Coadaptation of Helicobacter pylori and humans: ancient history, modern implications

Abstract

Humans have been colonized by Helicobacter pylori for at least 50,000 years and probably throughout their evolution. H. pylori has adapted to humans, colonizing children and persisting throughout life. Most strains possess factors that subtly modulate the host environment, increasing the risk of peptic ulceration, gastric adenocarcinoma, and possibly other diseases. H. pylori genes encoding these and other factors rapidly evolve through mutation and recombination, changing the bacteria-host interaction. Although immune and physiologic responses to H. pylori also contribute to pathogenesis, humans have evolved in concert with the bacterium, and its recent absence throughout the life of many individuals has led to new human physiological changes. These may have contributed to recent increases in esophageal adenocarcinoma and, more speculatively, other modern diseases.

Figure 1. Phylogeography of H. pylori.

(A) Genetic diversity. Neighbor-joining tree (Kimura 2-parameter) of 769 concatenated sequences from H. pylori, color-coded according to population assignment by structure into the populations H. pylori Europe (hpEurope), H. pylori Asia 2 (hpAsia2), H. pylori North East Africa (hpNEAfrica), H. pylori Africa 2 (hpAfrica2), H. pylori Africa 1 (hpAfrica1), with subpopulations H. pylori West Africa (hspWAfrica) and H. pylori South Africa (hspSAfrica), and H. pylori East Asia (hpEAsia), with subpopulations H. pylori American Indian (hspAmerind), H. pylori Maori (hspMaori), and H. pylori East Asia (hspEAsia). (B–E) Parallel geographic patterns of genetic diversity in humans and H. pylori. (B and C) Genetic distance in humans (B) and H. pylori (C) between pairs of geographic populations versus geographic distance between the two populations. F_ST is the proportion of the total genetic variance contained in a subpopulation relative to the total genetic variance. (D and E) Average gene diversity (H_S) in humans (D) and H. pylori (E) within geographic populations versus geographic distance from East Africa. r² = 0.77 (B); r² = 0.47 (C); r² = 0.85 (D); and r² = 0.59 (E). Confidence intervals are indicated by dotted lines. Reproduced with permission from Nature (5).

Figure 2. CagA phenotypes and variation.

Local and whole-cell effects of the H. pylori cag–encoded T4SS and its major effector protein, CagA. H. pylori, with an intact cag PaI, forms a T4SS, which injects CagA into epithelial cells (10). The T4SS tip protein, CagL, binds to and activates integrin α₅β₁, resulting in local activation of focal adhesion kinase (FAK) and then Src kinase (11). Activated kinases phosphorylate CagA at specific tyrosine residues, in turn activating local Src homology 2 domain–containing tyrosine phosphatase 2 (SHP-2) and therefore local signaling (12, 13, 125). A soluble component of bacterial peptidoglycan, γ-D-glutamyl-meso-diaminopimelic acid (ie-DAP) also enters the cell and is recognized by the intracellular innate immune pattern-recognition receptor Nod1, leading to stimulation of NF-κB (14). Furthermore, phosphorylated CagA itself, possibly when in excess or when trafficked deeper into the cell, also may activate NF-κB and have other whole-cell effects (, –17). Blue arrows indicate H. pylori components, black arrows indicate epithelial cell components, and red text indicates cellular effects.

Figure 3. Mechanisms for generating genetic diversity in H. pylori.

(A) Slipped-strand mispairing in a homopolymeric tract, leading to phase variation in surface antigen expression. Lewis (Le^X and Le^Y) expression in single colonies of an H. pylori strain were determined by ELISA, with transformed converted mean OD units (TCMO) calculated. Two major population groupings were observed, based on frame-status of futC, the gene encoding α-1,2-fucosytransferase. Reproduced with permission from Microbes and infection (S28). (B–D) Polymorphisms in the gene mutY, which encodes DNA glycosylase MutY. (B). Genotypes of 413 mutY homonucleotide tracts from the H. pylori multilocus sequence typing (MLST) database. (C) Chromatograph of the mutY homonucleotide with seven adenines (out of frame). (D) Chromatograph of in-frame mutY (eight adenines). When mutY is out of frame, the H. pylori cells have a mutator phenotype, augmenting genomic point mutation. Reproduced with permission from Journal of bacteriology (S29). (E–G) Effect of exposure to RNS and ROS in frequency of deletions involving DNA repeats. (E) Deletion cassette. Cells with this were exposed to RNS (F) or ROS (G) and deletion frequency was calculated. Asterisks indicate significant (P < 0.05) increases in point mutation frequencies when compared with those calculated for cells incubated in 0 nM of SNP or methyl viologen. aphA, gene encoding aminoglycoside resistance; CAT, chloramphenicol acetyl transferase; CmR, resistant to chloramphenicol; IDS, identical repeat sequence; KanS, susceptible to kanamycin. Reproduced with permission from FASEB journal (S27). (H) Proposed mechanism of RuvB/RecG Holliday junction resolution. Two H. pylori DNA processing pathways may compete for the same Holliday junction intermediate, which can branch migrate (left pathway) because of RuvAB and be resolved by RuvC, restoring replication fork, enabling loading of the replisome (small oval). Alternatively, (middle pathway) RecG (gray circle) can branch migrate Holliday junctions, but without resolution, leading to cell death. Addition of RusA restores the RecG pathway, leading to recombinational repair. The incomplete recG pathway reflects a tension between DNA repair and antirepair. Reproduced with permission from Journal of bacteriology (S26).

Figure 4. Variation of interactive factors.

(A) Model of alternative host interactions according to status of mutable loci, modeled on the cag PaI. The H. pylori genome contains multiple hypermutable loci, creating many contingency genes. The status of each gene confers a particular phenotype to the H. pylori cell, affecting its host interactions. The strain on the left has an operating genetic element, which induces a greater host response; on the right is the same strain with a deleted element, inducing a lower response. The host responses create environmental constraints that select within the H. pylori population, creating a dynamic equilibrium (56). (B) Microevolution of cagA within a family. All four subjects in family F12 are colonized with strain 25, and subject D is also colonized with strain 26. Subjects C and D both have two clones of strain 25 with cagA with four and five type C (active) TPMs – these have evolved by simple duplication of the TPM-containing region. They are identical between these subjects, and so likely have been passed between them. Strain 25 in subject A possesses cagA with a variable region (VR) that is nearly identical to strain 26, implying these strains have recombined in subject D: strain 25 has acquired cagA from strain 26 and then been passed to subject A. Duplication of the TPM-C motif may have occurred within subject D or subject A. Strain 25 from subject B lacks the entire cag PaI and may have evolved by deletion from strain 25 from any family member. Solid lines indicate identical strains between hosts, whereas dashed lines represent proposed transmission. Adapted with permission from Clinical cancer research (43) (B).

Figure 5. Th subsets in H. pylori–associated health and disease.

H. pylori colonization is associated with strong Th1 and Treg responses. We speculate that historically the Treg response has been sufficient to downregulate the local gastric Th1 response thereby avoiding excessive gastric inflammation and gastroduodenal disease. Tregs are also induced by other microbes and through bystander effects may downregulate the H. pylori–associated Th1 response and disease. A low level of gastric Tregs is associated with an increased risk of peptic ulceration. We speculate that pre-19th–century humans had healthy levels of Tregs and thus that H. pylori–associated diseases (particularly peptic ulceration) were unusual. Either of two hypotheses could causally explain the rise in atopic and allergic disease with the disappearance of H. pylori. In the first hypothesis, loss of other infections common in childhood has led to reduced Tregs and thus to loss of Th2 suppression and increased Th2 diseases. Over the same time frame, the loss of Th1 suppression has led to the rise in H. pylori–associated diseases. In modern life, H. pylori is a marker for other childhood infections and a strong Treg response, explaining the negative association between H. pylori and diseases such as asthma. In the second hypothesis, loss of H. pylori itself has led to reduced Treg populations and a subsequent increase in Th2 responses; this could only be the case if H. pylori–associated Tregs had a systemic effect, which now has been observed. These hypotheses are not mutually exclusive.

Figure 6. Overviews of H. pylori relationships to health and disease.

(A) Ancient, premodern, and postmodern stomachs. From ancient times, normal human physiology in the presence of H. pylori pan-gastritis has avoided disease until the gastric cancers of old age. We speculate that premodern changes in the pattern of colonization and inflammation in the stomach resulted in changes in physiology and the rise of peptic ulcer disease (PUD). In the postmodern (current) era, the absence of H. pylori leads to distorted physiology, to which we have not fully adapted. This may have led to disease in some children and adults but avoids gastric cancer in old age. (B) A model of the proposed biphasic nature of H. pylori and human disease. Because we have coevolved with H. pylori, the changed physiology resulting from an H. pylori–free stomach may contribute to some modern diseases. Thus, from a postmodern viewpoint, H. pylori may confer benefits to humans early in their life span. Possible examples include reducing infectious diseases, controlling allergy, regulating gastric hormones such as leptin and ghrelin (benefits uncertain), and reducing gastroesophageal reflux disease sequelae. Later in life, H. pylori has biological costs, inducing ulcers, (possible) metabolic disturbances, anemia, and gastric cancers, all more prominent in an ageing population. In both A and B, black text indicates information for which there is strong evidence — for these, the balance is toward a net deleterious effect of H. pylori on human health — and red text indicates information for which evidence remains under debate. cag-negative strains are less interactive with humans, conferring smaller risks and putative benefits.