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Bacillus clausii's protective and restorative mechanisms in PPI-induced gut imbalance using SHIME technology


EFSM: 2023;3:230034DOI: 10.52778/efsm.23.0034Publication date: 05.10.2023
Zefferino Righetto, Daniel Marquez and Marcos Perez III, MD

Long-term use of proton pump inhibitors (PPI) may lead to gut flora imbalance, which may be restored using probiotics. The study demonstrated the probiotic effects of B. clausii on gut microbiota health following PPI-induced dysbiosis using the Simulator of the Human Intestinal Microbial Ecosystem® (SHIME) model. The probiotic specifically improved microbial diversity and butyrate levels, among other observed effects.

Recent evidence has shown that beyond antibiotics, proton pump inhibitors (PPI) can also induce dysbiosis [1–3]. A probiotic containing Bacillus clausii strains O/C, N/R, SIN and T (EG) established its effectiveness and safety over decades and has been an effective adjunct to triple therapy (two antibiotics and a PPI) for treatment of Helicobacter pylori infections, in preventing digestive symptoms originally attributed to antibiotics [4, 5]. Now, B. clausii’s role in maintenance and restoration of gut microbiota with PPI use is proven [6].

Triple-Mucosal-Simulator of the Human Intestinal Microbial Ecosystem® (Triple-M-SHIME) model

Duysburgh et al. (2023) set up an in vitro Triple-M-SHIME model for 9 weeks using fecal samples from a donor with high levels of butyrate-producing species (Fig. 1). The aim was to replicate the different regions of a specific donor’s gastrointestinal tract (i.e., ileum, proximal and distal colon) and their corresponding microbiota [7]. Changes in microbial ecosystem and metabolic activities were evaluated in the three study arms namely: Control (PPI alone), Preventive (PPI + Enterogermina® [EG] administered together) and Curative (PPI + EG administered afterwards). In addition, PPI-induced dysbiosis related outcomes and post hoc hypotheses on B. clausii mechanism of action were explored.

Microbial community composition and associated changes

B. clausii levels were significantly elevated in both, lumen and mucosa of the control and preventive arm of the treatment stage which was vice-versa in EG-treated arms at washout stage (p < 0.001 for all comparisons). This indicates the survival and replication of these B. clausii strains in both luminal and mucosal environments. A higher microbial diversity was reported in both of these environments during the treatment stage for control (p < 0.001 each) and preventive arm (p < 0.05 each) and washout stage for curative arm (p < 0.001 each; Fig. 2).

B. clausii was able to maintain the bacteria count of inherent bacteria such as Gemmiger formicilis and Akkermansia muciniphila of the distal colon in both, curative and preventive arms, and Prevotella denticola of the proximal colon in the preventive arm, which would have been otherwise reduced by the PPI.

A significant increase in butyrate levels at various stages in respective arms of the study implied a role of EG in increasing levels of this short-chain fatty acid in: 

  • treatment stages of preventive and curative arms (p < 0.004 each)
  • proximal and distal colon of preventive (treatment stage) and curative arms (washout stage) vs treatment stage of respective PPI control arms (p < 0.001 each)
Butyrate, the primary source of intestinal cells energy, influences gut motility and its endocrine functions, permeability and immune responses [8]. Hence, increased butyrate levels after probiotic use suggest a beneficial role in maintenance of overall gut health [8].

Other notable findings of this study include a role of B. clausii in reducing PPI-induced dysbiosis by increasing gut microbial diversity; opposing the PPI-induced effects on gut microbiota levels (especially Coriobacteriaceae, Selenomonadaceae, Akkermansiaceae, G. formicilis, A. muciniphila, S. bovis and P. denticola); and conversion of acetate into butyrate, thereby elevating butyrate levels and its producers.

While in vitro models offer a convenient and non-invasive approach to elucidate mechanisms, the study authors are aware of methodological limitations such as controlling confounders, translating results in vivo and clinical practice, and extrapolating findings to human population. The study nonetheless offers a source for validation of findings in future investigations using more robust study designs.

Summary

The innovative Triple-M-SHIME model replicating PPI-induced dysbiosis provides insights on the potential mechanisms on how to promote digestive health by improving gut microbiota stability and increasing butyrate production.

Literature

  1. Lo WK, Chan WW. Proton pump inhibitor use and the risk of small intestinal bacterial overgrowth: A meta-analysis. Clin Gastroenterol Hepatol. 2013;11:483–90. doi: 10.1016/j.cgh.2012.12.011.
  2. Naito Y, Kashiwagi K, et al. Intestinal dysbiosis secondary to proton-pump inhibitor use. Digestion. 2018;97:195–204. doi: 10.1159/000481813.
  3. Macke L, Schulz C, et al. Systematic review: The effects of proton pump inhibitors on the microbiome of the digestive tract-evidence from next-generation sequencing studies. Aliment Pharmacol Ther. 2020;51:505–26. doi: 10.1111/apt.15604.
  4. Nista EC, Candelli M, et al. Bacillus clausii therapy to reduce side-effects of anti-Helicobacter pylori treatment: Randomized, double-blind, placebo controlled trial. Aliment Pharmacol Ther. 2004;20:1181–8. doi: 10.1111/j.1365-2036.2004.02274.x.
  5. Plomer M, Perez III M, et al. Effect of Bacillus clausii capsules in reducing adverse effects associated with Helicobacter pylori eradication therapy: A randomized, double-blind, controlled trial. Infect Dis Ther. 2020;9(4):867–78. doi: 10.1007/s40121-020-00333-2.
  6. Ghelardi E, Abreu y Abreu AT, et al. Current progress and future perspectives on the use of Bacillus clausii. Microorganisms. 2022;10(6):1246. doi: 10.3390/microorganisms10061246
  7. Duysburgh C, Verstrepen L, et al. Investigation of Enterogermina’s protective and restorative mechanisms on the gut microbiota with PPI, using SHIME Technology. Nutrients 2023;15(3):653. doi: 10.3390/nu15030653.
  8. Martin-Gallausiaux C, Marinelli L, et al. SCFA: Mechanisms and functional importance in the gut. Proc Nutr Soc. 2021;80(1):37–49. doi:10.1017/S0029665120006916

Acknowledgements: The authors thank Paula Fontanilla, PhD, for critically reviewing the manuscript for scientific content and Ashwitha A, an employee of Sanofi, for providing writing and editorial support.

Conflict of interest: Z. Righetto, D. Marquez, M. Perez III are employees of Sanofi.

Disclosure: Publication funded by Sanofi.

Affiliation/Correspondence: Zefferino Righetto, Sanofi, Frankfurt, Germany, Daniel Marquez, Sanofi, CDMX Ciudad de Mexico, Mexico and Marcos Perez III, MD, Sanofi, Frankfurt, Germany
Submission date: 23.06.2023Acceptance date: 21.08.2023Publication date: 05.10.2023
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