Helicobacter pylori's unconventional role in health and disease

Abstract

The discovery of a bacterium, Helicobacter pylori, that is resident in the human stomach and causes chronic disease (peptic ulcer and gastric cancer) was radical on many levels. Whereas the mouth and the colon were both known to host a large number of microorganisms, collectively referred to as the microbiome, the stomach was thought to be a virtual Sahara desert for microbes because of its high acidity. We now know that H. pylori is one of many species of bacteria that live in the stomach, although H. pylori seems to dominate this community. H. pylori does not behave as a classical bacterial pathogen: disease is not solely mediated by production of toxins, although certain H. pylori genes, including those that encode exotoxins, increase the risk of disease development. Instead, disease seems to result from a complex interaction between the bacterium, the host, and the environment. Furthermore, H. pylori was the first bacterium observed to behave as a carcinogen. The innate and adaptive immune defenses of the host, combined with factors in the environment of the stomach, apparently drive a continuously high rate of genomic variation in H. pylori. Studies of this genetic diversity in strains isolated from various locations across the globe show that H. pylori has coevolved with humans throughout our history. This long association has given rise not only to disease, but also to possible protective effects, particularly with respect to diseases of the esophagus. Given this complex relationship with human health, eradication of H. pylori in nonsymptomatic individuals may not be the best course of action. The story of H. pylori teaches us to look more deeply at our resident microbiome and the complexity of its interactions, both in this complex population and within our own tissues, to gain a better understanding of health and disease.

Figure 1. Distinct pathologies of H. pylori–induced disease.

(A) Duodenal ulcer disease correlates with high inflammation in the antrum (red bursts), lower levels of inflammation in the corpus, and high acid secretion (+). (B) Gastric ulcer or adenocarcinoma correlates with increased inflammation in the corpus, low acid secretion, and multifocal atrophy (wavy lines).

Figure 2. Mechanisms that create genetic diversity in H. pylori.

Colored arrows represent different genes, and the correspondingly colored triangles, rectangles, and circles represent the proteins encoded by these genes. Diversification mechanisms (right side of figure) include spontaneous point mutations, slipped-strand mispairing, and intragenomic recombination. Allelic changes involving nonsynonymous point mutations and mosaic genes resulting from intragenomic recombination can alter the function and/or the antigenic epitopes of the encoded protein. Gene expression can also be regulated by gene conversion resulting from intragenomic recombination, and phase variation mediated by slipped-strand mispairing. Reassortment of genes (left side of figure) by natural transformation with exogenous DNA also contributes to genetic diversity. Natural transformation with DNA from a superinfecting strain, for example, can introduce new genes and new alleles of already present genes (horizontal gene transfer). Similarly, natural transformation with DNA from a variant clone of the same strain can further propagate an advantageous allele acquired by within-genome diversification.