After being ingested and entering the human stomach, Helicobacter pylori (H. pylori) adopts several effective strategies to adhere to and colonize the gastric mucosa and move to different regions of the stomach to obtain more nutrients and escape from the harsher environments of the stomach, leading to acute infection and chronic gastritis, which is the basis of malignant gastric tumors. The endoscopic manifestations and pathological features of H. pylori infection are diverse and vary with the duration of infection. In this review, we describe the endoscopic manifestations of each stage of H. pylori gastritis and then reveal the potential mechanisms of bacterial intragastric colonization and migration from the perspective of endoscopists to provide direction for future research on the effective therapy and management of H. pylori infection.

More than half of the world’s population is estimated to be infected by the gram-negative, flagellated, spiral-shaped bacterium Helicobacter pylori (H. pylori)[1]. The bacterium has received intensive attention because H. pylori infection is closely associated with the development of peptic ulcers, mucosa-associated lymphoid tissue lymphoma and gastric cancer (GC), resulting in at least 500000 deaths per year[2-4]. The slow carcinogenic process is known as Correa’s cascade[5]: At first, gastritis occurs in all infected individuals[2], and then a series of intermediate stages (characterized by precancerous lesions), including atrophy, intestinal metaplasia (IM) and dysplasia, may slowly develop, and eventually, 1%-3% of infected patients develop gastric malignant tumors[6].

All gastric mucosal lesions that occur after H. pylori infection can be observed by skilled endoscopists through upper gastrointestinal endoscopy. Based on the Kyoto classification of gastritis, endoscopic features, such as nodularity, diffuse redness, spotty redness, mucosal swelling, enlarged folds, xanthoma, atrophy and IM, are helpful in diagnosing H. pylori gastritis[7]. Atrophy can be endoscopically identified with high confidence by applying the Kimura-Takemoto classification[8], while IM and dysplasia can be diagnosed more accurately with advanced image-enhanced endoscopy (IEE)[9].

The highly motile pathogen H. pylori usually infects young children[3] and initiates acute infection that lasts for only a few weeks[10,11] and chronic inflammation that can last for the lifetime of the host[12]. Its ability to swim in the gastric mucus and colonize the stomach enables it to survive in the hostile gastric environment[13] and leads to various endoscopic and histological features as gastric mucosal lesions progress[14]. Many articles and reviews have reported the underlying mechanisms, but few have linked endoscopic features to mechanisms. Therefore, in the following sections, we describe the endoscopic manifestations of each stage of H. pylori gastritis and summarize the process and potential mechanisms of intragastric colonization by H. pylori and its migration.

Acute H. pylori infection only lasts for a few weeks[10,11] and has been rarely observed or reported in recent decades. The endoscopic manifestation of gastric erythema and a gaping pylorus[10,11] is always featureless. Although the gastric mucosa does not appear damaged at this stage, initial colonization of the mucosa is the basis of a series of lesions, such as atrophic gastritis, peptic ulcer and even gastric carcinoma.

The prevalence of H. pylori infection is high, but colonization by this microbe is not easy. Multiple spontaneous eradication events may occur before colonization, leading to acute infection[15]. Sophisticated strategies have been adopted by H. pylori that have enabled it to adapt to and survive in the hostile gastric environment.

When H. pylori is ingested by adults, it is almost completely destroyed in the gastric acid, while it is easier to survive in the stomach of children younger than the age of five, both in developing and developed countries[3]. Bucker et al[3] simulated the pH changes of the postprandial stage in babies, young children and adults and suggested that the bacteria were easiest to reach the mucus layer in young children, whose feature of postprandial gastric condition is moderate food-induced pH elevation and slow reacidification.

During the process of slow reacidification, the urease enzyme is believed to play a key role in bacterial survival and adhesion. Urea is degraded by the urease enzyme, which buffers the cytoplasm and periplasm[16]. This confers many benefits. First, H. pylori prefers to live in an environment with elevated pH. A recent study[17] showed that H. pylori does not escape from phosphate buffer solutions of pH 6.6 and 7.0. Second, intracellular urease could also increase membrane potential, thereby allowing protein synthesis at a low pH[18]. Third, mucosal viscosity highly depends on acidity[19]. At a less acidic pH, the mucus is less gel-like, which enables H. pylori to more easily move through the mucus layer[20]. Fourth, trefoil factor 1 (TFF1) is a member of the trefoil peptide family of proteins and is coexpressed with Mucin-5AC (MUC5AC), a gel-forming mucin that is predominantly secreted and expressed by gastric surface epithelial cells in the stomach[21]. The optimum pH for bacterial binding to TFF1, which thereby promotes colonization, was found to be 5.0-6.0[22]. In addition, urea and bicarbonate were considered to have a chemotactic effect on H. pylori in vitro[23], but research by Schreiber et al[13] shows that neither the urea/ammonium gradient nor the bicarbonate/CO₂ gradient are essential for the orientation of H. pylori in vivo.

However, this does not mean that a neutral or alkaline environment is suitable for H. pylori. Previous studies have shown that H. pylori is sensitive to alkaline conditions[24], and its growth is limited at neutral pH[25]. To prevent lethal alkalinization of the cytoplasm, H. pylori utilizes a proton-gated channel, UreI, which regulates the uptake of urea[26] and only functions in conditions of an acidic pH; thus, the transport of urea into the bacterial cell does not occur at a neutral pH[24]. Therefore, H. pylori prefers a weakly acidic environment.

The epithelial surface of the stomach is covered with an approximately 300 μm thick layer of secreted mucus, which mainly consists of mucins Mucin 6 (MUC6) and MUC5AC[27]. MUC6 exists in each layer of the mucus gel, while MUC5AC is mainly present on the surface and bottom. The increase in the viscosity of gastric mucus gel is due to this natural stratification of mucins[28]. While protecting gastric epithelial cells, the mucus layer also plays an important role in the colonization process. The pH is approximately neutral at the epithelium and very acidic (pH 1-2) close to the lumen[21], resulting in a mucus pH gradient that can be used by H. pylori for precise spatial orientation[13]. The membrane-bound chemoreceptor TlpA of H. pylori detects and mediates repulsion from environments with a lower pH, and the cytoplasmic chemoreceptor TlpD mediates both attraction to higher pH environments and repulsion from lower pH environments[17,29]. Under this chemotactic effect, H. pylori penetrates the gastric mucus quickly and reaches the narrow region within 25 μm of the gastric epithelial surface with the help of its two to six sheathed unipolar flagella and helical shape[30,31].

After approaching the lower mucus layer, the majority of H. pylori swim in gastric mucus, while others directly adhere to epithelial cells[13,31]. Although it is considered a noninvasive gastric pathogen to date[19], H. pylori can indeed bind to, invade, be internalized into and proliferate in gastric epithelial cells[27,32]. The invasiveness of H. pylori may partially depend on the strain. Research by Camorlinga-Ponce et al[33] showed that CagA-negative bacteria adhered to the surface of the apical epithelium, while CagA-positive bacteria were identified in the intercellular spaces or the immediate vicinity of epithelial cells. Sigal et al[34] found a subgroup of H. pylori associated with cells deep in the antral glands. These microbes can promote gland hyperplasia by inducing stem cell proliferation and expansion and altering gene expression of stem cells[34].

H. pylori adheres to epithelial cells mainly by outer membrane proteins (OMPs). Blood group antigen-binding adhesion (BabA) and sialic acid-binding adhesion (SabA) are important OMPs[19,27]. Lewis antigens are common in normal, infected and inflamed gastric mucosa[35,36]. BabA can identify and bind to Lewis b antigen[35], while SabA can bind to the antigens Lewis a and Lewis X[36], and its expression can quickly respond to the changes in the stomach or different areas of the stomach, enabling the bacteria to adapt to host’s immune responses and varied microenvironments to maintain long-term colonization and infection[37]. In addition to BabA and SabA, other surface proteins, such as AlpA, AlpB, DupA, outer inflammatory protein A (OipA) and HopZ, are considered related to adhesion, but none of them has been shown to be essential to adhesive mechanisms[38]. After H. pylori adheres to epithelial cells, the Cag type IV secretion system (T4SS) promotes CagA translocation into host cells, resulting in changes in cell shape, disruption of cell‒cell junctions, altered cell polarity and cell adhesion, increased cell motility and cell migration, increased cell proliferation, β-catenin activation, and epithelial-mesenchymal transition[39]. Some bacteria are internalized into the cytoplasm of gastric epithelial cells through endocytosis within 45 minutes of bacterial attachment to the cell surface[32]. H. pylori can replicate and proliferate in epithelial cells[40], escape the immune response, and exit cells to colonize and infect cells again when the external environment is suitable for survival[27].

In an artificial ingestion study[10], histological examination during the acute phase of H. pylori infection showed many polymorphonuclear neutrophil leucocytes (PMNs) in the lamina propria and on the surface of the mucosa and an absence of intracellular mucus. Spiral bacilli adhered to the surface and glandular epithelium as well as among PMNs in the mucus[10]. Zhao et al[41] proposed a novel staging strategy according to the depth and degree of gastric mucosal injury induced by H. pylori infection and the progression of lesions. Stage I means the bacteria were present in the mucus layer, stage IIA refers to the specific adhesion to and selective destruction of gastric epithelial cells, and stage IIB refers to the degeneration and shedding of surface mucus cells[41]. It seems that stages I and II are consistent with the pathological characteristics of acute H. pylori infection.

Cases of H. pylori gastritis that are observed by doctors usually involve chronic gastritis that has lasted for years[42]. Chronic gastritis has various endoscopic findings, among which nodularity, diffuse redness, spotty redness, xanthoma, mucosal swelling, enlarged folds, atrophy, and IM are common in H. pylori-infected gastric mucosa[43,44] (Figure 1). Considering the severity and progression of chronic H. pylori gastritis, we discuss endoscopic manifestations and potential mechanisms from the following three aspects: (1) Early stage of H. pylori infection; (2) corpus inflammation; and (3) atrophy and intestinal metaplasia, which are summarized in Table 1.

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Figure 1 Endoscopic features without and with Helicobacter pylori infection. A: Antrum without Helicobacter pylori infection; B: Corpus without Helicobacter pylori infection; C: Nodularity; D: Diffuse redness; E: Spotty redness; F: Mucosal swelling; G: Enlarged folds; H: Xanthoma; I: Atrophy; J: Intestinal metaplasia; K: Light-blue crest; L: White opaque substance.

H. pylori has shared a coevolutionary history with humans for more than 60000 years[41,95]. Human migration has led to the global distribution of the bacterium from East Africa to other continents[19]. In addition to geographical migration, H. pylori has the ability to move between different regions of the stomach.

The motility of H. pylori provided by its flagella and helical shape is the basis of intragastric migration. The bacterium possesses two to six sheathed unipolar flagella[96]. The sheath, which consists of both proteins and lipopolysaccharide, protects the flagellar filaments from gastric acid[97]. Expression of the two major flagellar proteins, FlaA and FlaB, is required for full motility of the bacteria[21]. An efficient screw-like movement resulting from the characteristic helical shape of H. pylori also provides an advantage for penetrating the gastric mucus layer[98]. Any mutation in the genes associated with bacterial morphology, such as Ccrp89, Ccrp58, Ccrp1142 and Ccrp1143, can lead to a deficiency in bacterial shape and motility[99].

The chemotaxis system of H. pylori is necessary for intragastric migration. Chemotactic signals sensed by chemoreceptors are transmitted to the histidine kinase CheA through the coupling protein CheW or CheV1[100]. Repellents activate CheA autophosphorylation, and CheY is subsequently phosphorylated via histidine-to-aspartate phosphorelay[101]. Phosphorylated CheY interacts with the flagellar motor, causing it to rotate clockwise and the bacteria to reverse or change direction[56]. Alternatively, the bacteria swim straight because chemicals perceived as attractants squelch CheA autophosphorylation[56]. As described above, the ability of chemoreceptors to sense pH guides the bacteria to the surface of the gastric epithelium. It has been suggested that different regions of the stomach contain unique chemotactic signals[51]. The gastric antrum is usually the first colonized area because of its weaker acidic environment but not due to chemotaxis. The chemotactic signals produced by the antrum or transition zone play an important role in the increase in H. pylori numbers that occurs from 14 h to 1 wk after colonization[51]. Chemotaxis is also required when H. pylori migrates to the corpus from the antrum but is not needed for the increase in bacterial populations after the initial colonization of the corpus[27]. In addition, H. pylori can swim toward injured epithelia[102].

H. pylori can simultaneously survive in the antrum and the corpus in general. However, when atrophy occurs, an environment that is unfavorable to the growth of H. pylori develops, and the bacteria can only be found in a small percentage of endoscopic biopsy specimens[103]. Research has revealed that atrophy in the corpus manifests as a continuous sheet of pseudopyloric metaplasia and forms an advancing histologically atrophic front, the presence of which is similar to the spread of antral mucosa toward the corpus and is faster in the lesser curvature[104]. This pattern is the same as the endoscopic atrophic border described by Kimura and Takemoto[8]. This may indicate that the suitable region in which H. pylori survives shrinks as the atrophic front advances and is well discriminated by the endoscopic atrophic border.

In addition, H. pylori can migrate to the duodenum and colonize the duodenal gastric metaplasia (DGM) with a bacterial density 100-fold lower than that in the antrum[105,106]. DGM is characterized by the metaplastic replacement of normal duodenal epithelial cells with cells displaying a phenotype similar to that of mucus-secreting cells of the gastric mucosa[107]. It is frequently found in patients with duodenal ulcers with a prevalence of 72 to 90% and is associated with the chronicity and recurrence of duodenal ulcer disease[108-110]. The exact pathogenesis of DGM remains unclear. It is speculated that a high acid burden in the duodenum caused by increased gastrin secretion and the inflammatory damage to duodenal mucosa induced by bacterial cytotoxin may lead to the development of DGM in patients with H. pylori infection[109]. Liu and Wright[111] considered that metaplastic cells originate from Brunner's gland duct epithelium or basal buds growing out of the crypts of Lieberkühn and migrate in straight lines. However, Shaoul et al[112] suggested that DGM develops from goblet cells that simultaneously express gastric antigens, MUC5AC and TFF1, and intestinal antigen, MUC2 core antigen, migrate upward and transform to foveolar-like cells at the site of early metaplastic patches. Published results about the association between H. pylori infection and DGM are also conflicting. Some studies reported that H. pylori infection was one of the independent risk factors for DGM[113], the amount of H. pylori in the duodenal bulb might be related to the extent of gastric metaplasia in the duodenal bulb[114], and the presence of DGM significantly decreased after H. pylori eradication[109]. However, some researchers have suggested that DGM is associated with high acid output in the stomach rather than gastric H. pylori infection[115-117].

The endoscopic characteristics of the cardia have received little attention in previous studies. In recent years, cardiac nodularity, which involves the appearance of miliary nodules or scattered small whitish circular colorations within 2 cm of the esophagogastric junction, has been proposed by researchers[46,118].

Cardia glands lack chief cells and parietal cells, and have similar characteristics to the pyloric glands[53]. The cardiac and pyloric glands secrete mucus and bicarbonate and are involved in the defense of the gastric epithelium[46]. In addition, both of them secrete MUC6 and pepsinogen II rather than pepsinogen I[46]. Unlike the fundic glands, the similarity of the cardiac and pyloric glands may lead to the appearance of cardiac nodularity.

Nodularity can be observed more frequently in the stomach of children and improves gradually with age[119,120]. Reportedly, the eradication of H. pylori in patients with antral nodularity could effectively prevent diffuse-type GC[119]. A study by Nishikawa et al[119] suggested that compared with patients without cardiac nodularity, patients with cardiac nodularity were significantly younger and had lower IM scores. Therefore, cardiac nodularity may also be a feature of the early stage of H. pylori infection, but further research is needed to analyze its clinicopathological importance.

H. pylori infection has received worldwide attention for decades. In this review, we described the process of intragastric colonization by H. pylori and its migration and tried to identify a link between endoscopic manifestations and potential mechanisms. Upper gastrointestinal endoscopy and pathological examination of biopsy specimens are useful tools for diagnosing H. pylori-induced gastritis and estimating the risk of H. pylori-induced GC. In addition to animal models, exploring the mechanisms of H. pylori infection requires biopsy sampling. However, extensive study is needed to evaluate the association between endoscopic manifestations and mechanisms.