Multiple Acid Sensors Control Helicobacter pylori Colonization of the Stomach

Abstract

Helicobacter pylori’s ability to respond to environmental cues in the stomach is integral to its survival. By directly visualizing H. pylori swimming behavior when encountering a microscopic gradient consisting of the repellent acid and attractant urea, we found that H. pylori is able to simultaneously detect both signals, and its response depends on the magnitudes of the individual signals. By testing for the bacteria’s response to a pure acid gradient, we discovered that the chemoreceptors TlpA and TlpD are each independent acid sensors. They enable H. pylori to respond to and escape from increases in hydrogen ion concentration near 100 nanomolar. TlpD also mediates attraction to basic pH, a response dampened by another chemoreceptor TlpB. H. pylori mutants lacking both TlpA and TlpD (ΔtlpAD) are unable to sense acid and are defective in establishing colonization in the murine stomach. However, blocking acid production in the stomach with omeprazole rescues ΔtlpAD’s colonization defect. We used 3D confocal microscopy to determine how acid blockade affects the distribution of H. pylori in the stomach. We found that stomach acid controls not only the overall bacterial density, but also the microscopic distribution of bacteria that colonize the epithelium deep in the gastric glands. In omeprazole treated animals, bacterial abundance is increased in the antral glands, and gland colonization range is extended to the corpus. Our findings indicate that H. pylori has evolved at least two independent receptors capable of detecting acid gradients, allowing not only survival in the stomach, but also controlling the interaction of the bacteria with the epithelium.

Impact factors that modulate gastric cancer risk in Helicobacter pylori‐infected rodent models

“…In C57BL/6 mouse models, HpSS1 preferentially colonizes the antral mucosa and the transition zone between the antrum and the body . PPI treatment promoted H pylori colonization in the corpus, which was consistent with the worsening of atrophic corpus gastritis and promotion of GC development in the presence of H pylori . Similarly, the gastric pits of the corpus mucosa in HSD‐fed mice were shown to be colonized by H pylori more frequently than those in mice on a normal diet.…”

Helicobacter pylori Senses Bleach as a Chemoattractant Using a Cytosolic Chemoreceptor

“…H. pylori is a notoriously persistent colonizer often retained for an individual’s lifetime, causing chronic gastritis that can proceed to ulcers or adenocarcinoma. H. pylori requires chemotaxis to colonize the stomach and seek out injured gastric tissue (Aihara et al, 2014; Huang et al, 2017; Rolig et al, 2012). To persistently colonize the stomach, H. pylori uses a limited chemoreceptor repertoire to integrate information about chemical gradients, both pre-existing and of its own making.…”

“…Now, we add to this picture chemoattraction to HOCl produced by H. pylori -induced neutrophil infiltration. The fact that TlpD mediates both direct HOCl sensing and pH responses complicates what conclusions can be drawn from tlpD mutants (Collins et al, 2018; Huang et al, 2017; Rolig et al, 2012; Schweinitzer et al, 2008) however consistent with a role in TlpD mediating chemoattraction toward HOCl, H. pylori deficient in tlpD exhibit defects in stomach colonization and fail to persist in the antrum, the region of highest inflammation (Huang et al, 2017; Rolig et al, 2012). In conclusion, our findings reveal that H. pylori has the surprising capacity of chemoattraction toward bleach, a compound commonly viewed as a noxious oxidant and antimicrobial, which may help enable its persistence in chronically inflamed host tissue.…”

“…1A). Environmental chemicals that elicit a chemoresponse by H. pylori include acid as a chemorepellent (Goers Sweeney et al, 2012; Huang et al, 2017), and urea as a chemoattractant (Huang et al, 2015), which both serve to direct H. pylori from the stomach lumen to the gastric epithelium. Experiments with Tlp genetic deletions have implicated chemoreceptors in cellular sensing processes, but only two chemoeffectors have been confirmed in biochemical experiments to be direct binding interactions between ligand and receptor: TlpB sensing of urea (Goers Sweeney et al, 2012; Huang et al, 2015) and TlpC sensing of lactate (Machuca et al, 2017), though the latter receptor is not conserved and apparently dispensable.…”

“…Some progress has been made for understanding direct ligand sensing by TlpA, for which recent crystal structures suggest binding of a small hydrophobic ligand (Goers Sweeney et al, 2012). Sensing of pH remains more complicated to understand, as genetic knockouts indicate signals are integrated from TlpA, B, and D (Huang et al, 2017), and no direct sensing mechanism is known for TlpD.…”