Recent insights on challenges encountered with phage therapy against gastrointestinal-associated infections

Abstract Gastrointestinal (GI) infections, caused by pathogens such as Escherichia coli , Salmonella sp., Shigella sp., and Clostridium difficile , pose significant global health challenges due to their prevalence, severity, and increasing resistance to conventional treatments. While phage therapy offers a targeted, adaptable, and potentially safer approach for treating these infections, several challenges hinder its widespread clinical application. This review explores the current state of phage therapy for GI-associated infections, highlighting key obstacles such as phage stability in the harsh GI environment, host immune responses that can impede phage efficacy, phage-bacteria interactions, and bacterial adaptation mechanisms, such as mutations in phage receptors, which can lead to phage-insensitive mutants. Additionally, the specificity of phages to bacterial strains necessitates the development of diverse phage cocktails tailored to individual infections. The complex interactions between phages and the gut microbiome present challenges in ensuring that phage therapy does not disrupt beneficial gut bacteria. Despite these challenges, advances in phage isolation, genetic engineering, and delivery systems offer promising avenues to optimize phage therapy for GI infection. This review underscores the pharmacokinetics and pharmacodynamics of phage therapy while emphasizing the need for multidisciplinary approaches to overcome existing barriers and translate this innovative treatment into clinical practice. Accordingly, ongoing research is necessary to optimize phage delivery methods, develop effective phage combinations, and understand the interactions between phages and the gut microbiome to ensure safe and effective treatments.