Phage therapy through oral combination targets IBD-related gut bacteria and saves useful microbes

Phage therapy through oral combination targets IBD-related gut bacteria and saves useful microbes ...

For the first time, an international team of researchers has devised an orally administered phage-mix therapy that can precisely target and suppress gut bacteria associated with inflammatory bowel diseases (IBD). The research also demonstrates the potential for using phages to treat intestinal disorders.

Eran Elinav, PhD, director of the Weizmann Institute of Science and the German National Cancer Center (DKFZ), believes that phages may be used as a precision weapon in combating a group of commensal strains contributing to IBD, as well as against other illnesses, including obesity, diabetes, cancer, neurodegenerative diseases, and more.

Elinav is the corresponding author of the teams' published paper in Cell, titled Targeted suppression of human IBD-associated gut microbiota commensals by phage consortia for treatment of intestinal inflammation.

IBD is a group of inflammatory gut disorders that affect millions of people across the world. The authors argue that ulcerative colitis (UC), Crohns disease (CD) and indeterminate colitis are auto-inflammatory disorders that are linked to sustained tissue damage. Previous research has shown that antibiotics are beneficial for friendly as well as pathogenic gut bacteria.

The authors noted that there has been interest and some success in the possibility to utilize systemic phage therapy as a rescue therapy against multi-drug resistant pathogens. However, long-term use of oral phage therapy as a therapy for non-communicable disease remains elusive.

The Elinavs team, in collaboration with a group of international scientists and the Weizmann Institute of Sciences spinoff BiomX, compared the gut microbiota compositions of 537 IBD patients to those of healthy controls enrolled in cohort studies in France, Israel, the United States, and Germany. They found that although they were not affected by disease flare-ups, the transfer of clinical IBD-associated Kp strains improved intestinal inflammation.

Elinav and his colleagues then scanned and isolated tens of thousands of bacteria from environmental samples. Some 40 phages identified effective against the IBD-contributing Kp strains, including strains that had already developed phage resistance.

Elinav explains that if the bacteria mutate, or render one of their receptors resistant to a phage, there will be back-ups.

The biggest obstacle to using phage therapies is that there is a constant arm battle between bacteria and phages, according to Eran Elinav, PhD, director of the Weizmann Institute of Science and the German National Cancer Center (DKFZ). If you apply a single phage on a bacterium, the organism will likely develop resistance mechanisms very rapidly. To our knowledge, we are the first to utilize an orally administered phage combination therapy against a disease-contributing gut commen

Elinav and his team discovered the most efficient phage combination containing five phages for suppressing Kp strains in vitro as well as in murine IBD models, in which the phage cocktail reduced inflammation and tissue damage.

The team conducted a first-in-human Phase I clinical investigation on 18 healthy volunteers' phages. They concluded that the phages could survive at high levels and remain active throughout the gastrointestinal tract when administered with antibiotics. There were no serious treatment-related adverse events in phage-treated participants, according to the researchers. Kp2 suppression and possible off-target effects, induced by the whole phage combination, merit further studies in humans carrying IBD-relevant Kp2 strains.

Elinav and his team are planning to continue testing the 5-phage cocktail in a later Phase II investigation involving IBD patients who carry the disease-contributing Kp strains. They are also working to identify bacteria associated with other illnesses against which they might develop other effective phage combination therapies, according to Elinav.

The authors noted that a patient-based identification of dominant pathobionts and an in vitro evaluation of their suppressive ability might enhance the personalization of such phage therapy, as a companion diagnostic.

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