Reconsidering early Yersinia pestis ecology: Enteric origins, gene loss, and a human-mediated reservoir hypothesis

Yersinia pestis, the causative agent of plague, emerged through a rapid evolutionary transition from the enteric bacterium Yersinia pseudotuberculosis (Achtman et al., 1999). As seen in Fig. 1, this transition involved extensive genome reduction, loss of gastrointestinal-associated traits, and the later acquisition of vector-specific adaptations such as the murine toxin gene (ymt), enabling survival in flea midguts (Hinnebusch et al., 1996; Chouikha and Hinnebusch, 2012). While the molecular basis of this transformation is well characterized, the ecological and epidemiological context of early Y. pestis persistence remains incompletely understood. In particular, the reservoir and transmission dynamics of Late Neolithic-Bronze Age (LNBA) Y. pestis lineages, documented across a wide geographic range from Western Europe to Central and East Asia, remain unresolved (Rasmussen et al., 2015; Light-Maka et al., 2025). Here, we synthesize genomic, anthropological, and ecological evidence to propose a constrained hypothesis in which humans functioned as an early reservoir or amplifier host for Y. pestis prior to full flea specialization. Building on the enteric ancestry of the pathogen, we argue that prolonged intimate contact between humans and domesticated animals within pastoralist lifeways provided a plausible pre-vector transmission ecology, facilitating persistence with limited mortality. This model offers a parsimonious explanation for the early geographic dispersal of Y. pestis, its low inferred virulence in LNBA contexts, and its later transition to highly lethal, vector-mediated pandemics (Cui et al., 2013). Historical textual traditions repeatedly reference pestilence in ways consistent with episodic, non-famine epidemics, suggesting that recurrent disease phenomena were recognized well before medieval outbreaks. While necessarily inferential, this framework generates testable predictions for future ancient DNA studies and underscores the importance of integrating evolutionary genomics with anthropological context in reconstructing the early history of plague. This study proposes a testable framework rather than asserting a definitive transmission mechanism.