Gut microbiota dysbiosis: Pathogenic drivers and emerging phage-based therapeutics.

Abstract

Gut microbiota dysbiosis driven by pathogenic and opportunistic bacteria, including Clostridioides difficile, adherent-invasive Escherichia coli (AIEC), Salmonella enterica serovar Typhimurium, Fusobacterium nucleatum, Klebsiella pneumoniae, Enterococcus faecalis, and Campylobacter spp., disrupts colonization resistance, epithelial barrier integrity, and immune homeostasis, thereby contributing to the development of inflammatory and metabolic diseases. In this review, we summarize the mechanisms through which these microorganisms promote gut dysbiosis and critically evaluate current microbiome-targeted therapeutic strategies, including fecal microbiota transplantation (FMT), live biotherapeutic products (LBPs), probiotics, and bacteriophage (phage) therapy. We review the preclinical and emerging clinical evidence supporting phage-based targeting of major dysbiosis-associated pathogens and examine the principal challenges limiting clinical translation, including phage resistance, immune-mediated clearance, safety considerations related to temperate phages, manufacturing and delivery constraints, and regulatory barriers. Although evidence remains predominantly preclinical, advances in phage engineering, artificial intelligence-guided phage selection, and systems-level microbiome modeling are expanding the potential of personalized phage therapeutics. Collectively, these developments position bacteriophage therapy as a promising addition to future microbiome-directed strategies for restoring gut microbial homeostasis and managing dysbiosis-associated disease.