The Age of Next-Generation Therapeutic-Microbe Discovery: Exploiting Microbe-Microbe and Host-Microbe Interactions for Disease Prevention

Abstract

Humans are considered "superorganisms," harboring a diverse microbial collective that outnumbers human cells 10 to 1. Complex and gravely understudied host- and microbe-microbe interactions-the product of millions of years of host-microbe coevolution-govern the superorganism in almost every aspect of life functions and overall well-being. Abruptly disrupting these interactions via extrinsic factors has undesirable consequences for the host. On the other hand, supplementing commensal or beneficial microbes may mitigate perturbed interactions or enhance the interactive relationships that ultimately benefit all parties. Hence, immense efforts have focused on dissecting the innumerable host- and microbe-microbe relationships to characterize if a "positive" or "negative" interaction is at play and to exploit such behavior for broader implications. For example, microbiome research has worked to identify and isolate naturally antipathogenic microbes that may offer therapeutic potential either in a direct, one-on-one application or by leveraging its unique metabolic properties. However, the discovery and isolation of such desired therapeutic microbes from complex microbiota have proven challenging. Currently, there is no conventional technique to universally and functionally screen for these microbes. With this said, we first describe in this review the historical (probiotics) and current (fecal microbiota or defined consortia) perspectives on therapeutic microbes, present the discoveries of therapeutic microbes through exploiting microbe-microbe and host-microbe interactions, and detail our team's efforts in discovering therapeutic microbes via our novel microbiome screening platform. We conclude this minireview by briefly discussing challenges and possible solutions with therapeutic microbes' applications and paths ahead for discovery.

Keywords: defined microbial consortia; fecal microbiota transplant; host-microbe interactions; microbe-microbe interactions; next-generation sequencing; probiotics; therapeutic microbes; unculturables.

FIG 1

Milestones in the discovery of potential therapeutic microbes in human evolution (80, 81, 91, 99, 135–138).

FIG 2

FMT applications in selected noninfectious conditions and infectious diseases (58, 89, 91, 133, 139–142). These include gastrointestinal illness (143), obesity (141), autism (144), dysbiosis resulting from antibiotics (142), and infection with rotavirus (88), Candida (58), and C. difficile (90, 145).

FIG 3

Schematic representation of a microbiome screening platform to identify therapeutic microbes against the antibiotic-resistant pathogens C. difficile and MRSA (146).

FIG 4

Circular flow diagram highlighting the critical steps needed for therapeutic-microbe discovery. (1) Therapeutic-microbe source: human, animal, or environment. (2) Next-generation culturing methodologies (ichip, large-cohort cultivation, etc.) to collect unculturable microbes. (3) Isolating, cataloguing, and preservation of cultured novel microbial species to generate a large microbial biobank. (4) Generating and sharing high-density microbial cell arrays for microbe-pathogen screening. (5) Concomitant analysis of real-time genome sequencing and high-resolution microscopy to identify potential therapeutic microbes. (6) Preclinical testing of isolated therapeutic microbes. (7) Initiation of clinical trials to appreciate efficacy of therapeutic microbes and subsequent mass production, per FDA guidelines. A.I., artificial intelligence.