Effects of Helicobacter pylori infection on intestinal microbiota, immunity and colorectal cancer risk

Abstract

Infecting about half of the world´s population, Helicobacter pylori is one of the most prevalent bacterial infections worldwide and the strongest known risk factor for gastric cancer. Although H. pylori colonizes exclusively the gastric epithelium, the infection has also been associated with various extragastric diseases, including colorectal cancer (CRC). Epidemiological studies reported an almost two-fold increased risk for infected individuals to develop CRC, but only recently, direct causal and functional links between the chronic infection and CRC have been revealed. Besides modulating the host intestinal immune response, H. pylori is thought to increase CRC risk by inducing gut microbiota alterations. It is known that H. pylori infection not only impacts the gastric microbiota at the site of infection but also leads to changes in bacterial colonization in the distal large intestine. Considering that the gut microbiome plays a driving role in CRC, H. pylori infection emerges as a key factor responsible for promoting changes in microbiome signatures that could contribute to tumor development. Within this review, we want to focus on the interplay between H. pylori infection, changes in the intestinal microbiota, and intestinal immunity. In addition, the effects of H. pylori antibiotic eradication therapy will be discussed.

Keywords: Helicobacter pylori; antibiotics; colorectal cancer; eradication therapy; immune response; intestinal microbiome.

Figure 1

H. pylori possesses unique properties and virulence factors for successful colonization and manipulation of the host’s immune system. Acid neutralization by the enzyme urease and adherence factors of H. pylori, such as BabA, SabA and HopQ, are important for colonization of the gastric mucosa. Damage of gastric epithelial cells by vacuolization occurs by the virulence factor VacA and inflammation and pro-carcinogenic signaling is then induced by the cytotoxin-associated antigen pathogenicity island (CagPAI). Finally, VacA and gGT manipulate immune responses by inhibiting both CD4⁺ and CD8⁺ T cell responses and promoting the expansion of Treg cells in order to enable bacterial persistence.

Figure 2

H. pylori-specific CD4⁺ T-cells are primed in the small intestinal Peyer´s patches and mesenteric lymph nodes. 1) DCs in the PPs and MLNs capture H. pylori and prime naïve CD4⁺ Tcells. 2) Those H. pylori antigen-specific CD4⁺ T-cells subsequently home to the gastric mucosa and induce gastritis. The activation of CD4⁺ T-cells in the small intestine, which is required for H. pylori-induced gastric inflammation, suggests a mechanism for extragastric immunomodulation.

Figure 3

H. pylori infection increases the risk for CRC by inducing pro-inflammatory immune responses and intestinal microbiome changes. (A) In the small and large intestinal epithelia, represented schematically in the illustration, H. pylori infection, particularly with CagA positive strains, promotes a pro-inflammatory immune response characterized by CD3⁺ T-cell infiltration and IFNγ secretion and activates pro-carcinogenic pSTAT3 signaling. Concomitant with the reduction of Treg cells, the infection induces pathogenic FoxP3⁺/IL-17⁺ T-cells, which may dampen tumor-specific CD8⁺ T-cells. Also, the increase of regulatory DCs by H. pylori may impair CD8⁺ T-cell effector functions contributing to colon cancer. (B) Furthermore, H. pylori infection indirectly affects the intestinal microbiota by increasing mucus-degrading and pro-carcinogenic species and reducing beneficial metabolite-producing bacteria. Together with the loss of mucus-producing goblet cells and intestinal barrier impairment, the infection results in a leaky gut and increased antigen influx, which further manifests as inflammation in the epithelium. These H. pylori-induced disturbances of the intestinal immunity and microbiome promote CRC development.

Figure 4

H. pylori eradication treatment can have different effects on the risk for CRC. (A) H. pylori eradication may prevent CRC by increasing and decrease the detrimental effects of the infection, particularly by reducing pro-inflammatory CD3⁺ T-cells and pSTAT3 signaling and increasing regulatory T-cells, thereby inducing immunological homeostasis in the small intestine and colon. In addition, the number of mucus-producing goblet cells may be restored, as well as the intestinal epithelial barrier function. Antibiotic treatment might only induce short-term intestinal dysbiosis, which finally recovers to a healthy composition with high microbial diversity. (B) However, there may also be a “point-of-no-return” in infected hosts, in which H. pylori-induced changes in the intestinal and colonic immune response and microbiome get imprinted and remain after antibiotic eradication. High levels of pro-inflammatory T-cells together with a low number of regulatory Treg cells may remain, as well as persistent activation of pSTAT3 signaling. Furthermore, antibiotic therapy leads to microbial dysbiosis and a reduction of alpha-diversity. These changes contribute to a leaky gut with antigen influx leading to a vicious pro-inflammatory cycle. Thus, colon carcinogenesis can not anymore be prevented by H. pylori eradication. Shown is a schematic representation of the intestinal epithelium.