Metabolic adaptation of Yersinia pestis during flea colonization

Yersinia pestis, the causative agent of plague, has evolved a dual lifestyle enabling survival in both mammalian hosts and hematophagous flea vectors. While mammalian virulence has been extensively studied, the flea stage represents a highly selective and metabolically constraining environment that plays a decisive role in transmission. Following ingestion during a blood meal, Y. pestis establishes within the flea digestive tract, where it must withstand nutrient limitation, oxidative stress, osmotic pressure, and antimicrobial factors while forming a proventricular biofilm essential for gut blockage and subsequent transmission. This review synthesizes current knowledge of the metabolic strategies deployed by Y. pestis during flea colonization, highlighting a coordinated shift toward amino acid and lipid-derived carbon sources, strict dependence on the pentose phosphate pathway, and a central role for lipoate metabolism. We discuss how these metabolic adaptations are tightly integrated with regulatory networks involving c-di-GMP signaling, two-component systems, and global regulators such as RovM and Hfq, ensuring that biofilm formation occurs only when energetic conditions permit. Finally, we address unresolved questions regarding metabolic flux dynamics, interactions with the flea microbiota, and lineage-specific variation, emphasizing the need for future systems-level analyses. Together, this review positions flea colonization as an active and evolutionarily refined phase that shapes the transmission success of Y. pestis.