A Taxonomy-Agnostic Approach to Targeted Microbiome Therapeutics-Leveraging Principles of Systems Biology

Abstract

The study of human microbiomes has yielded insights into basic science, and applied therapeutics are emerging. However, conflicting definitions of what microbiomes are and how they affect the health of the "host" are less understood. A major impediment towards systematic design, discovery, and implementation of targeted microbiome therapeutics is the continued reliance on taxonomic indicators to define microbiomes in health and disease. Such reliance often confounds analyses, potentially suggesting associations where there are none, and conversely failing to identify significant, causal relationships. This review article discusses recent discoveries pointing towards a molecular understanding of microbiome "dysbiosis" and away from a purely taxonomic approach. We highlight the growing role of systems biological principles in the complex interrelationships between the gut microbiome and host cells, and review current approaches commonly used in targeted microbiome therapeutics, including fecal microbial transplant, bacteriophage therapies, and the use of metabolic toxins to selectively eliminate specific taxa from dysbiotic microbiomes. These approaches, however, remain wholly or partially dependent on the bacterial taxa involved in dysbiosis, and therefore may not capitalize fully on many therapeutic opportunities presented at the bioactive molecular level. New technologies capable of addressing microbiome-associated diseases as molecular problems, if solved, will open possibilities of new classes and categories of targeted microbiome therapeutics aimed, in principle, at all dysbiosis-driven disorders.

Keywords: FMT; dysbiosis; microbiome; phage therapy; systems biology; targeted therapeutics.

Figure 1

Systems-wide Impacts of Dysbiosis. General impact of microbiome status on function of the “host” or holobiont. Both positive and negative effects are mediated by bioactive molecules produced by bacteria, viruses, and fungi in the gut microbial ecosystem. Reproduced with permission from SNCSC from: Dekaboruah, E.; Suryavanshi, M.V.; Chettri, D.; Verma, A.K. Human microbiome: an academic update on human body site specific surveillance and its possible role. Archives of microbiology 2020, 202, 2147–2167, doi:10.1007/s00203-020-01931-x [13].

Figure 2

Microbiome Ecosystem in Health. In health, a self-regulated ecosystem forms, driven by diet and environmental factors that promote a diverse, pathogen-resistant microbiota, which in turn produces predominantly beneficial metabolites and limited exposure to deleterious microorganism-produced bioactive molecules. A normal mucous layer is maintained, and epithelial cell barrier function is sustained, limiting the amounts of lumenal materials translocated into the circulation and maintaining a low-inflammation, low oxidant-stress environment. Created with BioRender.com.

Figure 3

Microbiome Ecosystem in Dysbiosis. Dysbiosis is commonly triggered by dietary and other environmental factors, which differentially support opportunistic pathogens/pathobionts as microbial constituents. “Blooms” of pathobionts exclude beneficial bacteria from ecological niches, resulting in low-diversity populations dominated by bacteria that contribute to “molecular pollution” in the ecosystem. Such “pollution” consists of high levels of toxic or damaging bacterial metabolites, virulence factors, and microbe-associated molecular patterns (MAMPs). These disruptions contribute to a thinning mucous layer, support build-up of biofilms that can harbor and protect pathobionts, and damage epithelial junctional proteins resulting in influx of bioactive molecules into the epithelial layer and into the circulation, where they drive elevated levels of inflammation both within the gut and in extra-intestinal tissues. Created with BioRender.com.

Figure 4

Schematic diagram of FMT—a taxon-agnostic, non-targeted approach to microbiome therapeutics, showing strengths and vulnerabilities compared with other modalities.

Figure 5

Schematic diagram of bacteriophage therapy, a taxon-dependent, targeted approach to microbiome therapeutics, showing strengths and vulnerabilities compared with other modalities.

Figure 6

Shows a schematic summary of the pros and cons of taxon-dependent metabolic toxins, a taxon-dependent, targeted approach to microbiome therapeutics, showing strengths and vulnerabilities compared with other modalities.