**7.2 Motility**

In early childhood, *H. pylori* infection is obtained through oral-oral or oral-fecal infection. The microbe has to enter its chosen location of colonization, the mucosa of the gastric antrum in the first phase towards colonization. *H. pylori* has formed a spiral mode and unipolar scourge to enter the gastric niche to transit the mucus membrane that overlays the gastric epithelial surface. Host factors steer the migration of *H. pylori* towards the gastric mucosa by means of the chemical reaction of bacteria.

The transcription from intracellular localized components to extracellular flagellar filaments is transient regulated by the expression of the flagellar gene. *H. pylori* is primarily present on the usual acid-secreting stomach, with about one-third of the mucus layer next to the epithelial cells (0–5 μm) in a predominant 15–30 μm mucus above the antrum [107]. About 2 percent of bacteria bind to the gastric epithelium. In order to colonize this niche, the bacteria find that the host attractants or repellents and travel toward or away from them, respectively.

Urea, bicarbonate, pH, zinc, nickel, arginine, glutamine, histidine, and other amino acids elicit chemotactic responses by *H. pylori* [108–112]. These chemotactic factors are sensed by methylaccepting chemotaxis proteins (MCPs) that transduce the signal and alter flagellar rotation. *H. pylori* has at least four MCPs, the membrane proteins TlpA, TlpB, and TlpC and the cytoplasm located TlpD. TlpA senses arginine, other amino acids, and bicarbonate [108]; TlpB is required for pH and urea taxis and also senses the quorum sensing molecule autoinducer- 2 (AI-2) [113]; TlpC regulates whether acid is sensed as an attractant or repellent [111]; and TlpD senses the internal energy state of the bacterium [114].

#### **7.3 Acid acclimation**

Colonization is prevented by gastric acid. *H. pylori* is a neutrophil that rises from pH 6.0 to 8.0 and lives from pH 4.0 to 8.0. Since the median pH of the stomach is less than 2.0 and *H. pylori* not only lives in this high acidity, but also prospers, the single acid acclimation process has evolved. The ability of *H. pylori* to retain a nearneutral periplasmic pH in an acidic environment is accurate [115]. This is different from the acid resistance mechanism which enables a cytoplasmic pH near 5 to allow bacteria to transit the stomach [116]. Examples of proteins involved with acid resistance include the glutamate decarboxylase- glutamate aminobutyrate antiporter and the arginine decarboxylase-arginineagmatine antiporter, which consume protons and produce carbon dioxide, and the proton transporters including the F 1 F 0 ATPase and the Na +/2H + antiporter [117, 118]. These systems are designed to control the cytoplasm but do not monitor the pH of periplasm.

Gastric colonization is not possible if cytoplasmic pH cannot be elevated to a level that allows critical metabolic processes such as protein synthesis, a level of buffering that requires periplasmic pH regulation [116]. While *H. pylori* expresses some of the known acid resistance or tolerance genes [119], these proteins complement rather than explain gastric colonization. The principle component of acid acclimation is the neutral pH optimum, highly expressed cytoplasmic urease enzyme. The *H. pylori* urease gene cluster is made up of seven genes under the control of two promoters. *ureA* and *ureB*, under the control of the first promoter, encode the structural subunits of the urease enzyme [120].

Urease is a hexameric heterodimer that requires nickel incorporation for activation. Downstream from the second promoter are *ureI*, *ureE*, *ureF*, *ureG*, and *ureH* [121]. *ureI* encodes in an operon the only integral membrane protein. The Cytoplasmic proteins *UreE, UreF, UreG, and UreH* help to integrate nickel in apourease*.*

Urease is required for acid survival and gastric colonization [122, 123]. *H. pylori* urease production is constitutive, contributing about 10 percent of the total cell protein [124, 125]. A neutral pH-based cytoplasmic enzyme catalyzes the degradation of urea into carbonic acid and, eventually. With a low pH activity and inactivation, the pH-reduced into the region contained inside the intestines, the activity curve of the free urease is optimum near neutral. The activity of urease in intact bacteria is marginal at neutral pH and increases to no more than pH 6 to roughly pH 2.5 [126]. This curve of activity indicates a limit to urea entry to the enzyme. The only membrane protein of the urease gene cluster, UreI, was seen as a proton gated urea channel, which enables urea into cytoplasm at acidic pH [127]. Deletion of *ureI* leads to loss of acid activation of urease [125]. ureI deletion mutants cannot live in acid at physiologic urea concentrations. Periplasmic pH sinks as well as the medium pH drops. This leads to opening of UreI, movement of urea into the cytoplasm, and breakdown to the eventual end products of carbon dioxide and ammonia, catalyzed by the urease enzyme. The two gasses then buffer the periplasm to the pH range that is consistent with neutrophil survival without having to adjust the atmosphere with bulk pH.

Ni 2+ per active site are required for activation of urease, and a large fraction of urease can be inactive, especially at neutral pH [128, 129]. This will likely avoid the over-alkalization of this neutrophil in situations where the pH increases, and would thus create a urease pool that is primed and ready to go into action in setting a decrease in pH [130]. UreE forms a heterodimer with UreG and UreF with UreH, as evidenced by yeast two hybrid and homology analysis, and these protein pairs bind urease most likely via UreB to aid with nickel incorporation and enzyme activation [131, 132]. Each accessory protein has a specific role in urease activation. UreE aids directly with incorporation of nickel into the active site [132]. UreF prevents premature nickel binding [133]. UreG provides energy for assembly of urease. UreH provides stability for apourease [134]. A broad number of regulatory mechanisms, many of which are involved in acid survival, can be controlled directly and indirected by the nickel regulation protein NikR [135]. For example, NikR has been shown both in vitro and in vivo to positively regulate expression of *ureA* [136–139].

### **7.4 pH alteration and treatment efficacy**

*H. pylori* is unique for survival in an acidic gastric environment, but bacteria are separated and formed at neutral pH as a neutrophil. Transcription of growthdependent genes in higher medium pH is increased [140]. Most antibiotics used in treating *H. pylori* infection are bacterial-dependent for optimum effectiveness. Ampicillin is slightly more effective at near-neutral pH against *H. pylori* in vitro [140]. Adding bismuth to the treatment regimens also has a pH effect, at least in part, because the compound impairs the proton entry and reduces the decrease in cytoplasmic pH with medium acidification, which improves bacterial metabolism and increased antibiotic effectiveness [141]. With this in mind, The more bacteria are separated in the therapeutic cycle, the more successful conventional treatment, a proton pump inhibitor and a triple or quadruple therapy regimen of antibiotics are used. This concept is likely homologous to the concept of persisters seen across bacterial species.

Persisters are members of a bacterial population that survive exposure to bactericidal antibiotics yet, when re-cultured, display the same antibiotic sensitivity as the population as a whole [142, 143]. *H. pylori* that are not dividing at administered at antibiotic time will not be eliminated, leaving a limited population

#### *Pathophysiology of* H. pylori *DOI: http://dx.doi.org/10.5772/intechopen.96763*

of viable bacteria that can restore stomach colonization when antibiotics are stopped. At recommended doses, drugs currently available in acid blockade will not achieve the required sustained pH shift to imitate the bactericidal effect seen in in vitro studies [140, 144].

The current treatment effectiveness challenges can be solved by introducing non antibiotic treatment schemes, using the colonization mechanisms mentioned here, by prevention, intervention or acclimatization of motility, adhesion or acidity. The in vitro efficacy of the carbonic anhydrase inhibitor acetazolamide against *H. pylori* is one example of a potential treatment targeting acid acclimation and periplasmic pH regulation [123]. In the creation of new and better treatment regimes, a continuous research and understanding of the molecular processes of *H. pylori* gastric colonization are crucial.
