Salmonella spp. express Salmonella pathogenicity island 1 Type III Secretion System 1 (T3SS-1) genes to mediate the initial phase of interaction with their host. Prior studies indicate short-chain fatty acids, microbial metabolites at high concentrations in the gastrointestinal tract, limit population-level T3SS-1 gene expression. However, only a subset of Salmonella cells in a population express these genes, suggesting short-chain fatty acids could decrease T3SS-1 population-level expression by acting on per-cell expression or the proportion of expressing cells. Here, we combine single-cell, theoretical, and molecular approaches to address the effect of short-chain fatty acids on T3SS-1 expression. Our in vitro results show short-chain fatty acids do not repress T3SS-1 expression by individual cells. Rather, these compounds act to selectively slow the growth of T3SS-1–expressing cells, ultimately decreasing their frequency in the population. Further experiments indicate slowed growth arises from short-chain fatty acid–mediated depletion of the proton motive force. By influencing the T3SS-1 cell-type proportions, our findings imply gut microbial metabolites act on cooperation between the two cell types and ultimately influence Salmonella’s capacity to establish within a host.

沙门氏菌属 表达沙门氏菌致病岛 1 III 型分泌系统 1 (T3SS-1) 基因以介导与宿主相互作用的初始阶段。先前的研究表明，短链脂肪酸、胃肠道中高浓度的微生物代谢物会限制人群水平的 T3SS-1 基因表达。然而，只有沙门氏菌的一个子集群体中的细胞表达这些基因，表明短链脂肪酸可以通过作用于每个细胞的表达或表达细胞的比例来降低 T3SS-1 群体水平的表达。在这里，我们结合单细胞、理论和分子方法来解决短链脂肪酸对 T3SS-1 表达的影响。我们的体外结果表明，短链脂肪酸不会抑制单个细胞的 T3SS-1 表达。相反，这些化合物选择性地减缓表达 T3SS-1 的细胞的生长，最终降低它们在人群中的频率。进一步的实验表明，生长缓慢是由短链脂肪酸介导的质子动力消耗引起的。通过影响 T3SS-1 细胞类型比例，沙门氏菌在宿主体内建立的能力。