The gut is a very complex place. It is home to a variety of microbes, including phages. How phages interact in this vicinity is only just starting to be thoroughly characterized. This makes it an exciting time to work in this field, but also presents a challenge. Our challenge is how to use phage to only kill specific strains in the gut in order to prevent life-threatening bacterial infections.
The drug resistance problem
Multidrug resistant (MDR) strains of bacteria are infecting millions of people yearly. Many of these deadly strains are enteric—bacteria that naturally reside in the gut. By eliminating these strains from the gut, we may be able to prevent life-threatening disease as well as the spread of drug resistance.
The problem with ExPEC
My work has focused on the use of phages to treat Extraintestinal pathogenic E. coli or ExPEC. These pathogens are the number one cause of UTI and the primary cause of both neonatal meningitis and adult bacteremia. These strains are multidrug-resistant and likely responsible for the global dissemination of drug resistance. More troubling, these pathogens have been found in our companion animals, in our food, and within our own gut: the primary ExPEC reservoir.
How phages can help
Phages have the ability to kill or lyse drug-resistant strains of bacteria. They are also evolvable, and we can evolve them to lyse bacterial strains that have developed resistance to phages. The greatest benefit to using phages in the gut is phage specificity. Phages can target and lyse specific strains of bacteria while leaving the rest of the microbiota intact.
Targeting ExPEC with phages
We have been able to isolate a library of phages that target MDR ExPEC strains. Common laboratory phages do not infect these bacteria. So, most of our ExPEC-targeting phages have been isolated from known reservoirs of ExPEC, including chickens, pigeons, ducks, and dogs. Using these phages, we have been able to treat MDR bacteremia in mouse models that recapitulate ExPEC disease. However, our ultimate goal is to remove these strains from their primary reservoir to prevent disease and the dissemination of drug-resistant strains.
Phage therapy in the human gut
Since the discovery of phages, these predatory viruses have been used to treat people with intestinal bacterial infections. There are many individual accounts of their successful use in the gut.
Of the major clinical trials related to gut therapy, one is frequently mentioned and cited—the Phase I/II trial for E. coli pediatric diarrhea in Bangladesh in 2009. In this trial, hospitalized children received either a cocktail of T4 phages, a cocktail of phages directed against E. coli and Proteus species, or saline. The trial was halted due to lack of efficacy, although there were no reported adverse effects. One hypothesis proposed for the lack of efficacy was low phage titers in the gut. This may have been attributed to how it was dosed: orally, without antacid. Phages are pH-sensitive, and do not normally survive gastric transit. Also, the low titer may have been attributed to the characteristics of the pathogen within the gut. Low pathogen titer in the gut could reduce phage titer in the gut, because phages require bacteria to replicate.
What’s needed next
Before phages can be used in the gut, it is important to understand the gut environment, and to understand how the targeted pathogen colonizes this environment. Phages should be tested in model systems that can recapitulate human disease. A library of phages suited to target these pathogens within this environment is also needed. Overcoming these challenges will allow us to use phages to eliminate deadly MDR bacteria from the gut and prevent disease.
McCallin, S., & Brüssow, H. (2017). Clinical Trials of Bacteriophage Therapeutics. Bacteriophages: Biology, Technology, Therapy, 1-29.
Brüssow, H. (2017). Phage therapy for the treatment of human intestinal bacterial infections: soon to be a reality?