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  • 1. Aims and Scope

    Gut and Liver is an international journal of gastroenterology, focusing on the gastrointestinal tract, liver, biliary tree, pancreas, motility, and neurogastroenterology. Gut atnd Liver delivers up-to-date, authoritative papers on both clinical and research-based topics in gastroenterology. The Journal publishes original articles, case reports, brief communications, letters to the editor and invited review articles in the field of gastroenterology. The Journal is operated by internationally renowned editorial boards and designed to provide a global opportunity to promote academic developments in the field of gastroenterology and hepatology. +MORE

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    Yong Chan Lee Professor of Medicine
    Director, Gastrointestinal Research Laboratory
    Veterans Affairs Medical Center, Univ. California San Francisco
    San Francisco, USA

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    Deputy Editor
    Jong Pil Im Seoul National University College of Medicine, Seoul, Korea
    Robert S. Bresalier University of Texas M. D. Anderson Cancer Center, Houston, USA
    Steven H. Itzkowitz Mount Sinai Medical Center, NY, USA
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    All papers submitted to Gut and Liver are reviewed by the editorial team before being sent out for an external peer review to rule out papers that have low priority, insufficient originality, scientific flaws, or the absence of a message of importance to the readers of the Journal. A decision about these papers will usually be made within two or three weeks.
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Letter to the Editor

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Considering the Long-Conflicting Topic of Empirical or Nonconventional Helicobacter pylori Eradication Regimens

Jannis Kountouras

Second Medical Clinic, School of Medicine, Ippokration Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece

Correspondence to: Jannis Kountouras
ORCID https://orcid.org/0000-0001-6459-5136
E-mail jannis@auth.gr

Received: October 21, 2022; Revised: December 28, 2022; Accepted: January 12, 2023

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Gut Liver 2023;17(4):659-660. https://doi.org/10.5009/gnl220450

Published online March 14, 2023, Published date July 15, 2023

Copyright © Gut and Liver.

To the Editor,

Τo overcome the influence of Helicobacter pylori-linked antibiotic resistance, Na et al.1 administered therapies based on susceptibility pretesting by multiplex polymerase chain reaction or sequencing records, although without culture, which have been proposed as more rational approaches than the empirical use of standard H. pylori treatment regimens. Specifically, in their retrospective study,1 they reported that after the estimation of clarithromycin susceptibility, short-term (7 days) first-line H. pylori eradication regimens based on these multiplex polymerase chain reaction or sequencing records exhibited an overall high but suboptimal effectiveness; comparable results were also obtained by a 14-day eradication regimen. Moreover, the authors did not consider culture-based H. pylori susceptibility assessment for additional antibiotics, which may have influenced the H. pylori eradication rates.

Beyond the empirical first-line H. pylori eradication studies considered by the authors,1 a large number of published studies have investigated H. pylori eradication regimens, including empirical second- and third-line regimens and/or strategies against H. pylori-resistant strains. For instance, recent data has reported a suboptimal efficacy of empirical second-line H. pylori eradication regimens.2 Thus, new therapeutic approaches are warranted.

After reviewing the abovementioned literature (although probably impossible), which may generate iatrogenic or even possible economic bias, such studies appear to be conducted without any potential novelty. Thus, the researchers may address the developing novel approaches, thereby recommending more effective strategies and evading citing the formerly recognized and repetitive data of increasingly ineffective antibiotic empirical or non-empirical combinations introduced. These combinations, beyond other critical concerns, render such monotonous studies rather insufficient for the regular reader.

Focusing on such previous studies, for instance, the Spanish group Hp-EuReg reported that the introduction of statins would not be sufficient to increase the H. pylori eradication rate.3 However, other studies have shown that the addition of statins to the conventional clarithromycin-based triple therapeutic regimen significantly increased the H. pylori eradication rate and displayed direct antibacterial action, synergistic action with antibiotics, and the ability to trigger the host human immune system against H. pylori.4

Concerning H. pylori-resistant strains, the mechanisms underlying this resistance represent a crucial topic that commonly forces investigators to experiment, sometimes blindly, by empirically administering several antibiotics in diverse regimens, occasionally giving the feeling of a musical medley that does not match, which can reduce the prestige of the underlying science. Thus, the researchers have to consider the diverse topics involved in the failure to eradicate H. pylori, such as novel H. pylori genotypes with high pathogenicity, unsuitable patient collaborations, smoking, the presence of point mutations, an augmented H. pylori burden, gastric acid pH, immunosuppressant characteristics, the intracellular existence of H. pylori and/or biofilm creation connected with efflux pumps (transporters removing antibiotics from the cellular interior) and underlying issues which induce antibiotic resistance.5

H. pylori can form a biofilm in the stomach, which drastically reduces sensitivity to antibiotics and other antimicrobial compounds, and represents an independent mechanism that may be involved in the development and/or intensification of the antibiotic resistance. This H. pylori biofilm seems to be a main reason for the failure to eliminate infections triggered by H. pylori; antimicrobial compounds cannot efficiently penetrate and destroy the biofilm; and H. pylori antibiotic, such as clarithromycin, resistance mutations are commonly created in biofilms. Moreover, biofilm-adapted H. pylori demands a time dependent 4- to16-fold increment in minimum repressing levels of clarithromycin. Therefore, altering the pathologies of H. pylori biofilm can offer an efficient approach to avoid the failures of existing H. pylori therapeutic regimens. In this regard, exposure to high human β-defensins 1-4 concentrations considerably inhibits the capability of biofilm formation by H. pylori, a finding principally attributed to the antibacterial action of human β-defensins.6

Moreover, H. pylori induces an intracellular niche the protects the bacterium from antibiotic eradication therapy, allowing persistence and recolonization. This intracellular niche may also contribute to bacterial evasion of the host immune responses. In this regard, for instance, VDP, a direct vitamin D metabolite, possesses an H. pylori-specific antimicrobial ability through human β-defensins induction from infected macrophages, thus creating a promising therapeutic potential. Notably, addition of vitamin D3 to the conventional clarithromycin-based triple therapeutic approach also results in a significant eradication rate for H. pylori infection.7

Autophagy is involved in H. pylori-induced gastritis, and chronic H. pylori infection promotes gastric malignancy growth and progression by considerably weakening the autophagic process; although autophagy offers an anti-carcinogenic effect in normal tissues, an excess of altering triggers, like H. pylori infection, prevent its activity thereby promoting cancer development. The clarification of the interaction among H. pylori and autophagic process has driven investigators to examine the effect of the regulators of the autophagic process to control H. pylori infection in an effort to improve the increasing antibiotic resistance.

Therefore, researchers should consider such abovementioned and additional novel approaches for treating H. pylori infection, thereby offering the Hp-GlobalReg groups the chance to further investigate novel topics and abandon conventional, recurrent, non-efficacious therapeutic strategies that may trigger a vicious cycle with suboptimal effects.

No potential conflict of interest relevant to this article was reported.

  1. Na SY, Kim BW, Kim MJ, Choe Y, Kim JS. Effective eradication regimen and duration according to the clarithromycin susceptibility of Helicobacter pylori determined using dual priming oligonucleotide-based multiplex polymerase chain reaction. Gut Liver. Epub 2022 Feb 28; https://doi.org/10.5009/gnl220256.
    Pubmed CrossRef
  2. Nyssen OP, Vaira D, Pérez Aísa Á, et al. Empirical second-line therapy in 5000 patients of the European Registry on Helicobacter pylori Management (Hp-EuReg). Clin Gastroenterol Hepatol 2022;20:2243-2257.
    Pubmed CrossRef
  3. Caldas M, Pérez-Aisa Á, Tepes B, et al. The role of statins on Helicobacter pylori eradication: results from the European Registry on the Management of H. pylori (Hp-EuReg). Antibiotics (Basel) 2021;10:965.
    Pubmed KoreaMed CrossRef
  4. Hassan AM, Shawky MA, Mohammed AQ, Haridy MA, Eid KA. Simvastatin improves the eradication rate of Helicobacter pylori: upper Egypt experience. Infect Drug Resist 2019;12:1529-1534.
    Pubmed KoreaMed CrossRef
  5. Moghadam MT, Chegini Z, Norouzi A, Dousari AS, Shariati A. Three-decade failure to the eradication of refractory Helicobacter pylori infection and recent efforts to eradicate the infection. Curr Pharm Biotechnol 2021;22:945-959.
    Pubmed CrossRef
  6. Kazakos EI, Dorrell N, Polyzos SA, Deretzi G, Kountouras J. Comment on "Effect of biofilm formation by clinical isolates of Helicobacter pylori on the efflux-mediated resistance to commonly used antibiotics". World J Gastroenterol 2017;23:6194-6196.
    Pubmed KoreaMed CrossRef
  7. El Shahawy MS, Shady ZM, Gaafar A. Influence of adding vitamin D3 to standard clarithromycin-based triple therapy on the eradication rates of Helicobacter pylori infection. Arab J Gastroenterol 2021;22:209-214.
    Pubmed CrossRef

Article

Letter to the Editor

Gut and Liver 2023; 17(4): 659-660

Published online July 15, 2023 https://doi.org/10.5009/gnl220450

Copyright © Gut and Liver.

Considering the Long-Conflicting Topic of Empirical or Nonconventional Helicobacter pylori Eradication Regimens

Jannis Kountouras

Second Medical Clinic, School of Medicine, Ippokration Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece

Correspondence to:Jannis Kountouras
ORCID https://orcid.org/0000-0001-6459-5136
E-mail jannis@auth.gr

Received: October 21, 2022; Revised: December 28, 2022; Accepted: January 12, 2023

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Body

To the Editor,

Τo overcome the influence of Helicobacter pylori-linked antibiotic resistance, Na et al.1 administered therapies based on susceptibility pretesting by multiplex polymerase chain reaction or sequencing records, although without culture, which have been proposed as more rational approaches than the empirical use of standard H. pylori treatment regimens. Specifically, in their retrospective study,1 they reported that after the estimation of clarithromycin susceptibility, short-term (7 days) first-line H. pylori eradication regimens based on these multiplex polymerase chain reaction or sequencing records exhibited an overall high but suboptimal effectiveness; comparable results were also obtained by a 14-day eradication regimen. Moreover, the authors did not consider culture-based H. pylori susceptibility assessment for additional antibiotics, which may have influenced the H. pylori eradication rates.

Beyond the empirical first-line H. pylori eradication studies considered by the authors,1 a large number of published studies have investigated H. pylori eradication regimens, including empirical second- and third-line regimens and/or strategies against H. pylori-resistant strains. For instance, recent data has reported a suboptimal efficacy of empirical second-line H. pylori eradication regimens.2 Thus, new therapeutic approaches are warranted.

After reviewing the abovementioned literature (although probably impossible), which may generate iatrogenic or even possible economic bias, such studies appear to be conducted without any potential novelty. Thus, the researchers may address the developing novel approaches, thereby recommending more effective strategies and evading citing the formerly recognized and repetitive data of increasingly ineffective antibiotic empirical or non-empirical combinations introduced. These combinations, beyond other critical concerns, render such monotonous studies rather insufficient for the regular reader.

Focusing on such previous studies, for instance, the Spanish group Hp-EuReg reported that the introduction of statins would not be sufficient to increase the H. pylori eradication rate.3 However, other studies have shown that the addition of statins to the conventional clarithromycin-based triple therapeutic regimen significantly increased the H. pylori eradication rate and displayed direct antibacterial action, synergistic action with antibiotics, and the ability to trigger the host human immune system against H. pylori.4

Concerning H. pylori-resistant strains, the mechanisms underlying this resistance represent a crucial topic that commonly forces investigators to experiment, sometimes blindly, by empirically administering several antibiotics in diverse regimens, occasionally giving the feeling of a musical medley that does not match, which can reduce the prestige of the underlying science. Thus, the researchers have to consider the diverse topics involved in the failure to eradicate H. pylori, such as novel H. pylori genotypes with high pathogenicity, unsuitable patient collaborations, smoking, the presence of point mutations, an augmented H. pylori burden, gastric acid pH, immunosuppressant characteristics, the intracellular existence of H. pylori and/or biofilm creation connected with efflux pumps (transporters removing antibiotics from the cellular interior) and underlying issues which induce antibiotic resistance.5

H. pylori can form a biofilm in the stomach, which drastically reduces sensitivity to antibiotics and other antimicrobial compounds, and represents an independent mechanism that may be involved in the development and/or intensification of the antibiotic resistance. This H. pylori biofilm seems to be a main reason for the failure to eliminate infections triggered by H. pylori; antimicrobial compounds cannot efficiently penetrate and destroy the biofilm; and H. pylori antibiotic, such as clarithromycin, resistance mutations are commonly created in biofilms. Moreover, biofilm-adapted H. pylori demands a time dependent 4- to16-fold increment in minimum repressing levels of clarithromycin. Therefore, altering the pathologies of H. pylori biofilm can offer an efficient approach to avoid the failures of existing H. pylori therapeutic regimens. In this regard, exposure to high human β-defensins 1-4 concentrations considerably inhibits the capability of biofilm formation by H. pylori, a finding principally attributed to the antibacterial action of human β-defensins.6

Moreover, H. pylori induces an intracellular niche the protects the bacterium from antibiotic eradication therapy, allowing persistence and recolonization. This intracellular niche may also contribute to bacterial evasion of the host immune responses. In this regard, for instance, VDP, a direct vitamin D metabolite, possesses an H. pylori-specific antimicrobial ability through human β-defensins induction from infected macrophages, thus creating a promising therapeutic potential. Notably, addition of vitamin D3 to the conventional clarithromycin-based triple therapeutic approach also results in a significant eradication rate for H. pylori infection.7

Autophagy is involved in H. pylori-induced gastritis, and chronic H. pylori infection promotes gastric malignancy growth and progression by considerably weakening the autophagic process; although autophagy offers an anti-carcinogenic effect in normal tissues, an excess of altering triggers, like H. pylori infection, prevent its activity thereby promoting cancer development. The clarification of the interaction among H. pylori and autophagic process has driven investigators to examine the effect of the regulators of the autophagic process to control H. pylori infection in an effort to improve the increasing antibiotic resistance.

Therefore, researchers should consider such abovementioned and additional novel approaches for treating H. pylori infection, thereby offering the Hp-GlobalReg groups the chance to further investigate novel topics and abandon conventional, recurrent, non-efficacious therapeutic strategies that may trigger a vicious cycle with suboptimal effects.

CONFLICTS OF INTEREST

No potential conflict of interest relevant to this article was reported.

References

  1. Na SY, Kim BW, Kim MJ, Choe Y, Kim JS. Effective eradication regimen and duration according to the clarithromycin susceptibility of Helicobacter pylori determined using dual priming oligonucleotide-based multiplex polymerase chain reaction. Gut Liver. Epub 2022 Feb 28; https://doi.org/10.5009/gnl220256.
    Pubmed CrossRef
  2. Nyssen OP, Vaira D, Pérez Aísa Á, et al. Empirical second-line therapy in 5000 patients of the European Registry on Helicobacter pylori Management (Hp-EuReg). Clin Gastroenterol Hepatol 2022;20:2243-2257.
    Pubmed CrossRef
  3. Caldas M, Pérez-Aisa Á, Tepes B, et al. The role of statins on Helicobacter pylori eradication: results from the European Registry on the Management of H. pylori (Hp-EuReg). Antibiotics (Basel) 2021;10:965.
    Pubmed KoreaMed CrossRef
  4. Hassan AM, Shawky MA, Mohammed AQ, Haridy MA, Eid KA. Simvastatin improves the eradication rate of Helicobacter pylori: upper Egypt experience. Infect Drug Resist 2019;12:1529-1534.
    Pubmed KoreaMed CrossRef
  5. Moghadam MT, Chegini Z, Norouzi A, Dousari AS, Shariati A. Three-decade failure to the eradication of refractory Helicobacter pylori infection and recent efforts to eradicate the infection. Curr Pharm Biotechnol 2021;22:945-959.
    Pubmed CrossRef
  6. Kazakos EI, Dorrell N, Polyzos SA, Deretzi G, Kountouras J. Comment on "Effect of biofilm formation by clinical isolates of Helicobacter pylori on the efflux-mediated resistance to commonly used antibiotics". World J Gastroenterol 2017;23:6194-6196.
    Pubmed KoreaMed CrossRef
  7. El Shahawy MS, Shady ZM, Gaafar A. Influence of adding vitamin D3 to standard clarithromycin-based triple therapy on the eradication rates of Helicobacter pylori infection. Arab J Gastroenterol 2021;22:209-214.
    Pubmed CrossRef
Gut and Liver

Vol.18 No.3
May, 2024

pISSN 1976-2283
eISSN 2005-1212

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