The Physiology and Metabolism of the Human Gastric Pathogen Helicobacter pylori

Abstract

Helicobacter pylori is a spiral Gram-negative microaerophilic bacterium that causes one of the most common infections in humans; approximately 30-50% of individuals in Western Europe are infected and the figure is nearly 100% in the developing world. It is recognized as the major aetiological factor in chronic active type B gastritis, and gastric and duodenal ulceration and as a risk factor for gastric cancer. H. pylori normally inhabits the mucus-lined surface of the antrum of the human stomach where it induces a mild inflammation, but its presence is otherwise usually asymptomatic. A variety of virulence factors appear to play a role in pathogenesis. These include the vacuolating cytotoxin VacA, cytotoxin-associated proteins, urease and motility. All are under intense study in an attempt to understand how the bacterium colonizes and persists in the gastric mucosa, and how H. pylori infections lead to the disease state. Although an explosion of research on H. pylori has occurred within the past 15 years, most efforts have been directed at aspects of the bacterium and disease process which are of direct clinical relevance. Consequently, our knowledge of many aspects of the physiology and metabolism of H. pylori is relatively poor. This should change rapidly now that the complete genome sequence of a pathogenic strain has been determined. This review focuses attention on these more fundamental areas of Helicobacter biology. Analysis of the genome sequence and some detailed metabolic studies have revealed solute transport systems, an incomplete citric acid cycle and several incomplete biosynthetic pathways, which largely explain the complex nutritional requirements of H. pylori. The microaerophilic nature of the bacterium is of particular interest and may be due in part to the involvement of oxygen-sensitive enzymes in central metabolic pathways. However, the biochemical basis for the requirement for CO2 has not been completely explained and a major surprise is the apparent lack of anaplerotic carboxylation enzymes. Although genes for glycolytic enzymes are present, physiological studies indicate that the Entner-Doudoroff and pentose phosphate pathways are more active. The respiratory chain is remarkably simple, apparently with a single terminal oxidase and fumarate reductase as the only reductase for anaerobic respiration. NADPH appears to be the preferred electron donor in vivo, rather than NADH as in most other bacteria. H. pylori is not an acidophile, and must possess mechanisms to survive stomach acid. Many studies have been carried out on the role of the urease in acid tolerance but mechanisms to maintain the protonmotive force at low external pH values may also be important, although poorly understood at present. In terms of the regulation of gene expression, there are few regulatory and DNA binding proteins in H. pylori, especially the two-component 'sensor-regulator' systems, which indicates a minimal degree of environmentally responsive gene expression.