Metagenomic and single-cell RNA-Seq survey of the Helicobacter pylori–infected stomach in asymptomatic individuals

Abstract

Helicobacter pylori colonization of the gastric niche can persist for years in asymptomatic individuals. To deeply characterize the host–microbiota environment in H . pylori –infected (HPI) stomachs, we collected human gastric tissues and performed metagenomic sequencing, single-cell RNA-Seq (scRNA-Seq), flow cytometry, and fluorescent microscopy. HPI asymptomatic individuals had dramatic changes in the composition of gastric microbiome and immune cells compared with noninfected individuals. Metagenomic analysis uncovered pathway alterations related to metabolism and immune response. scRNA-Seq and flow cytometry data revealed that, in contrast to murine stomachs, ILC2s are virtually absent in the human gastric mucosa, whereas ILC3s are the dominant population. Specifically, proportion of NKp44 + ILC3s out of total ILCs were highly increased in the gastric mucosa of asymptomatic HPI individuals, and correlated with the abundance of selected microbial taxa. In addition, CD11c + myeloid cells and activated CD4 + T cells and B cells were expanded in HPI individuals. B cells of HPI individuals acquired an activated phenotype and progressed into a highly proliferating germinal-center stage and plasmablast maturation, which correlated with the presence of tertiary lymphoid structures within the gastric lamina propria. Our study provides a comprehensive atlas of the gastric mucosa–associated microbiome and immune cell landscape when comparing asymptomatic HPI and uninfected individuals.

Helicobacter pylori induces a novel form of innate immune memory via accumulation of NF-кB proteins

“…Innate immune cells, particularly monocytes, are known to rapidly extravasate from blood vessel to sites of ongoing inflammation and infection ( 31 , 32 ). Accordingly, monocytes can be found in increased numbers in H. pylori -infected murine ( 33 ) and human epithelial tissue ( 3 ). Activation of monocytes and other myeloid cells can be further regulated by functional adaptations induced by previous encounters with various priming agents, and these adaptations can lead to both a reduction as well as an increase in inflammatory potential of an immune cell – referred to as tolerance and training, respectively ( 34 , 35 ).…”

“…This hyperactivity could contribute to gastric pathology and inflammation in the context of H. pylori infection. The spike in innate immune cell reactivity after contact with the pathogen could also concurrently contribute to the disappearance of other bacterial species from the gastric compartment in presence of the H. pylori : several reports have shown dramatic gastric microbiota composition changes upon infection with H. pylori , as the microbial diversity of the stomach severely decreases in H. pylori -positive individuals ( 3 , 51 , 52 ). Intriguingly, Ferreira and colleagues reported that dysbiosis and loss of microbial richness was even more pronounced in gastric carcinoma samples ( 53 ), albeit the relative abundance of H. pylori decreased, implying that the damage may have been done.…”

“…Extensive inflammation of the gastric epithelium is a hallmark of H. pylori infection and is assumed to be one of the main drivers of gastric carcinogenesis. Immune cells migrating into the gastric epithelium, recruited from peripheral blood or adjacent lymphoid structures (such as mucosa-associated lymphoid tissue), produce a variety of pro-inflammatory cytokines and chemoattractant molecules, which increase the influx of additional immune cells ( 3 , 4 ). This vicious cycle may lead to severe consequences, including atrophy of the gastric epithelium and manifestation of ulcers and neoplastic lesions ( 5 ), which are a result of overt immune activation, among other factors.…”

Eradicate Helicobacter pylori first, or treat peptic ulcer disease?

“… 22 In addition, metagenomic and single-cell RNA-Seq analysis revealed dramatic changes in the composition of gastric microbiome and immune cells in Hp -infected asymptomatic individuals. 23 Eradication of Hp also induced increased long-term resistant bacteria communities in the gut. 24 These imply an interplay between Hp and gastrointestinal microbiota.…”

A spatially mapped gene expression signature for intestinal stem-like cells identifies high-risk precursors of gastric cancer

“…Helicobacter pylori (Hp) is the etiologic agent most closely associated with intestinal-type GC, 19,20 and most prior studies of gastric precursors have either focused on Hp-infected individuals or have drawn from populations with high Hp prevalence. [21][22][23][24] However, Hp infection has been rapidly declining in Western nations, and most patients diagnosed with GIM have undergo bacterial eradication per clinical guidelines. 25 Moreover, patients with GIM remain at significantly elevated risk even following Hp eradication.…”