Quorum-sensing, microbiome interactions, and emerging artificial intelligence-assisted anti-virulence strategies in Salmonella Typhi: a critical review of translational opportunities and challenges.

Typhoid fever, caused by Salmonella enterica subsp. enterica serovar Typhi (Salmonella Typhi), remains a significant global health challenge that is increasingly complicated by the emergence and spread of multidrug-resistant (MDR) and extensively drug-resistant strains. Growing limitations of antibiotic-centered treatment strategies have stimulated interest in anti-virulence approaches targeting bacterial regulatory networks rather than viability alone. Among these, quorum-sensing (QS), particularly the LuxS-mediated autoinducer-2 (AI-2) signaling system, has emerged as a potential regulator of virulence-associated phenotypes, biofilm formation, stress adaptation, microbial communication, and host-associated persistence. This review critically evaluated the current understanding of QS biology in S. Typhi while distinguishing experimentally validated findings from evidence extrapolated from non-typhoidal Salmonella and other enteric bacteria. We examine the ecological interplay between QS, gut microbiome dynamics, and host responses, highlighting how microbial communication networks influence pathogen adaptation and colonization resistance. Emerging anti-QS strategies, including microbiome-mediated quorum quenching, probiotics, postbiotics, phytochemicals, antimicrobial peptides, bacteriophage-associated approaches, signal-degrading enzymes, and nucleic acid-based interventions, are comparatively assessed with respect to their mechanisms, evidence strength, translational readiness, and limitations. The review further explores the role of artificial intelligence (AI), multi-omics integration, and systems-level analytical frameworks in target identification, microbial network reconstruction, biomarker discovery, and therapeutic prioritization. Despite promising advances, substantial barriers remain, including limited in vivo validation, insufficient mechanistic evidence in S. Typhi, lack of clinically validated QS-associated biomarkers, microbiome variability, ecological safety concerns, and challenges related to delivery, scalability, and regulatory approval. Collectively, current evidence supports QS-targeted interventions as promising but predominantly investigational strategies that may complement existing antimicrobial, vaccine-based, and public-health approaches for typhoid control.