Study Highlights

• Across 4 geographically distinct IBD cohorts (n=537) in France, Israel, the United States, and Germany, researchers identified a clade of Kp strains with unique antibiotics resistance and mobilome signature that were strongly associated with IBD exacerbation and severity.
• Transferring Kp strains that were clinically associated with IBD and isolated from stool samples into colitis-prone, germ-free, and colonized mice enhanced intestinal inflammation.
• Through stepwise generation and testing of 41 phages infecting Kp, researchers developed a lytic 5-phage combination based on genetic profiles, structural features seen on microscopy, and extensive combinatorial screening for activity against various Kp strains, including antibiotic- resistant strains.
• This phage cocktail targeted sensitive and resistant IBD-associated Kp clade members via distinct mechanisms.
• Treating colitis-prone mice with this lytic 5-phage combination resulted in effective Kp suppression, leading to attenuated inflammation, tissue damage, and disease severity.
• Proof-of-concept assessment of Kp-targeting phages showed that they were stable in an artificial human gut.
• In a first-in-human phase I clinical trial of 18 healthy volunteers, the orally administered combination phage therapy was well-tolerated, with phage multiplication and accumulation in the lower gut, no off-target changes, and gastric acid-dependent phage resilience, safety, and viability.
• The investigators concluded that their orally administered combination phage therapy was feasible to avoid resistance, while effectively inhibiting bacterial pathogens contributing to noncommunicable disease such as IBD.
• They described their orally administered combination phage therapy as the first "silver bullet" approach offering precise suppression of disease-causing gut microbes without harming the surrounding microbiome.
• The study suggests that IBD could be managed with treatment other than antibiotics, which are less specific, may have adverse effects, and promote emergence of antibiotic resistance and MDR organisms.
• The techniques used in this study may facilitate identification of specific clades of disease-contributing bacteria and strains ("driver" strains) while differentiating them from many other strains present at altered levels secondary to disease-related processes ("passenger" strains).
• This could help target treatment toward pathogenic strains in given clinical contexts.
• As lytic phages self-replicate in the host, phages would self-maintain as long as target pathogen levels exceed a threshold, but then decline once bacterial target suppression is achieved.
• Given the resistance-avoiding qualities of phages given orally, the investigators are hopeful that phage therapy will 1 day be used with induction therapy in IBD to help quench acute disease exacerbation, or as maintenance therapy, in which chronic bacterial phage suppression may delay or prevent disease flare-ups.
• As phage-resistant bacteria often have enhanced susceptibility to antibiotics, phage therapy combined with antibiotics may generate synergistic activity even when pathogens have shown antibiotic resistance.
• If the phage cocktail is found to be safe and effective in larger clinical trials, it could potentially lead to the development of treatments for IBD and other conditions affected by gastrointestinal bacteria, including obesity, diabetes, neurodegenerative disease, and perhaps even cancer.
• Although the cause and cure for IBD are unknown, improvement of inflammation and tissue damage induced by the phage cocktail suggests that phage therapy may ultimately relieve some painful symptoms of UC and CD.
• Although further research is needed, personalized therapies might ultimately be developed for a variety of disorders, in which the disease-causing strains of gut bacteria would be identified in each patient and a phage cocktail could be designed to target only those strains.
• The effect of diet, age, and oral versus colonoscopy administration methods and transit time on the gut microbiome and effectiveness of phage treatment should be studied further.
• Combined oral and systemic phage administration might optimize therapy, especially against invasive pathogens, but further studies are needed.