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 presents the possibility of using phages to modulate the gut microbiome to improve health.
Led by scientists from the Weizmann Institute of Science in Israel, the new study analyzed the composition of the gut microbiota of 537 patients with IBD and found that these people tended to have more bacteria called Klebsiella pneumoniae(Kp). When they transplanted Kp into mice, the animals developed severe intestinal inflammation and tissue damage, suggesting that these Kp strains may contribute to the worsening of IBD.
The researchers then identified 40 phages that appear to be effective against IBD-contributing Kp strains and narrowed them down to a combination of five phages, each using a different receptor to enter bacteria and kill them through different mechanisms.
Even if bacteria mutate, making one of their receptors resistant, there will be safeguards, said Eran Elinav, director of the Department of Systems Immunology, Weizmann Institute of Science and Microbiome & Cancer Division, German National Cancer Center (DKFZ) and corresponding author of the study. Effective cocktail design can prevent the formation and spread of phage-resistant bacteria, he added.
“To our knowledge, we are the first to use an orally-administered phage combination therapy against a disease-contributing gut commensal, while addressing the huge problem of phage resistance and treating a disease not transmissible”, said Dr Elinav.
Efficiency
Studies in test tubes and lab mice have shown that this phage cocktail can suppress Kp and reduce inflammation and associated tissue damage.
“This proof-of-concept study uses phages as a precision weapon to suppress 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 bugs associated with IBD, as well as commensals implicated in other diseases, including obesity, diabetes, cancer, neurodegenerative diseases, etc.
Expert: “Phages have enormous potential in the management of intestinal disorders and health”
Independently commenting on the research, Mark Miller, PhD, of Kaiviti Consulting, LLC, told NutraIngredients-USA the multi-level comprehensive study “points out that phages have enormous potential in the management of gut disorders and health.
“This is an impressive collaborative study that provides stellar ‘proof-of-principle’ that phages play a role in mitigating pathology caused by antibiotic-resistant bacteria, in this case inflammatory bowel disease. intestine (IBD) where flare-ups of the disease are caused by the pathogen, Klebsiella pneumoniae.
Crucially, using these phages did not cause dysbiosis, Dr. Miller added. “Microbiome diversity was intact except for the target, Klebsiella, whose levels were significantly decreased by phage therapy,” he noted.
“This study is essential for several reasons,”added Dr. Miller. “First, it clearly demonstrates that phage therapy is effective in reversing the devastating effects of antibiotic-resistant bacteria in predictive models. Second, it shows that the phages are orally active and safe. They don’t disrupt the good bacteria that exist in our microbiome, and they don’t target host cells. »
Dr Miller said phages offer enormous potential in the management of diseases caused by antibiotic resistant bacteria, “where we essentially lack therapeutic resources.
“This article highlights the potential of phages. He points out that there is significant hope for conditions of massive societal concern – the endemic presence of antibiotic-resistant bacteria.
Let’s move on to humans
Dr Elinav and his colleagues 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 without affecting the surrounding microbiota.
“Phage therapy showed an excellent safety profile, with no adverse effects”, commented Dr. Miller. “It is really encouraging.”
The research team now plans to test the 5-phage cocktail in a phase II trial enrolling patients with IBD who harbor the disease-contributing Kp strains.
Additionally, Elinav and her team would work on identifying bacteria associated with other diseases and developing effective phage combination therapies against them.
“What we envision is a precision medical pipeline,” Elinav said. “Using it, we can characterize the pathogenic bacteria of a person suffering from a disease related to the intestinal microbiota, and then apply phage therapy that would be adapted to the individual to suppress the bacteria.
Funding
The project was financially supported 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 the treatment of gut inflammation”
Authors: S. Federici et al.
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