Comparative Genomics and Functional Profiling Reveal Lineage-Specific Metabolic Adaptations in Globally Emerging...

Salmonella Kentucky comprises two major lineages, ST152 and fluoroquinolone-resistant (Flu^R) ST198, which have diverged genotypically and phenotypically along distinct evolutionary and epidemiological trajectories. ST198 is linked to global human disease, while ST152 is primarily animal-associated in the U.S. We hypothesized that lineage-specific metabolic adaptations contribute to their differing host associations and pathogenicity.

We performed comparative metabolic profiling of ST198 (n = 3) and ST152 (n = 4) strains across 948 substrates and environmental conditions. Growth assays tested the ability of these lineages and other non-typhoidal Salmonella (NTS) serovars (n = 5) to utilize myo-inositol and lactulose as sole carbon sources. Comparative genomic analyses of 294 ST198, 173 ST152, and 1300 other NTS serovars identified nutrient utilization genes.

ST198 exhibited significantly higher respiratory activity and broader metabolic versatility across carbon, nitrogen/sulfur sources, and stress conditions. The canonical iol gene cluster for myo-inositol catabolism was conserved in ST198 but absent in ST152, which nonetheless showed weak growth on myo-inositol, suggesting an alternative metabolic pathway for myo-inositol may exist. We also report for the first time that, despite lineage-specific differences in metabolic efficiency, multiple NTS serovars, including S. Kentucky, can metabolize lactulose, a synthetic disaccharide traditionally associated with beneficial gut microbes. These results suggest the potential existence of a novel lactulose metabolic pathway in NTS.

These findings highlight ST198's metabolic adaptability and reveal novel metabolic capacities in NTS. A mechanistic understanding of nutrient utilization pathways, particularly of myo-inositol and lactulose, will provide novel insights into the mechanisms underlying nutrient metabolism that likely modulate the ecological success and pathogenic potential of NTS in human and animal hosts.