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Gamma-glutamyltransferase of Helicobacter pylori alters the proliferation, migration, and pluripotency of mesenchymal stem cells by affecting metabolism and methylation status

  • Microbial Pathogenesis and Host-Microbe Interaction
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Abstract

Virulence factor gamma-glutamyltransferase (GGT) of H. pylori consumes glutamine (Gln) in the stomach to decrease the tricarboxylic acid metabolite alpha-ketoglutarate (α-kg) and alter the downstream regulation of α-kg as well as cellular biological characteristics. Our previous research indicated that under H. pylori infection, mesenchymal stem cells (MSCs) migrated to the stomach and participated in gastric cancer (GC) development either by differentiating into epithelial cells or promoting angiogenesis. However, how MSCs themselves participate in H. pylori-indicated GC remains unclear. Therefore, a GGT knockout H. pylori strain (Hp-KS-1) was constructed, and downstream histone H3K9 and H3K27 methylation and the PI3K/AKT signaling pathway of α-kg were detected using Western blotting. The biological characteristics of MSCs were also examined. An additive α-kg supplement was also added to H. pylori-treated MSCs to investigate alterations in these aspects. Compared to the control and Hp-KS-1 groups, H. pylori-treated MSCs reduced Gln and α-kg, increased H3K9me3 and H3K27me3, activated the PI3K-AKT signaling pathway, and promoted the proliferation, migration, self-renewal, and pluripotency of MSCs. The addition of α-kg rescued the H. pylori-induced alterations. Injection of MSCs to nude mice resulted in the largest tumors in the H. pylori group and significantly reduced tumor sizes in the Hp-KS-1 and α-kg groups. In summary, GGT of H. pylori affected MSCs by interfering with the metabolite α-kg to increase trimethylation of histone H3K9 and H3K27, activating the PI3K/AKT signaling pathway, and promoting proliferation, migration, self-renewal, and pluripotency in tumorigenesis, elucidating the mechanisms of MSCs in GC development.

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Acknowledgements

This study was supported by the National Natural Science Foundation of Hubei Province (No. 2017CFA061).

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  1. Department of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, P. R. China

    Zeyu Wang, Weijun Wang, Huiying Shi, Lingjun Meng, Xin Jiang, Suya Pang, Mengke Fan & Rong Lin

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  1. Zeyu Wang
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ZW: performed project design, most of the experiments/data analysis, and wrote the manuscript; WW and HS: assisted in project design, manuscript revision and helped in experiments; LM: helped in project design and some of the experiments/data analysis, SP, XJ, and MF: helped in some of the experiments; RL: performed the project design, supervision, and manuscript revision.

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Correspondence to Rong Lin.

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All animal experiments were conducted under the approval of the Medical Ethics Committee of Wuhan Union Hospital of Huazhong University of Science and Technology (S-028.19-12-12).

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Wang, Z., Wang, W., Shi, H. et al. Gamma-glutamyltransferase of Helicobacter pylori alters the proliferation, migration, and pluripotency of mesenchymal stem cells by affecting metabolism and methylation status. J Microbiol. 60, 627–639 (2022). https://doi.org/10.1007/s12275-022-1575-4

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