Rehabilitation of a misbehaving microbiome: phages for the remodeling of bacterial composition and function

Abstract

The human gut microbiota is considered an adjunct metabolic organ owing to its health impact. Recent studies have shown correlations between gut phage composition and host health. Whereas phage therapy has popularized virulent phages as antimicrobials, both virulent and temperate phages have a natural ecological relationship with their cognate bacteria. Characterization of this evolutionary coadaptation has led to other emergent therapeutic phage applications that do not necessarily rely on bacterial eradication or target pathogens. Here, we present an overview of the tripartite relationship between phages, bacteria, and the mammalian host, and highlight applications of the wildtype and genetically engineered phage for gut microbiome remodeling. In light of new and varied strategies, we propose to categorize phage applications aiming to modulate bacterial composition or function as "phage rehabilitation." By delineating phage rehab from phage therapy, we believe it will enable greater nuance and understanding of these new phage-based technologies.

Keywords: Microbiome; Virology.

Graphical abstract

Figure 1

Mechanisms of phage interaction with bacteria and the mammalian host (A) Infection of bacteria with virulent phage leads to cell lysis and the release of progeny phage. (B) Temperate phage infection of a host bacterium can lead to the lytic life cycle or genomic integration into the bacterial chromosome as a prophage and the lysogenic life cycle. (C) Phage can attach to the mucosa through interactions with the capsid. (D and E) (D) Phage can cross the intestinal epithelium through transcytosis or (E) within a bacterial cell.

Figure 2

Modulation of bacterial function by genetically engineered phage (A) Over-expression of wildtype rpsL expressed from λ phage re-sensitizes the host bacterium to the antibiotic, streptomycin. (B) CRISPR-Cas elements expressed from a λ prophage or an M13 phagemid can re-sensitize bacteria to β-lactam antibiotics through the cleavage of plasmids containing antibiotic resistance genes (e.g., β-lactamases). (C) Expression of a transcriptional repressor for Shiga toxin (Stx) from a λ prophage can inhibit production of the toxin from bacteria colonizing the murine gut. (D) Expression of a nuclease inactivated Cas9 element from a λ prophage can be programmed to repress the expression of specific genes, such as a fluorescent marker protein, Red Fluorescent Protein (RFP).