Life science
Medicine, Drug discovery

Pathogenic metabolites in Helicobacter pylori thatexacerbate gastritis
Research Institute for Microbial Diseases / Immunology Frontier Research Center
Professor Sho Yamasaki
Researchmap https://researchmap.jp/read0117961

Life science

Abstract

Structureofofα-cholesterylglucoside,
α-cholesterylglucoside,
αCAG
Structure
αCAG

In this study, we clarified the mechanism by which Helicobacter
pylori (H. pylori), a gram-negative bacterium, causes gastritis. H.
pylori induces gastritis by extracting cholesterol from host cells
and subsequently adds sugars and lipids within the bacterium toproduce compounds that induce gastritis. These compounds arerecognized by the host receptors-Mincle and DCAR, leading to
the development of gastritis. Inhibition of this modification pathway
prevents H. pylori-induced gastritis.

▍ Background & Results
H. pylori is believed to cause chronic gastritis and gastric cancer. It is estimated that H. pylori infects approximately 50% of theworld’s population, including nearly 60 million people in Japan.
Usually, it is possible to eradicate H. pylori by using antibacterial
drugs and gastric acid secretion inhibitors; however, cases of unsuccessful treatment after two rounds of eradication and disruptionof the bacterial flora balance by antimicrobial agents are challenge.
H. pylori is believed to cause gastritis by over-activating the hostimmune system, but the surface of H. pylori has a structure thatcannot be recognized by innate immune receptors on macrophages and dendritic cells; therefore, the mechanism by which it activates the host immune system remains unclear. The significanceof this study proposes a novel therapeutic concept that allows
H. pylori to “coexist” in the host body without using antimicrobial
agents and yet suppress H. pylori-induced gastritis.

▍ Significance of the research and Future perspectives
In this study, we identified a lipid component of H. pylori that induces the production of inflammatory cytokines in the host (mice).
They found that the substance is recognized by a host innate immune receptor called Mincle. When mice lacking the gene for Mincle, the receptor for αCAG, were infected with H. pylori, there wasno difference in the number of organisms in their bodies comparedwith wild-type mice infected with H. pylori. Despite this lack of difference in the number of bacteria in their bodies, the mice showed lessactivation of immune cells and less gastritis. Furthermore, we foundthat αCPG, which is structurally similar to αCAG, was recognizedby an innate immune receptor called DCAR and activated the hostimmune system. Next, we created a strain of H. pylori lacking thegene for cholesteryl glucosyltransferase (Hp0421), which is required
for the synthesis of αCAG and αCPG. Mice infected with this strainof H. pylori showed less gastritis than those infected with wild-type H.
pylori, although the number of bacteria remained the same. Hp0421
is an enzyme unique to the genus Helicobacter, to which H. pylori
belongs, making it a highly specific and safe therapeutic target.
This treatment suppresses the inflammatory response caused by H.
pylori, which is a very different concept from eradication, and suggests that “coexistence” rather than eradication may be a treatment
option to prevent H. pylori from causing harm to the host.

Main Figures

Structure of α-cholesterylglucoside, αCAG

Main Figures

Main Figures
Identification of host-side receptors that recognize αCAG

AH. pylori

B

Identification of host-side receptors that recognize αCAG
H. pyloriAA) H&E (HE) staining and immunohistochemical
staining of anti-CD3 and F4/80 of stomach sections
from uninfected and H. pylori–infected mice after
8 wk. Scale bar, 100 µm.

BB) The numbers of Ly6G+CD11b+ or
F4/80+CD11b+ cells In gastric MNC frommice at 6Structure of α-cholesterylglucoside,
αCAG 6 wk after infection.

Identification of host-side receptors that recognize αCAGA) H&E (HE) staining and immunohistochemical
staining of anti-CD3 and F4/80 of stomach sections
from uninfected and H. pylori–infected mice after
8 wk. Scale bar, 100 µm.

B) The numbers of Ly6G++CD11b++ orF4/80++CD11b++ cells In gastric MNC frommice at 6Structure of α-cholesterylglucoside,
αCAG 6 wk after infection.

P a t e n t Japanese Patent Application No. 2020-157742
Nagata, Masahiro; Toyonaga, Kenji; Ishikawa, Eri et al. Helicobacter pylori metabolites exacerbate gastritis through C-type lectin receptors, Journal ofTr e a t i s e
Experimental Medicine. 2021 Jan 4;218(1): e20200815. doi: 0.1084/jem.20200815.
https://resou.osaka-u.ac.jp/ja/research/2020/20200929_4
UR
L http://www.biken.osaka-u.ac.jp/achievement/research/2020/146
https://medical.nikkeibp.co.jp/leaf/mem/pub/report/202012/568092.html?pr=1
K e y w o r d chronic gastritis, helicobacter pylori, C-type lectin receptors, cholesteryl glucosyltransferase