Julius Goepp, Thomas Patton, Paul Cox

Bacteriophage viruses (“phages”) were first proposed in the early 20^th century, prior to the discovery of antibiotics, as a means of controlling or eliminating infectious bacteria^1,2. After falling out of favor with the advent of antibiotics, phage therapy is experiencing a renaissance in treatment of antibiotic-resistant bacterial infections³, and now in the field of microbiome therapeutics^1,3,4.

Phages are highly species- and often strain-specific viruses that rapidly replicate within, and then destroy target bacterial cells^3-5.  Phages endogenous to gut microbiomes are increasingly recognized as important dynamic factors in overall microbiome composition and function – indeed, it has been suggested that some of the microbiome composition changes seen in microbiome-associated disorders (MADs) like inflammatory bowel disease (IBD), for example, are driven at least in part by “blooms” of endogenous phages⁴. This is an area of microbiome science that remains in its infancy, but such deleterious phages may ultimately themselves represent targets for selective therapeutic microbiome modification^6,7.

In the context of microbiome therapeutics, “phage therapy” refers to the administration of phage viruses to selectively reduce populations of pathobionts known to promote MADs. Preclinical studies have demonstrated successful resolution of dysbiotic microbiomes and improvements in phenotype in alcoholic liver disease⁸, intestinal inflammation and IBD^9,10, colorectal cancer and others^10-14.

Phage therapies offer several key advantages in the quest for targeted microbiome therapeutics. From a research perspective, experimental phage applications can help in understanding the complex networks of bacterial contributions to MADs, even permitting identification of primary pathobiont “driver” strains and secondary “passenger” strains, in which altered abundance arises from disease-related processes, and whose alterations may be less effective in changing disease phenotype^10,15,16.

By selectively infecting and killing their target bacterial hosts, phages promise to entirely eradicate populations of pathobionts, reducing their impact on host tissues and ultimately phenotype^4,5. Phage host-specificity is determined by specific bacterial cell-binding structures that differ according to target hosts¹⁷. Their high host-specificity means that they can leave uninvolved or beneficial microorganisms largely intact, limiting off-target effects^4,5. Furthermore, rational selection of phages and target bacteria may permit development of phage therapeutics that can overcome development of individual bacterial resistance to specific phages, especially when various phages operate by different mechanisms in attacking their targets^10,18-20.

A recently published study highlights many of the promises of rationally-designed phage therapeutics in MADs, specifically in IBD¹⁰. Using metagenomic techniques, researchers identified a clade of strains of Klebsiella pneumoniae that were strongly associated with IBD disease exacerbation and severity; through experimental FMT of human IBD-associated K. pneumonia strains into mice, they were able to demonstrate microbiome-associated increased inflammation in recipient animals¹⁰. Subsequently, they generated a “cocktail” of five lytic phages known to lyse and destroy their target bacteria by different mechanisms, providing the requisite overlap in function to avoid resistance to any single phage. Experiments in colitis-prone mice showed that administration of this phage cocktail suppressed the offending K. pneumoniae strains, reducing the gut inflammatory response and disease severity as predicted. Further study in human volunteers demonstrated survival of the phages through the upper gastrointestinal tract and their viability in the colon, where the target bacteria are found.

These findings open the door to a form of “sculpting” of a disease-prone dysbiotic microbiome in humans, using phage therapeutic techniques, and provide a proof-of-principle that such selective microbiome modulation can have a direct beneficial effect in a chronic, human, noncommunicable disease, IBD, while raising the real possibility that similar interventions may arise in the cases of other MADs^9,10. Phage therapies, then, may be seen as highly targeted approaches to dysbiosis at the taxonomic level.

Limitations of microbiome phage therapies remain, however. While bacterial resistance can be reduced by careful selection of therapeutic phage combinations, we know from long experience with small-molecule antibiotics that bacteria can rapidly evolve strategies to overcome even the most carefully-designed, mechanistically overlapping therapies²¹. While few data exist in microbiomes, experience in complex macroscopic ecosystems suggests a real risk of unintended consequences produced by introduction or translocation of predators (the approximate equivalent of lytic phages in microbiomes), and suggest that suppression, rather than eradication, may sustain desired function with fewer long-term risks²².

One additional limitation applies to phage therapeutics in a microbiome setting, namely, the vital emerging roles of non-bacterial drivers of dysbiosis. These include viruses other than phages, which are increasingly recognized as important in maintaining gut ecological balance and contributors to dysbiosis in disease^23-26, as well as fungi and protozoans^27-31. Phages targeting bacteria exclusively are unable to directly affect these organisms of emerging importance. Furthermore, while phage therapeutics have been shown to indirectly affect bacterial metabolites, by their nature phages are unable to directly block or neutralize bacterial metabolites and virulence factors of the kind now recognized as important players in a dysbiotic molecular milieu⁵ Finally, phage therapeutics cannot be employed in managing microbiome disruptions mediated by molecular signals from the enormous mass of microbial “dark matter,” given that an identified living bacterium is required as a target/host.

Ultimately, in the context of the ecological definition of a microbiome, including not only bacterial taxa but also the products of the microbiota and the host environment, phage therapeutics can provide only partial solutions.

Figure 1 shows a schematic summary of the pros and cons of bacteriophage therapy. 

 

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