Researchers have developed a therapy that can target the bacteria behind inflammatory bowel disease (IBD) without damaging friendly gut bugs. The therapy is based on a combination of bacteria-killing viruses called phages.
IBD includes a group of chronic inflammatory disorders of the gut. Previous research has suggested that certain gut bacteria are linked to the disease. Phage therapies are a promising solution, but the problem is that bacteria develop resistance rapidly, explains Eran Elinav, Director of the Weizmann Institute of Science, Israel. ‘To our knowledge, we are the first to use an orally administered phage combination therapy against a disease-contributing gut commensal [microbe], while tackling the huge issue of phage resistance and treating a non-communicable disease.’
Elinav’s team, in collaboration with a group of international scientists, compared the gut microbiota compositions of 537 IBD patients to healthy controls enrolled in studies in France, Israel, the US and Germany (Cell, doi: 10.1016/j.cell.2022.07.003). The team found the IBD patients tended to have a group of bacteria called Klebsiella pneumoniae (Kp) enriched in their gut, especially those who were experiencing disease flare-ups. When they transplanted Kp into mice, they found mice developed a severe intestinal inflammation and tissue damage, suggesting that these Kp strains may make IBD worse.
Next, the team isolated thousands of bacteriophages – viruses that can target and infect bacteria – from environmental samples. They identified around 40 phages that appeared effective against the IBD-contributing Kp strains and then tested them in various combinations against the Kp strains. Each of the phages uses a different receptor to enter bacteria and kills them through different mechanisms. This means that even if the bacteria mutate, rendering one of their receptors resistant, there will be back-ups, Elinav says. An effective cocktail design can prevent phage-resistant bacteria from forming and spreading, he adds.
Elinav and his team discovered the most effective phage combination contained five phages and could suppress the Kp strains in the test tube and in mice IBD models, where the phage cocktail reduced inflammation and tissue damage.
The team further tested two phages from this cocktail in a Phase I trial involving 18 healthy volunteers. They found the phages could survive at high levels and remained active throughout the gastrointestinal tract when taken with antacids, while not impacting the surrounding microbiota. Participants reported no severe treatment-related issues. The team plans to further test the five-phage cocktail in a Phase II trial using IBD patients with the disease-contributing Kp strains.
The researchers are working to identify bacteria associated with other diseases and to develop effective phage combination therapies against them. ‘What we envisage is a precision medical pipeline,’ says Elinav. ‘Using it, we can characterise 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.’
‘This proof-of-concept study demonstrated that phages can reduce specific bacterial sub-groups associated with IBD and diminish their pro-inflammatory effects,’ comments Mikeljon Nikolich of the Walter Reed Army Institute of Research in Maryland, US. ‘This approach could hold promise if it can be made affordable and if it is reproducibly successful in identifying and targeting key bacterial contributors to IBD across diverse patient populations.’