Analysis of the roles of Helicobacter pylori lactate utilization genes in lactate-supplemented growth and bacterial pathogenesis
Helicobacter pylori is a human-adapted pathogen that colonizes the stomach and infects approximately half the world's population. H. pylori infection can induce erosive gastritis, peptic ulcers, and gastric cancer. H. pylori growth requirements in vivo are not yet fully understood, but one important molecule may be lactate. Lactate metabolism fulfills critical roles in mammalian and microbial homeostasis, through regulating immunological responses or serving as a precursor for various major microbial metabolites. Lactate exists in two enantiomers with distinct biological functions, L & D. L-lactate utilization in mammals and H. pylori has been studied more intensely relative to D-lactate metabolism and function. However, the physiological significance of mammalian D-lactate metabolism has become increasingly evident over the last decade. Recent findings such as the functional role of human D-LDH and the presence of neurotoxicity at physiological levels of D-lactate have contributed to the revaluation of mammalian D-lactate.In this work, we performed in vitro temporal chemotaxis assays to assess H. pylori ’s chemotactic response to both lactate isomers. We also created isogenic lactate uptake and metabolism mutants to assess the roles of these genes in lactate metabolism and stomach infection. Lactate supplementation growth assays were performed on lactate utilization mutants under various lactate concentrations, isomers and media compositions. In vivo murine infections with isogenic PMSS1 lactate metabolism mutants were performed to examine the significance of each lactate permease in gastric colonization. Here we report that D-lactate is a chemoattractant sensed at physiological concentrations by the TlpC chemoreceptor in a manner distinct from L-lactate. We also found that the absence of H. pylori lactate permeases alters in vitro growth response and significantly reduces in vivo gastric colonization. These findings suggest that lactate utilization confers a functional role in H. pylori growth and colonization.