Eliminating Pathobionts With Bacteriophages: A Novel Approach to Reduce Gut Inflammation in Inflammatory Bowel Diseases?

Abstract

Federici, Kredo-Russo S, Valdés-Mas R, et al. Targeted suppression of human IBD-associated gut microbiota commensals by phage consortia for treatment of intestinal inflammation. Cell 2022;185:2879–2898.e24. Gut microbes have been repeatedly linked to inflammatory bowel diseases (IBD), with reproducible changes demonstrated in diversity, composition, and function. Modest efficacy of microbe-altering treatments, including probiotics, antibiotics, and fecal microbial transplantation, and the lack of an obvious microbial pathogen causing IBD, have raised the discussion on cause versus effect regarding the role of microbes in IBD pathogenesis. In fact, both are likely important because animal models of IBD point to a causative role and the inflamed gut environment in IBD clearly impacts microbes. A recent article by Federici et al, published in Cell, supports a clear causative role of a specific bacterium (Klebsiella pneumonia [Kp]) and shows that selective elimination of Kp could provide a novel treatment approach for IBD. Remarkably, to overcome challenges with selective bacterial suppression, the authors developed a consortium of 5 bacteriophages able to target this pathobiont. Kp and associated antibiotic resistance genes were linked to both Crohn disease and ulcerative colitis in 4 cohorts from France, Israel, Japan, and the United States (found in approximately 40% of patients with IBD); Kp presence also correlated with disease severity. Metagenomics allowed for strain-level analysis, which identified specific IBD-associated strains (termed Kp2). Inoculating Kp2 (but not other strains) into germ-free mice induced gut inflammation, with immune features similar to those seen in human IBD, including a suppression of interleukin-10. When germ-free interleukin-10–/– mice were infected with Kp2, they developed more severe bowel inflammation. After identifying this candidate pathobiont, the researchers next isolated and screened phages to develop a consortium that would suppress Kp2. After a complex iterative process, a consortium of 5 phages was selected and tested in another mouse model (antibiotic-treated, specific pathogen-free mice). Indeed, treating mice infected with Kp2 with the phage cocktail reduced Kp2 colonization and gut inflammation in a dextran sodium sulfate mouse model, as well as a longer term germ-free Rag1–/– IBD model. To test the ability of these phages to survive in the human gut, the phages were passaged through a human gut simulator and showed good survival, although some phages were impacted by the low gastric pH. In a placebo-controlled randomized controlled trial, 14 healthy volunteers received 2 phages for 3 days and 4 received the control vehicle (all with omeprazole). The phages were detected in the stool of all individuals receiving them, even up to 3 days after discontinuing treatment, suggesting phage survival and persistence in the human gut. Only minor adverse events were reported, but these were similar in both groups. This comprehensive, multilayered study introduces a few key concepts that could impact IBD patient care. The identification of strain-level pathobionts supports microbe-targeted treatments, and the use of combined phage consortia is a promising, and likely safe, option for targeted elimination of pathobionts. Some challenges remain, such as identifying individuals most likely to benefit from such therapy (using personal and disease features), impact of diet and other treatments, and risk of complex resistance over time, but this ground-breaking work promises to open exciting opportunities for future IBD care.