Lactulose-Induced Transcriptional Reprogramming and Repression of Persistence-Associated Phenotypes in Non-Typhoidal...

Lactulose, a synthetic disaccharide widely used in human and veterinary medicine as a therapeutic and prebiotic, is generally assumed to be metabolized exclusively by commensal microbiota. We recently showed that non-typhoidal Salmonella (NTS) can also metabolize lactulose, but the genetic basis and functional consequences remain unclear. Here, we hypothesized that NTS encodes specific genetic determinants and regulatory networks for lactulose uptake, hydrolysis, and downstream metabolism. Using the globally disseminated NTS serotype S. Kentucky, we defined the lactulose-responsive transcriptome. Lactulose exposure induced a distinct gene network including candidate transporters, periplasmic binding proteins, and glycoside hydrolases predicted to cleave lactulose into galactose and fructose, with downstream metabolism via the mannitol cycle and Leloir-associated pathways. Notably, lactulose also triggered broad transcriptional remodeling that repressed genes encoding motility, fimbrial biosynthesis, and biofilm formation, resulting in significantly reduced motility and biofilm across NTS serotypes. These findings provide novel mechanistic insight into lactulose metabolism, suggesting that lactulose metabolism is concurrently associated with reduced expression of persistence-associated phenotypes in NTS under the conditions tested. This raises the possibility that lactulose exposure could influence NTS persistence in both the host-associated and environmental context. Follow-up studies are needed to validate the potential of these findings to reduce food safety and public health risks linked to persistence and transmission phenotypes.