The interaction between autophagy, Helicobacter pylori, and gut microbiota in gastric carcinogenesis

Abstract

Chronic infection with Helicobacter pylori is the primary risk factor for the development of gastric cancer. Hindering our ability to comprehend the precise role of autophagy during H. pylori infection is the complexity of context-dependent autophagy signaling pathways. Recent and ongoing progress in understanding H. pylori virulence allows new frontiers of research for the crosstalk between autophagy and H. pylori. Novel approaches toward discovering autophagy signaling networks have further revealed their critical influence on the structure of gut microbiota and the metabolome. Here we intend to present a holistic view of the perplexing role of autophagy in H. pylori pathogenesis and carcinogenesis. We also discuss the intermediate role of autophagy in H. pylori-mediated modification of gut inflammatory responses and microbiota structure.

Keywords: Helicobacter pylori; anticancer therapy; autophagy; gastric cancer; gut microbiota.

Figure 1.

The Molecular Mechanism of Autophagy Flux in The Host Cell. Upon suppression of MTORC1 or stimulation of AMP-activated protein kinase (AMPK), the autophagy process initiates following the activation of the ULK1 complex. Following ULK1 activation, membrane nucleation requires phosphatidylinositol-3-phosphate (PtdIns3P), which is produced by the lipid kinase function of the PtdIns3K-CI at the phagophore (the initial sequestering compartment). PtdIns3K-CI subunits include ATG14, PIK3C3, BECN1, PIK3R4/VPS15/p150 (phosphoinositide-3-kinase regulatory subunit 4), AMBRA1 (autophagy and beclin 1 regulator 1), and NRBF2 (nuclear receptor binding factor 2). Various membranous organelles such as the mitochondria, plasma membrane, and Golgi complex donate membrane precursor, contributing to phagophore expansion. Phagophore expansion proceeds as ATG12 conjugates to ATG5 and the non-covalent interaction of the ATG12–ATG5 complex with ATG16L1 forms the ATG12–ATG5-ATG16L1 ternary complex. The recruitment of WIPI2 (WD repeat domain, phosphoinositide interacting 2) and ZFYVE1/DFCP1 (zinc finger FYVE-type containing 1) by PtdIns3P promotes the conjugation of LC3 to PE (phosphatidylethanolamine). LC3 mediates selective autophagy by interacting with cargo and further facilitates phagophore expansion and sealing. ATG4 removes LC3 from the autophagosome outer membrane and then autophagosome-lysosome fusion is mediated by HOPS, small GTPase-family proteins such as RAB7, and soluble N-ethylmaleimide-sensitive fusion attachment protein receptors/SNAREs. The reformation of lysosomes from autolysosomes accelerates the next cycle of autolysosome formation.

Figure 2.

Autophagy and Acute Infection with H. pylori. H. pylori suppresses ILK to induce autophagy and apoptosis in the host cell. Urease-mediate accumulation of ammonia inhibits VacA degradation and augments VacA-induced apoptosis. The interaction of VacA with LRP1 stimulates ROS production, ER stress, apoptosis, and autophagy, which leads to CagA degradation. Similarly, CGT and OMV-derived PG induce autophagy, meanwhile, CGT prevents autophagosome-lysosome fusion. H. pylori-mediated mitochondrial perturbation, lysosomal damage, and MIR99B upregulation further trigger an autophagy response.

Figure 3.

Autophagy and Chronic Infection with H. pylori. Sustained exposure of the host cell to H. pylori mainly results in autophagy suppression. In the chronic stage of H. pylori infection, VacA and secretory protein HpGGT disrupt endolysosomal trafficking, leading to CagA accumulation and autophagy inhibition. H. pylori-mediated activation of NOD1 and expression of MIR30B and MIR30D further prevent autophagy flux. However, secretory protein Hp0175 and H. pylori-induced secretion of MIF from macrophages might induce the autophagy process in the host cell.

Figure 4.

H. pylori-Induced Gastric Cancer Through Autophagy Modulation. (A) EMT progression from chronic gastritis to dysplasia and carcinoma. (B) Acute H. pylori infection induces autophagy that can promote angiogenesis and the expression of the CD44 tumor marker. (C) Chronic H. pylori infection mainly suppresses autophagy, resulting in DNA damage, inflammation, and EMT progression.

Figure I.

Autophagy and Gut Immune Homeostasis. The gut microbiota, particularly probiotic strains, can induce autophagy, whereas pathogenic bacteria mainly suppress autophagy flux. Autophagy activation preserves the integrity of the epithelial barrier by stimulating the production of tight junctions while suppressing gap junctions. Autophagy-mediated secretion of CAMP and inhibition of ROS production and NLRP3 inflammasome activation reduce the risk of inflammation. Conversely, phosphoinositide 3-kinase/PI3K and the MTOR-HIF1A/HIF-1α (hypoxia inducible factor 1 subunit alpha) axis engage with ROS production by neutrophils. ATG7 contributes to the degranulation of mast cells. The MTOR complex is involved in eosinophil differentiation and infiltration. MTOR also activates bioenergetic metabolism via IL15 signaling in NK cells, whereas ATG3 is required for memory NK cell formation. The activation of AMPK, ULK1, ATG5, and ATG7 directs monocytes away from apoptosis and toward differentiation. ATG3, ATG16L1, and MAP1LC3-II regulate DC maturation, whereas ATG5, ATG7, ATG16L1, and BECN1 coordinate antigen presentation and cross-presentation. Furthermore, LPS-mediated stimulation of TLR4 in macrophages can trigger different autophagy signaling pathways.