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Human salmonellosis is a high-priority foodborne disease worldwide. The main reservoir of Salmonella is livestock, mainly swine and poultry that are infected both by generalist serovars and serovars adapted to them. The most widespread livestock-adapted serovars are attenuated in both their primary hosts and humans. We previously identified a lineage of the swine-adapted Salmonella Derby carrying mutations in Salmonella Pathogenicity Island-1(SPI-1) giving attenuation. To evaluate if SPI-1 decay is a general feature of swine-adapted serovars, we analyzed the Enterobase global population of Salmonella serovars most frequently isolated from swine. We found that deleterious mutations in SPI-1 are accumulated more in swine-adapted ( S . Derby and Salmonella Rissen) than in generalist ( Salmonella Typhimurium, I 1,4,[5],12:i:-, and Salmonella Infantis) serovars. The genomes carrying such mutations are widespread in the population of S . Derby and S . Rissen, indicating that the occurrence and fixation of deleterious mutations in SPI-1 are frequent. Similarly, also poultry-adapted Salmonella Kentucky has accumulated deleterious mutations in SPI-1, leading to over 70% of mutated genomes of this serovar compared with negligible proportions of mutated genomes in the generalist serovars from poultry. Although in vitro attenuation of S . Derby carrying mutated SPI-1 had been previously demonstrated, we showed the same phenotype for mutated S . Rissen. Considering also the known attenuation of S . Kentucky, our population-scale findings provide evidence of progressive evolution toward the attenuation of serovars adapted to the main animal reservoirs of human salmonellosis through the food chain. Intensive farming with a high density of animals could be a possible driver of this evolution.IMPORTANCEThis study shows at the global population level of Salmonella that the main attenuated serovars adapted to food-producing animals are undergoing convergent evolution toward further attenuation through the decay of SPI-1, considered critically important for the intestinal phase of Salmonella infection. The drivers of this evolution are unknown, but they could be attributed, at least in part, to the intensive farming of livestock with its high densities. On one side, our results contribute to the knowledge of the interaction between livestock populations and their host-adapted serovars of Salmonella . On the other side, the study provides scientific background for reconsidering the microbiological criteria adopted by the food safety legislation of many countries that ask for the absence of Salmonella in foods, regardless of any virulence evaluation of the detected strain. In this respect, the study provides molecular bases to investigate the virulence of different lineages within these host-adapted serovars., Competing Interests: The authors declare no conflict of interest.

Importance: This study integrated population data with in vitro assessment of virulence phenotypes to unveil that a considerable part of the global population of Salmonella Derby is evolving to enhance its host adaptation to the swine host and that this evolution is simultaneously increasing its attenuation for humans. The study shows that the fixation of deleterious mutations in SPI-1 has a role in this process. This evidence indicates that SPI-1 has a key role for S . Derby virulence in humans but not for its circulation in swine. The results show that genes generally considered essential for Salmonella pathogenesis do not play the same key role for all Salmonella serovars or lineages and/or all hosts. The study helps in understanding the molecular mechanisms underlying the ecology and host adaptation of Salmonella showing that the adaptation process can vary for different types of Salmonella and hosts., Competing Interests: The authors declare no conflict of interest.