Yifei Xu
Anna K. Walduck
Huafeng Pan- 1Department of Gastroenterology, Shenzhen Traditional Chinese Medicine Hospital, Shenzhen, China
- 2Rural Health Research Institute, Charles Sturt University, Orange, NSW, Australia
- 3Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, China
Editorial on the Research Topic
The pathogenesis and treatment of Helicobacter pylori-induced diseases
Helicobacter pylori (H. pylori) is a Gram-negative, spiral-shaped bacterium colonizing the stomach of more than half of the global population (Ansari and Yamaoka, 2022). The bacterium was discovered as a cause of chronic gastritis by Dr. Barry Marshall and Dr. Robin Warren in 1982 and became a focus of intense research in the following decades. It has been identified as the major infectious cause of atrophic gastritis, spasmolytic polypeptide-expressing metaplasia (SPEM), intestinal metaplasia (IM), atypical hyperplasia, and gastric cancer (Malfertheiner et al., 2023). Empirical triple (proton pump inhibitor + two antibiotics) and quadruple therapy (proton pump inhibitor + bismuth + two antibiotics), and even novel high-dose dual therapy (proton pump inhibitor + high dose amoxicillin), have been used to clear H. pylori in the clinic, but the increasing rate of drug resistance is bringing great challenges to effective bactericidal treatment worldwide (O’Connor et al., 2017; Liou et al., 2023). Gene mutation, efflux pump, coccoid and biofilm formation, and intracellular survival contribute to the known mechanisms of the bacteria against antibiotics (Kuo et al., 2017; Tshibangu-Kabamba and Yamaoka, 2021). Alternative therapies ranging from nanoparticles to phage therapy are in development, but while some plant extracts have shown promising adjuvant effects, many remain in the preclinical stage (Sousa et al., 2022).
Meanwhile, the phenomenon of heteroresistance (the presence of different drug-resistant or sensitive strains in different regions of the same stomach) of H. pylori may contribute to treatment failure, and current treatment recommendations do not address this issue (Mascellino et al., 2017; Rizvanov et al., 2019). A recent systematic review concluded that the prevalence of heteroresistance to the most frequently used drugs of metronidazole and clarithromycin was 7 and 14%, respectively, in H. pylori-positive samples (Kouhsari et al., 2022). Furthermore, the recent paradigm shift from empirical therapy to sensitivity-guided treatment recommendations (Graham and Moss, 2022) underlines that a single biopsy cannot be considered sufficient for determination of antimicrobial susceptibility (Mascellino et al., 2017). Increased sensitivity testing will lead to additional data on susceptibility patterns and a likely extension of our understanding of heteroresistance.
Other H. pylori-induced conditions such as intestinal metaplasia and atypical hyperplasia are difficult to reverse after late eradication treatment (Sung et al., 2020; Imai et al., 2021; Shah et al., 2021). The pressing need for new therapeutic strategies and drugs means that investigating the mechanisms by which H. pylori infection leads to pre-cancer and cancer is of high importance.
The infection process of H. pylori is complex. H. pylori survives acidic conditions in the stomach by producing urease, which hydrolyzes the urea and produces ammonia, neutralizing conditions in the vicinity of the bacterium (Li et al., 2019). Meanwhile, the flagella provide strong motility for H. pylori to penetrate the gastric mucus; this process is further enhanced by the urease enzyme, which reduces mucin viscosity (Celli et al., 2009; Sharndama and Mba, 2022). Colonization is mediated by adhesin proteins including the blood group antigen-binding adhesin (BabA) and sialic acid-binding adhesin (SabA), which bind to glycan receptors in the membrane of epithelial cell and prevent the elimination of gastric juice secretion (Bonsor and Sundberg, 2019). The type IV secretion system encoded by the Cag PAI gene island of H. pylori translocates the cytotoxin-associated gene A (CagA) and peptidoglycan to the host cell, triggering a cascade of signaling events including tight junction and cytoskeletal rearrangements (Sgouras et al., 2016). The other major virulence factor, vacuolating cytotoxin A (VacA), causes cell damage and is associated with severe disease, severe damage, and inhibition of T-cell responses (Takahashi-Kanemitsu et al., 2020). These extracellular bacteria respond to quorum-sensing molecules such as AI-2 to become motile spiral-shaped bacteria or resting-state coccoid forms within a biofilm (Sweeney et al., 2019). In addition, some bacteria invade the host cell and survive inside the autophagosomes, thus causing intracellular damage. Some clinical H. pylori strains have been reported to have strong cell invasive ability (Xu et al., 2021). In addition to killing or inhibiting the bacteria directly, the blocking of these infection processes presents a potential strategy for the treatment of H. pylori infection.
This Research Topic collects four articles, two of which are focused on the role of the Cag PAI system, one of which reveals the role of vitamin D3 in the inhibition of H. pylori, and another of which comprehensively reviews studies related to SPEM from 2002 to 2022.
Ray et al. reported on studies that demonstrate that the oxidation of curcumin is required for the growth inhibition of H. pylori. Bacteria such as Escherichia coli and Citrobacter rodentium that possess the curA gene, which promotes the reductive metabolism of curcumin, are resistant to the anti-bacterial effects of curcumin. H. pylori and the curA deletion mutants of E. coli were shown to be susceptible. Furthermore, curcumin inhibited the translocation and phosphorylation of CagA, reduced the phosphorylation of c-Src in a mouse organoid model, and decreased the expression of CXCL8 in AGS cells. Finally, H. pylori re-isolated from curcumin-fed mice in a phospholipid formulation appeared to be less virulent. The work provides mechanistic evidence that encourages the testing of curcumin as a dietary approach to inhibit the virulence of CagA. Although it is unlikely that the bacteria could be directly eliminated using curcumin solely, the long-lasting effects on the virulence of H. pylori has promising implications.
Zhou et al. used vitamin D receptor knock-down (VDR-KD) mice to explore the roles of vitamin D3 and vitamin D receptor in anti-H. pylori infection. Previous reports showed that vitamin D3 upregulated protein 1 deficiency promotes the development of H. pylori-induced gastric carcinogenesis, and H. pylori infection induces increased expression of the vitamin D receptor (Kwon et al., 2012; Guo et al., 2014). This study reveals the anti-H. pylori mechanism of vitamin D3 through enhancing the expression of vitamin receptor (VDR) and cathelicidin antimicrobial peptide (CAMP). Taken together, vitamin D3 could be used in the clinical management of H. pylori eradication and the possible prevention of H. pylori-induced tumorigenesis.
Cisplatin is one of the most powerful chemotherapeutic drugs used in clinical therapeutics, especially for the treatment of solid tumors including ovarian, testicular, and bladder cancer. Off-label uses for cisplatin include the treatment of gastric cancer and esophageal cancer. Lettl et al. employed a Cag type IV secretion reporter to screen the high-efficiency inhibitor targeting this system. Cisplatin and other platinum complexes were demonstrated to have DNA binding-independent inhibitory effects against different H. pylori processes including adherence and type IV secretion. This excellent study provides a new strategy to search for high-performance chemical compounds against H. pylori by using structural and chemical biology methods.
Spasmolytic polypeptide-expressing metaplasia (SPEM) cells are characterized by mucous cell-specific proteins such as spasmolytic polypeptide (TFF2) co-expressed with the chief cell characteristic in the basal region of the gland. Although the origin of these is still controversial, SPEM has been considered a precancerous lesion in recent years (Bockerstett et al., 2020). Liu et al. summarized publications about SPEM from between 2002 and 2022 using bibliometric analysis methods. The results showed that SPEM cell lineage differentiation, interaction with H. pylori, disturbances of the mucosal microenvironment, biomarkers, clinical diagnosis, and the outcomes of SPEM, as well as the development of proliferative SPEM animal models, were the major focus of research. Some rapid SPEM animal models have been established, but there is little doubt that H. pylori is the major pathogen causing SPEM in the clinic, indicating that concentration on H. pylori-induced SPEM rather than chemical triggers would promote a deeper understanding of the role of SPEM in clinical practice.
We hope this Research Topic provides valuable insight into the pathogenesis of H. pylori and the development of a new therapeutic strategy. In addition to focusing on the development of novel bacteriostatic and bactericidal compounds, targeting the infection and pathogenic process of H. pylori could also be an effective strategy for managing this chronic infection. The organic lesion induced by H. pylori is still a refractory disease in clinical settings, and the inhibition of SPEM malignant progression could be a therapeutic target in the prevention of gastric cancer.
Author contributions
All authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication.
Funding
This research was supported by the National Science Foundation of China (82204734), Scientific Research Project of Guangdong Bureau of Traditional Chinese Medicine (20221349), Shenzhen Science and Technology Innovation Commission (JCYJ20220531091815034, JCYJ20220531092401003, JCYJ20210324111602007), and Shenzhen Excellent Scientific and Technological Innovation Talent Training Project (RCBS20221008093126070). AW was funded by CSU.
Acknowledgments
We thank all the editors, authors, and reviewers who contributed their relevant work to this Research Topic.
Conflict of interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Publisher’s note
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References
Ansari, S., Yamaoka, Y. (2022). Helicobacter pylori infection, its laboratory diagnosis, and antimicrobial resistance: a perspective of clinical relevance. Clin. Microbiol. Rev. 35 (3), e0025821. doi: 10.1128/cmr.00258-21
Bockerstett, K. A., Lewis, S. A., Noto, C. N., Ford, E. L., Saenz, J. B., Jackson, N. M., et al. (2020). Single-cell transcriptional analyses identify lineage-specific epithelial responses to inflammation and metaplastic development in the gastric corpus. Gastroenterology 159 (6), 2116–2129.e2114. doi: 10.1053/j.gastro.2020.08.027
Bonsor, D. A., Sundberg, E. J. (2019). Roles of adhesion to epithelial cells in gastric colonization by Helicobacter pylori. Adv. Exp. Med. Biol. 1149, 57–75. doi: 10.1007/5584_2019_359
Celli, J. P., Turner, B. S., Afdhal, N. H., Keates, S., Ghiran, I., Kelly, C. P., et al. (2009). Helicobacter pylori moves through mucus by reducing mucin viscoelasticity. Proc. Natl. Acad. Sci. U.S.A. 106 (34), 14321–14326. doi: 10.1073/pnas.0903438106
Graham, D. Y., Moss, S. F. (2022). Antimicrobial susceptibility testing for Helicobacter pylori is now widely available: when, how, why. Am. J. Gastroenterol. 117 (4), 524–528. doi: 10.14309/ajg.0000000000001659
Guo, L., Chen, W., Zhu, H., Chen, Y., Wan, X., Yang, N., et al. (2014). Helicobacter pylori induces increased expression of the vitamin d receptor in immune responses. Helicobacter 19 (1), 37–47. doi: 10.1111/hel.12102
Imai, S., Ooki, T., Murata-Kamiya, N., Komura, D., Tahmina, K., Wu, W., et al. (2021). Helicobacter pylori CagA elicits BRCAness to induce genome instability that may underlie bacterial gastric carcinogenesis. Cell Host Microbe 29 (6), 941–958.e910. doi: 10.1016/j.chom.2021.04.006
Kouhsari, E., Sadeghifard, N., Khadiv, A., Sayadi, H., Amiriani, T., Ghafourian, S., et al. (2022). Heteroresistance to clarithromycin and metronidazole in patients with a Helicobacter pylori infection: a systematic review and meta-analysis. Ann. Clin. Microbiol. Antimicrob. 21 (1), 19. doi: 10.1186/s12941-022-00509-3
Kuo, Y. T., Liou, J. M., El-Omar, E. M., Wu, J. Y., Leow, A. H. R., Goh, K. L., et al. (2017). Primary antibiotic resistance in Helicobacter pylori in the Asia-pacific region: a systematic review and meta-analysis. Lancet Gastroenterol. Hepatol. 2 (10), 707–715. doi: 10.1016/s2468-1253(17)30219-4
Kwon, H. J., Won, Y. S., Nam, K. T., Yoon, Y. D., Jee, H., Yoon, W. K., et al. (2012). Vitamin D3 upregulated protein 1 deficiency promotes n-methyl-N-nitrosourea and Helicobacter pylori-induced gastric carcinogenesis in mice. Gut 61 (1), 53–63. doi: 10.1136/gutjnl-2011-300361
Li, H., Wang, R., Sun, H. (2019). Systems approaches for unveiling the mechanism of action of bismuth drugs: new medicinal applications beyond Helicobacter pylori infection. Acc Chem. Res. 52 (1), 216–227. doi: 10.1021/acs.accounts.8b00439
Liou, J. M., Jiang, X. T., Chen, C. C., Luo, J. C., Bair, M. J., Chen, P. Y., et al. (2023). Second-line levofloxacin-based quadruple therapy versus bismuth-based quadruple therapy for Helicobacter pylori eradication and long-term changes to the gut microbiota and antibiotic resistome: a multicentre, open-label, randomised controlled trial. Lancet Gastroenterol. Hepatol. 8 (3), 228–241. doi: 10.1016/s2468-1253(22)00384-3
Malfertheiner, P., Camargo, M. C., El-Omar, E., Liou, J. M., Peek, R., Schulz, C., et al. (2023). Helicobacter pylori infection. Nat. Rev. Dis. Primers 9 (1), 19. doi: 10.1038/s41572-023-00431-8
Mascellino, M. T., Porowska, B., De Angelis, M., Oliva, A. (2017). Antibiotic susceptibility, heteroresistance, and updated treatment strategies in Helicobacter pylori infection. Drug Des. Devel Ther. 11, 2209–2220. doi: 10.2147/dddt.S136240
O’Connor, A., O’Morain, C. A., Ford, A. C. (2017). Population screening and treatment of Helicobacter pylori infection. Nat. Rev. Gastroenterol. Hepatol. 14 (4), 230–240. doi: 10.1038/nrgastro.2016.195
Rizvanov, A. A., Haertlé, T., Bogomolnaya, L., Talebi Bezmin Abadi, A. (2019). Helicobacter pylori and its antibiotic heteroresistance: a neglected issue in published guidelines. Front. Microbiol. 10. doi: 10.3389/fmicb.2019.01796
Sgouras, D., Tegtmeyer, N., Wessler, S. (2019). Helicobacter pylori in Human Diseases, Advances in Microbiology, Infectious Diseases and Public Health Volume 11. Exp Med Biol. 1149, 35–56.
Shah, S. C., Piazuelo, M. B., Kuipers, E. J., Li, D. (2021). AGA clinical practice update on the diagnosis and management of atrophic gastritis: expert review. Gastroenterology 161 (4), 1325–1332.e1327. doi: 10.1053/j.gastro.2021.06.078
Sharndama, H. C., Mba, I. E. (2022). Helicobacter pylori: an up-to-date overview on the virulence and pathogenesis mechanisms. Braz. J. Microbiol. 53 (1), 33–50. doi: 10.1007/s42770-021-00675-0
Sousa, C., Ferreira, R., Azevedo, N. F., Oleastro, M., Azeredo, J., Figueiredo, C., et al. (2022). Helicobacter pylori infection: from standard to alternative treatment strategies. Crit. Rev. Microbiol. 48 (3), 376–396. doi: 10.1080/1040841x.2021.1975643
Sung, J. J. Y., Coker, O. O., Chu, E., Szeto, C. H., Luk, S. T. Y., Lau, H. C. H., et al. (2020). Gastric microbes associated with gastric inflammation, atrophy and intestinal metaplasia 1 year after Helicobacter pylori eradication. Gut 69 (9), 1572–1580. doi: 10.1136/gutjnl-2019-319826
Sweeney, E. G., Nishida, A., Weston, A., Bañuelos, M. S., Potter, K., Conery, J., et al. (2019). Agent-based modeling demonstrates how local chemotactic behavior can shape biofilm architecture. mSphere 4 (3). doi: 10.1128/mSphere.00285-19
Takahashi-Kanemitsu, A., Knight, C. T., Hatakeyama, M. (2020). Molecular anatomy and pathogenic actions of Helicobacter pylori CagA that underpin gastric carcinogenesis. Cell Mol. Immunol. 17 (1), 50–63. doi: 10.1038/s41423-019-0339-5
Tshibangu-Kabamba, E., Yamaoka, Y. (2021). Helicobacter pylori infection and antibiotic resistance - from biology to clinical implications. Nat. Rev. Gastroenterol. Hepatol. 18 (9), 613–629. doi: 10.1038/s41575-021-00449-x
Keywords: Helicobacter pylori, spasmolytic polypeptide expressing metaplasia, natural product (NP), pathogenesis, treatment
Citation: Xu Y, Walduck AK and Pan H (2023) Editorial: The pathogenesis and treatment of Helicobacter pylori-induced diseases. Front. Cell. Infect. Microbiol. 13:1219503. doi: 10.3389/fcimb.2023.1219503
Received: 09 May 2023; Accepted: 26 June 2023;
Published: 03 July 2023.
Edited by:
Costas C Papagiannitsis, University of Thessaly, GreeceReviewed by:
Jaroslav Hrabak, Charles University, CzechiaAmin Talebi Bezmin Abadi, Tarbiat Modares University, Iran
Copyright © 2023 Xu, Walduck and Pan. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Anna K. Walduck, anwalduck@csu.edu.au; Huafeng Pan, gzphf@gzucm.edu.cn