The human microbiome is composed of diverse populations that include bacteria, fungi, bacteriophages and viruses, and it is unique to each individual and body site (e.g., gut, skin, nostrils, etc.). The microbiome and its host interact dynamically, and usually coexist in harmony. However, a disruption of microbiome homeostasis can lead to disease in the host, while conversely some host diseases cause an imbalance of the microbiome.
With the availability of genome sequencing, and omics-tools (metagenomics, metabolomics and metatranscriptomics) the far-reaching role of the microbiome in human health has become more apparent. Until recently, infections by Clostridioides difficile (C. difficile) were recognized as the primary disease associated with the microbiome. However, there is now evidence that the microbiome may play an important role in a myriad of diseases that include diabetes, obesity and neurodegenerative conditions. In addition to its role in the clinical manifestation of disease, the microbiome can also influence treatment outcome by modulating drug metabolism and/or the host’s response to therapies such as immune checkpoint inhibitors in oncology.
Throughout this series of blog posts and proprietary research DRG will explore the application of microbiome based therapies across different therapeutic areas – including infectious diseases, oncology, and immune disorders. Although there are many therapies at various stages of development, they can be split into two major categories:
Microbiome modulation. This approach consists of altering the microbial flora composition, which can be achieved through administration of the following treatments or procedures:
- Prebiotics: Prebiotics are defined as non-digestible food components that are substrates of select bacterial populations already established in the host’s microbiome. Their use leads to an enrichment of those subpopulations, and to a “healthier” microbiome.
- Probiotics: Probiotics consist of specific bacteria/strains that are often administered with the intent of conferring benefits, which can include the prevention of intestinal disorders or health promotion.
- Fecal microbiota transplantation (FMTs). FMTs are an area where many advances have been made, particularly in the treatment of difficile infections. The principle behind this approach is the inoculation of bacteria present in feces that will displace or outcompete the native microflora/colonizing pathogens. The most basic FMTs, also called first-generation FMTs, consist of the direct transfer of fecal material from a healthy donor to a patient, with minimal processing. Based on the effectiveness of first-generation FMTs in treating disease, some companies have started to develop the so-called second generation FMTs, which are commercially prepared fecal transplants from donor sample banks, as well as third-generation FMTs that comprise laboratory grown, fully characterized microbial consortia (single or multiple strains).
- Phage therapy. Phages are highly specific bacterial viruses that can be found in the microbiome and are responsible for maintaining an appropriate balance between bacterial species. Some phages can lead to bacterial death through lysis; due to the increasing rates of antimicrobial resistance, there has been a rekindled interest in the therapeutic applications of phages due to their high specificity to specific bacterial strains and/or species. Upon isolation, they can be used for targeted therapy, allowing the elimination of the disease-causing pathogenic species with minimal collateral damage to other bacteria.
- Natural molecules. Some bacteria naturally produce proteins/peptides that have potent antimicrobial activity (i.e., bacteriocins such as lantibiotics or thuricin); these molecules are chemically and structurally different from currently available antibiotics, and have the potential to be developed for the treatment of bacterial infections. Other bacteria synthesize bioactive molecules that can play a role in the host’s physiology, such as exopolysaccharides or polyunsaturated fatty acids, which can be explored for their intrinsic properties (e.g., immunomodulatory properties, decrease in blood cholesterol levels).
Microbiome engineering. A different approach relies on genetically engineering bacteria to be used as vehicles to deliver drugs or genes, and thereby treat disease. The bacteria are provided with novel enzymatic pathways through the introduction of new genes, which can result in the secretion of enzymes with specific properties (e.g. degradation of phenylalanine) or the synthesis of products with intrinsic activity (e.g. human trefoil factor). This can be a particularly useful approach when the mechanism of disease is well understood, as it allows to directly approach the treatment of the disease, while in contrast, the impact of microbiome modulation in a disease can be more difficult to interpret. While development of new therapies using modulation approaches is more advanced than this strategy, there are already some assets in clinical stages of development.
In what direction are we moving towards?
Despite advances in microbiome-targeting therapies, we are just starting to understand the complex interactions within the microbiome and also between the microbiome and its hosts, limiting our ability to effectively manipulate this multi-faceted organism and understand the implications of such manipulation. However, as we will discuss in the coming months, the microbiome could prove an important source of novel approaches for the treatment of multiple indications.
Nuno Antunes is a Senior analyst on Infectious, Niche, & Rare Disease team at DRG, currently covering the hospital antibiotic markets, including Gram-Negative Infection and C. difficile Infection.
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