Helicobacter pylori persistence: biology and disease

Abstract

Helicobacter pylori are bacteria that have coevolved with humans to be transmitted from person to person and to persistently colonize the stomach. Their population structure is a model for the ecology of the indigenous microbiota. A well-choreographed equilibrium between bacterial effectors and host responses permits microbial persistence and health of the host but confers risk of serious diseases, including peptic ulceration and gastric neoplasia.

Figure 1

Models of the cross-signaling between obligate parasites and their hosts. (a) H. pylori in the gastric (antral) niche, inhabiting the luminal mucus layer overlaying the epithelium. Scale bar: 1 μm. (b) Model 1: A coevolved microbe sends chemical and physical (contact) signals to its host. The host’s signals, including motion, temperature, and chemicals (including host-defense molecules), affect microbial growth. In a local niche, equilibrium can be reached if there is negative feedback in the cross-signaling , S1). The microbial signals may alter selection of growing host-cell populations (e.g., by antiapoptotic mechanisms). (c) Model 2: The microbial population includes genetic variants. Now, the host signals select for different bacterial phenotypes, and thus genotypes. (d) Model 3: Due to ongoing variation and selection, each microbe becomes a microbial population of related variants. The signals of each variant affect not only the local host signals, but also those affecting other microbial populations. This is represented by two distinct microbial populations, with each signaling the host (S₁, S₂) and inducing specific host signals (HS₁, HS₂). Increasing numbers of populations markedly and nonlinearly increase the complexity. (e) Model 4: The microbial populations are not clonal but can exchange genetic information; host selection, based on microbial genes or gene fragments rather than cells, determines the (dynamic) equilibria between the microbial populations (MP_n). For the naturally competent, extensively recombining H. pylori cells, model 4 best reflects the fluidity of population structures during persistent colonization (, S2, S3). (f) Schematic of adaptation to individual hosts. After H. pylori acquisition and expansion into a major niche, early selection allows occupation of microniches, where further local selection determines predominant populations. Both local selection and global selection determine overall population structure, and the probability of transfer of particular genotypes to new hosts. Local resource differences and barriers to diffusion of bacterial cells allow establishment of distinct subpopulations. External fluctuations, such as incomplete antibiotic treatment, can markedly change genotype distribution.

Figure 2

CagA interaction with epithelial cells. H. pylori cells with intact cag islands, including an active type IV secretion system, possess a pilus composed of CagY protein. The cagA product is injected into the cytoplasm of the host cell, where tyrosine (Y) residues near its COOH-terminus are phosphorylated. Phosphotyrosine-CagA interacts with several major signal-transduction pathways in the host cell (, S113), affecting phenotypes including cell morphology, proliferation, and apoptosis (see text). ERK, extracellular signal–regulated kinase; PTPase, protein-tyrosine phosphatase; P, phosphate.

Figure 3

VacA polymorphism and function. (a) VacA polymorphism. The gene, vacA, is a polymorphic mosaic with two possible signal regions, s1 and s2, and two possible mid-regions, m1 and m2. The translated protein is an autotransporter with N- and C-terminal processing during bacterial secretion. The s1 signal region is fully active, but the s2 region encodes a protein with a different signal-peptide cleavage site, resulting in a short N-terminal extension to the mature toxin that blocks vacuolating activity and attenuates pore-forming activity. The mid-region encodes a cell-binding site, but the m2 type binds to and vacuolates fewer cell lines in vitro. (b) VacA biological activities. Secreted VacA forms monomers and oligomers; the monomeric form binds to epithelial cells both nonspecifically and through specific receptor binding, for example, to Ptprz, which may modulate cell signaling. Membrane-bound VacA forms pores. Following VacA endocytosis, large vacuoles form, but, although marked in vitro, these are rarely seen in vivo. VacA also induces apoptosis, in part by forming pores in mitochondrial membranes, allowing cytochrome c (Cyt c) egress. Although the presence of cytoplasmic VacA is implied rather than demonstrated, yeast two-hybrid experiments show potential for specific binding to cytosolic targets including cytoskeletal proteins, consistent with observed cytoskeletal effects. Finally, VacA has suppressive effects on immune cell function. The relative importance of these effects on H. pylori persistence and host interaction remains unclear.

Figure 4

Relation of topography of inflammation to gastric physiology and clinical outcome. (a) H. pylori–induced antral-predominant inflammation. Antral inflammation results in hypergastrinemia, which stimulates a physiologically intact corpus to secrete acid, increasing risk for duodenal ulceration. (b) H. pylori–induced pan-gastritis. The inflammatory process suppresses corpus acid production, despite the gastrin stimulus from the antrum. Hypochlorhydria enhances risk of gastric ulcer and adenocarcinoma but conversely decreases risk for severe gastro-esophageal reflux disease and its sequelae. ECL, enterochromaffin-like.

Figure 5

The described effects of H. pylori on leptin and ghrelin, and postulated subsequent effects on satiety, energy expenditure, weight, and height. Although leptin and ghrelin have other important paracrine, autocrine, and endocrine effects, here we concentrate on actions that affect body habitus. The observed effects of H. pylori on leptin and ghrelin are based on observational and interventional (H. pylori eradication) human studies. Other observational human studies support the portrayed effects of H. pylori on weight and height.