequencing (NGS), drug developers can now gain valuable insights into how bacteria impact their program. This offers a host of benefits including enhanced stratification, de-risking, and drug efficiency, thereby improving the chances of successful outcomes.
This potential paradigm shift should have a revolutionary impact on pharmaceutical research and development. Furthermore, understanding how the microbiome influences drug metabolism and its complex interaction with the immune system requires one to accurately “see” individual microbiomes. The new tools provide insights into a patient’s microbiome that open new opportunities for truly personalised medicine. Using this information, drugs could be tailored to bacterial profiles, or bacteria could be introduced or removed to induce therapeutic response or to avoid toxic reactions that have been observed during drug development1
Traditionally, there have been two dominant methods for tracking gut bacteria. Both have presented significant drawbacks which have restricted their widespread application in drug development. One involves sequencing all or part of the 16S gene unique to bacteria, while the other encompasses sequencing the entire bacterial genome—an approach known as “metagenomics.” The former offers high throughput yet lacks resolution, and the latter provides high resolution but low throughput. This dichotomy has long required researchers to choose between data quantity and data quality, with most opting for neither. This is typical even when the microbiome could be the obvious place to look for non-response or toxicity, such as drugs targeting gut and autoimmune issues, or drugs which look to exploit the adaptive and innate immune systems. A host of other indications including cancer, diabetes, and neurodegenerative and infectious diseases have all been connected to the microbiome.
There is now a new approach that leverages long-read NGS technology that targets the 16S-ITS and partial 23S gene. This region carries sufficient variation to differentiate bacteria on a high-resolution (i.e., strain level) basis, while being a short enough sequence to facilitate high-throughput processing—a ‘Goldilocks’ solution to the prevailing conundrum. This approach has the potential to revolutionise our understanding of the microbiome, provide practical ways to see the role it plays in drug discovery and development, and lead to a new era in personalised medicine.
Recent studies underscore the power of this approach. In one such study2 that examined low PD-L1 immunotherapy response rates, this technique identified bacterial strains linked with response in humans. When these strains were introduced into non-responder mice, they became responders. The broader implications of such findings are monumental; at the very least, it demonstrates that a scalable technology exists to power patient stratification based on gut bacterial profiles and that it can be used to predict drug response. Introducing bacteria to a subject to induce response could be thought of as ‘personalising the patient’ rather than the drug, opening new paths to development and treatment success.
This technology’s applicability extends beyond clinical-stage research—it is invaluable in preclinical stages, as well. Current mouse models offer identical host genetics but overlook bacterial genetics. With up to 90% of blood metabolites either originating from or influenced by gut bacteria3, these new tools promise more effective mouse models, leading to valuable insights into potential drug candidates’ safety and efficacy before human trials, as well as identifying the source of unaccounted metabolism. Moreover, more accurate mouse studies could provide valuable data on dosage, administration frequency, and administration routes, while reducing clinical trial risks, development costs, and time to market.
Further, this technique can be instrumental for live biotherapeutic product (LBP) development. It’s crucial to monitor the whole microbiome and track individual biotherapeutic strains during research. Live biotherapeutic product developer Siolta Therapeutics published a study4 which concluded that this new long-read approach was the most effective for tracking biotherapeutics post-administration in humans. By providing a more complete picture of the microbiome, differentiating between biotherapeutics and closely related endogenous strains, this technique could accelerate the development of LBPs and help bring these innovative treatments to patients more quickly. Other studies have confirmed its utility in understanding the skin microbiome5 and tracking pathogens6.
Practical technologies that accurately track the microbiome, thereby enabling greater control at every stage of drug research and development, are essential and finally here. They offer drug developers new tools for enhancing stratification, enrichment, de-risking, safety and efficiency. This leads to quicker identification of efficacy and toxicity issues, higher success rates, and improved ROI for investors and sponsors. The unveiling of this long-standing “known unknown” is an exciting development—one capable of starting a revolution that should have an ever-increasing impact on the drug discovery and development industry for years to come.
About the author
Paul Denslow is the CEO of Intus Biosciences. Intus Bio’s world-leading technology identifies bacteria and delivers answers about the microbiome with unprecedented detail, accuracy, and scale. Its patented, validated Titan-1 platform combines high-throughput assay and analysis technology and is unique in generating strain-level information. The company provides research and commercial services across global pharmaceutical, diagnostic, and testing industries; is active in health, agricultural, and environmental fields; and continues to develop innovative new partnerships, technologies, and applications.
REFERENCES
- Rosshart, S. P. et al. Laboratory mice born to wild mice have natural microbiota and model human immune responses. Science (80-. ). 365, (2019)
- .Huang, J. et al. Ginseng polysaccharides alter the gut microbiota and kynurenine/tryptophan ratio, potentiating the antitumour effect of antiprogrammed cell death 1/programmed cell death ligand 1 (anti-PD-1/PD-L1) immunotherapy. Gut 71, Issue 4 (2022) 3
- Nat. Metab. 4, 1560–1572 (2022) 4
- Gehrig, J. L. et al. Finding the right fit: evaluation of short-read and long-read sequencing approaches to maximize the utility of clinical microbiome data. Microbial Genomics Vol 8, Issue 3 (2022)
- Rozas, M et al. MinION™ Nanopore Sequencing of Skin Microbiome 16S and 16S-23S rRNA Gene Amplicons Frontiers in Cellular and Infection Microbiology Vol 11 (2022)
- Graf, J. et al. High-Resolution Differentiation of Enteric Bacteria in Premature Infant Fecal Microbiomes Using a Novel rRNA Amplicon mBio Vol 12 No.1 (2021)
