An international team of researchers has for the first time designed an orally administered phage combination therapy that can precisely target and suppress gut bacteria associated with inflammatory bowel diseases (IBD). The study showcases the potential for using phages to treat diseases associated with gut microbiota.

Bacteriophages are viruses that can target and infect bacteria. “This proof-of-concept study utilizes phages as a precision weapon in suppressing a group of commensal strains contributing to IBD,” said said Eran Elinav, PhD, director of the Systems Immunology department, Weizmann Institute of Science and the Microbiome & Cancer Division, German National Cancer Center (DKFZ). “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.”

Elinav is corresponding author of the team’s published paper in Cell, which is titled “Targeted suppression of human IBD-associated gut microbiota commensals by phage consortia for treatment of intestinal inflammation.”

IBD includes a group of chronic inflammatory disorders of the gut that affect millions of people in the world. “Inflammatory bowel diseases (IBD), including ulcerative colitis (UC), Crohn’s disease (CD) and indeterminate colitis, are auto-inflammatory disorders characterized by an uncontrolled innate and adaptive immune response leading to sustained tissue damage,” the authors wrote. While the cause of IBD remains unclear, previous research has suggested that certain bacteria in the gut are linked to these diseases. Researchers have tried using antibiotics to treat IBD, but such therapies are not sufficiently specific or effective. Antibiotics kill the friendly as well as pathogenic gut bacteria, may cause adverse effects, and can give rise to antibiotic-resistant bacteria.

There has been interest and some success in the potential to use systemic phage therapy as a rescue treatment against multi-drug resistant pathogens, but this is limited toshort-term use, due to bacterial resistance, and host immunity, the authors noted. “However, long-term utilization of oral phage treatment as a means of sustained suppression of gastrointestinal pathobionts associated with non-communicable disease remains elusive to date,” the researchers commented.

For their reported work, Elinav’s team, in collaboration with a group of international scientists, and the Weizmann Institute of Science’s spinoff phage therapy company BiomX, compared the gut microbiota compositions of 537 IBD patients to those of healthy controls enrolled in cohort studies in France, Israel, the US, and Germany. The team found that IBD patients, despite their differences in geography, ethnicity and diet, tended to have a group of Klebsiella pneumoniae (Kp) strains enriched in their gut, especially in those individuals who were experiencing disease flare-ups. When these Kp were transplanted into mice, the animals developed a severe intestinal inflammation and tissue damage, suggesting that these Kp strains may contribute to worsening of IBD. “Transfer of clinical IBD-associated Kp strains into colitis-prone germ-free and colonized mice enhances intestinal inflammation,” they noted.

Elinav and team next scanned and isolated thousands of bacteriophages from environmental samples. They identified some 40 phages that appear to be effective against the IBD-contributing Kp strains, including strains that had already developed phage resistance.

The team tested the phages in various groups as a potential cocktail treatment against IBD-contributing Kp strains. Each phage in a combination treatment uses a different receptor to infect bacteria, and kills them through different mechanisms. The idea is that even if the bacteria mutate, rendering one of their receptors resistant to a phage, there will be back-ups, Elinav says. An effective cocktail design could thus prevent the formation and spread of phage-resistant bacteria.

“The biggest problem with applying phage therapies is that there is a constant arms race between bacteria and phages,” said Eran Elinav, PhD, director of the Systems Immunology department, Weizmann Institute of Science and the Microbiome & Cancer Division, German National Cancer Center (DKFZ). “If you apply a single phage on a bacterium, the bacterium would likely develop resistance mechanisms very rapidly. 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.”

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

The team further tested two representative phages from this cocktail in a first-in-human Phase I clinical trial involving 18 healthy volunteers. The trial, “ … aimed at assessing the viability of orally co-administered phages after passage through the GIT [gastrointestinal tract] of healthy individuals,” confirmed that the phages could survive at high levels and remain active throughout the gastrointestinal tract when taken with antacids and without impacting the surrounding microbiota. Oral esomeprazole was given to participants to increase gastric pH and optimize phage survival. There were no severe treatment-related adverse events. “No off-target dysbiosis was observed in phage-treated participants,” they stated. “Kp2 suppression and possible off-target effects, induced by the full phage combination, merit future studies in humans harboring IBD-relevant Kp2 strains.”

The team plans to further test the 5-phage cocktail in a subsequent Phase II trial involving IBD patients who carry the disease-contributing Kp strains. In addition, Elinav and team are working to identify bacteria associated with other diseases against which they might develop other effective phage combination therapies. “What we envision is a precision medical pipeline,” says 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.”

“Personalization of such phage treatment could be further achieved, as a companion diagnostic, by patient-based characterization of dominant pathobionts, coupled with an in vitro assessment of phage combination suppressive efficacy against them,” the authors commented. “Importantly, similar treatment approaches may be developed to target other IBD-targeting pathobionts identified in our study and in others, and be integrated with currently utilized immune-modulatory IBD treatments. Similar phage combination treatment could be harnessed to suppress pathobionts contributing to a number of other human diseases.”