Entering the era of phage therapy: A ‘happy hour’ for inflammatory bowel diseases

Inflammatory bowel disease (IBD) is a global disease1 with a multifactorial aetiology, including an interaction between genetic and environmental factors.2 Some gut pathobionts may contribute to uncontrolled intestinal inflammation in genetically susceptible individuals. The ability of viruses, under favourable conditions, to parasitize and destroy bacteria has a centuriesold history. Since their discovery, phages have been used as antimicrobial agents because of their cellular target specificity and interaction with the host immune system.3 After falling into disuse in the early postwar period with the development of antibiotics, the socalled ‘phage therapy’ has been back in the limelight recently to address the emergence of resistant bacteria. Phages' selectivity in killing susceptible bacteria makes them ideal candidates for microbiome modulation, explaining why they recently aroused interest in the treatment of IBD.4 In a pathfinder study, Federici et al. showed that a cocktail of phages successfully targeted a clade of Klebsiella pneumoniae (named ‘Kp2 strains’). 5 The authors identified Kp2 strains in IBD subjects across four globally distinct cohorts and demonstrated their overexpression during disease flareups, compared to a remission state (Figure 1(1)). In germfree and colitisprone mice models, the oral administration of Kp2 strains elicited a significant inflammatory response, with increased proinflammatory cells and markers of intestinal inflammation, thus supporting the metagenomic findings (Figure 1(2)). In the same study, a phage cocktail was isolated to specifically eradicate Kp2 pathobionts (Figure 1(3)). An iterative process selected 41 phages active against Kp2 strains. In addition, a 5phage subset was shown to reduce the bacterial burden of two IBDassociated Kp2 strains in a monocolonized colitis mouse model without evidence of antiphage resistance development (Figure 1(4)). Finally, two phages were coadministered to healthy volunteers in a randomized, singleblind, placebocontrolled clinical trial to investigate the feasibility of bacteriophage treatment in humans. The phage therapy was tolerated without significantly higher rates of adverse effects compared to the placebo group and proved its viability through the acidic environment of the stomach, displaying high phage titres in the stools for three days after the last administration (Figure 1(5)). Further studies in mice models with more diverse and realistic microbiota as well as in humans would reinforce the efficacy and specificity of this therapy. This landmark study proposes an alternative strategy to achieve immune modulation in IBD patients, who are mainly treated with biologics and immunosuppressants, and represents a breakthrough in the application of phage therapy for targeting pathobionts involved in the pathogenesis of human diseases. While the impact of the microbiome is evident in the context of IBD, its diversity and composition are now known to play a role in many noncommunicable diseases. Targeting the modification of gut bacteria is becoming a new frontier in many immunemediated disorders requiring a personalized medicine approach. While it is fundamental to rely on current therapeutic strategies to induce and maintain remission in these conditions, novel experimental interventions, which should be more patientspecific and are typically safe, could find their clinical application in preventing disease development in atrisk individuals. For example, an ongoing trial is analysing the impact of a healthy diet on highrisk firstdegree relatives of IBD patients, identified through analysis of the microbiome and inflammatory markers (https://clini caltr ials.gov/ct2/show/NCT05 211518). Phage therapy is an example of the resilience of science and of the human species exploiting an ancestral entity to deal with the potential threats of the modern world: multidrug resistant bacteria, the outbreak of noncommunicable diseases, and the cost of chronic therapies, to the healthcare system and to the patient. We are taking refuge in the past to implement old discoveries and turn them into newly accessible and customizable weapons to fight our own generation's battles.