The biodiversity of the human gut is significant: In addition to bacteria (the microbiome), and fungi (the mycobiome), the gut also contains hundreds of thousands of viruses called bacteriophages, which can infect bacteria.
New data published in the journal Cell now showcases the possibility of using phages for modulating the gut microbiome to improve health.
Led by scientists from Israel’s Weizmann Institute of Science, the new study analyzed the gut microbiota compositions of 537 IBD patients and found these people tended to have more bacteria called Klebsiella pneumoniae (Kp). When they transplanted Kp into mice, the animals developed a severe intestinal inflammation and tissue damage, suggesting that these Kp strains may contribute to worsening of IBD.
The researchers then identified 40 phages that appear to be effective against the IBD-contributing Kp strains and narrowed this down to a combination of five phages, each of which uses a different receptor to enter bacteria and kills them through different mechanisms.
Even if the bacteria mutate, rendering one of their receptors resistant, there will be back-ups, said Eran Elinav, director of the Systems Immunology department, Weizmann Institute of Science and the Microbiome & Cancer Division, German National Cancer Center (DKFZ) and the corresponding author of the study. An effective cocktail design can prevent phage-resistant bacteria from forming and spreading, he added.
“To our knowledge, we are the first to use an orally-administered phage combination therapy against a disease-contributing gut commensal, while tackling the huge issue of phage resistance and treating a non-communicable disease,” said Dr Elinav.
Efficacy
Studies in test tubes and lab mice showed that this phage cocktail could suppress Kp and reduce the associated inflammation and tissue damage.
“This proof-of-concept study utilizes phages as a precision weapon in suppressing a group of commensal strains contributing to IBD,” said Dr Elinav.
“But our vision is that this new modality could potentially be developed and applied against a number of other IBD-associated bugs, and also against commensals that are involved with other diseases, including obesity, diabetes, cancer, neurodegenerative diseases, and more.”
Expert: “Phages have massive potential in the management of gut disorders and health”
Commenting independently on the research, Mark Miller, PhD, from Kaiviti Consulting, LLC, told NutraIngredients-USA the comprehensive, multi-layered study “emphasizes that phages have massive potential in the management of gut disorders and health.
“This is an impressive collaborative study that provides stellar “Proof of Principle” that phages have a role in alleviating pathology driven by antibiotic resistant bacteria, in this case Inflammatory Bowel Disease (IBD) where disease flares are caused by the pathogen, Klebsiella pneumoniae.
Dr Miller added that, importantly, the use of these phages did not cause a dysbiosis. “The microbiome diversity was intact with the exception of the target, Klebsiella, whose levels were greatly diminished by phage therapy,” he noted.
“This study is critical for several reasons,” added Dr Miller. “Firstly, it clearly demonstrates that phage therapy is effective in negating the devastating effects of antibiotic resistant bacteria in predictive models. Secondly, it shows that phages are orally active and safe. They do not cause a disruption of the good bacteria that exist in our microbiome, and they do not target host cells.”
Dr Miller said that phages offer massive potential in managing disease driven by antibiotic-resistant bacteria, “where we have basically run out of therapeutic resources.
“This paper highlights the potential of phages. It emphasizes that there is significant hope for conditions of massive societal concern – the endemic presence of antibiotic resistant bacteria.”
Moving on to humans
Dr Elinav and his co-workers also conducted a Phase I human clinical trial with 18 healthy volunteers. The trial showed that the phages can survive at high levels and remain active throughout the gastrointestinal tract when taken with antacids while not impacting the surrounding microbiota.
“The Phage therapy presented an excellent safety profile, with no adverse events,” commented Dr Miller. “This is very encouraging.”
The research team now plans to test the 5-phage cocktail in a phase II trial encompassing IBD patients that harbor the disease-contributing Kp strains.
In addition, Elinav and his team are said to be working on the identification of bacteria associated with other diseases and the development of effective phage combination therapies against them.
“What we envision is a precision medical pipeline,” said Elinav. “Using it, we can characterize the pathogenic bacteria of a person suffering from a disease related to the gut microbiota, and then apply a phage therapy that would be tailored to the individual to suppress the bacteria.”
Funding
The project was supported financially by Takeda, Janssen, Abbott, Pfizer, Abbvie, Neopharm, Corundum Innovation Ltd, Mycolivia, and Nestlé.
Source: Cell
Published online ahead of print, doi: 10.1016/j.cell.2022.07.003
“Targeted suppression of human IBD-associated gut microbiota commensals by phage consortia for treatment of intestinal inflammation”
Authors: S. Federici et al.
