Safety analysis of a Russian phage cocktail: From MetaGenomic analysis to oral application in healthy human subjects

McCallin, Shawna; Sarker, Shafiqul Alam; Barretto, Caroline; Sultana, Shamima; Berger, Bernard; Huq, Sayeda; Krause, Lutz; Bibiloni, Rodrigo; Schmitt, Bertrand; Reuteler, Gloria; Brüssow, Harald

doi:10.1016/j.virol.2013.05.022

Cited by 220 publications

(167 citation statements)

References 47 publications

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“…Of the few studies examining phage therapy, none have reported any adverse effects on human health, or major alterations of the microbiome. 17 , 18 , 35 , 36 The present study corroborated those findings. Noteworthy, the bacteriophage cocktail did also lyse a large number of other E. coli strains in vitro ; i.e., it was not solely lytic for one targeted E. coli strain.…”

Section: Discussionsupporting

confidence: 92%

A bacteriophage cocktail targetingEscherichia colireducesE. coliin simulated gut conditions, while preserving a non-targeted representative commensal normal microbiota

et al. 2018

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Antibiotics offer an efficient means for managing diseases caused by bacterial pathogens. However, antibiotics are typically broad spectrum and they can indiscriminately kill beneficial microbes in body habitats such as the gut, deleteriously affecting the commensal gut microbiota. In addition, many bacteria have developed or are developing resistance to antibiotics, which complicates treatment and creates significant challenges in clinical medicine. Therefore, there is a real and urgent medical need to develop alternative antimicrobial approaches that will kill specific problem-causing bacteria without disturbing a normal, and often beneficial, gut microbiota. One such potential alternative approach is the use of lytic bacteriophages for managing bacterial infections, including those caused by multidrug-resistant pathogens. In the present study, we comparatively analysed the efficacy of a bacteriophage cocktail targeting Escherichia coli with that of a broad-spectrum antibiotic (ciprofloxacin) using an in vitro model of the small intestine. The parameters examined included (i) the impact on a specific, pre-chosen targeted E. coli strain, and (ii) the impact on a selected non-targeted bacterial population, which was chosen to represent a defined microbial consortium typical of a healthy small intestine. During these studies, we also examined stability of bacteriophages against various pH and bile concentrations commonly found in the intestinal tract of humans. The bacteriophage cocktail was slightly more stable in the simulated duodenum conditions compared to the simulated ileum (0.12 vs. 0.58 log decrease in phage titers, respectively). It was equally effective as ciprofloxacin in reducing E. coli in the simulated gut conditions (2–3 log reduction), but had much milder (none) impact on the commensal, non-targeted bacteria compared to the antibiotic.

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Section: Discussionsupporting

confidence: 92%

A bacteriophage cocktail targetingEscherichia colireducesE. coliin simulated gut conditions, while preserving a non-targeted representative commensal normal microbiota

et al. 2018

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“…23,24,45 This is not surprising as bacteriophages are the most abundant viruses present in the human GIT, being part of our natural microbiota, and are far more abundant than viruses infecting eukaryotic cells. 46,47 Recent virome studies on samples from IBD patients showed that the microbiota of these patients displayed an altered bacteriophage composition, raising questions about the possible role of these viruses in the disease.…”

Section: Discussionmentioning

confidence: 99%

“…21,22 Unlike antibiotics, they are highly specific, infecting only a limited number of strains within a given bacterial species, and have therefore,a much smaller impact on the composition of the microbiota. [23][24][25] In this study, we evaluated the potential of bacteriophages to decrease intestinal colonisation with AIEC bacteria, in wild-type and CEACAM6-expressing mice. Our results, demonstrating the high efficacy of bacteriophages in reducing intestinal colonisation of AIEC strain LF82, strongly support their clinical evaluation in CD patients.…”

Section: Introductionmentioning

confidence: 99%

Bacteriophages targeting adherent invasive Escherichia coli strains as a promising new treatment for Crohn's disease

Galtier

Sordi

Sivignon

et al. 2017

ECCOJC

112

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Background and Aims: Adherent invasive Escherichia coli [AIEC] are abnormally predominant on the ileal mucosa of Crohn's disease [CD] patients. They bind to the CEACAM6 receptor expressed on the surface of epithelial cells. We aimed to assess the potential of bacteriophages, viruses infecting bacteria, to decrease the levels of AIEC bacteria associated with the intestinal mucosa. Methods: We combined ex vivo and in vivo experiments with murine and human intestinal samples to quantify the ability of virulent bacteriophages to target the prototype AIEC strain LF82. Results: We found that three virulent bacteriophages were able to replicate in ileal, caecal and colonic sections and faeces homogenates from murine gut samples colonised with the prototype AIEC strain LF82. A single day of per os treatment with the three bacteriophages cocktail given to LF82-colonised CEABAC10 transgenic mice, expressing the human CEACAM6 receptor for AIEC, decreased significantly the number of AIEC in faeces and in the adherent flora of intestinal sections. In addition, a single dose of the cocktail reduced dextran sodium sulphate-induced colitis symptoms on conventional mice colonised with the strain LF82 over a 2-week period. The cocktail targeted also LF82 bacteria in homogenates of ileal biopsies taken from CD patients.Conclusions: These findings demonstrate that bacteriophages are a new treatment option for targeting AIEC in CD patients and represent a strong basis for a clinical trial evaluation.

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“…So far, Russian companies have not documented the composition of their phage cocktails, their preparation and purity, or their safety and efficacy in humans with scientific reports. Previously, we characterized the composition of our T4-like phage cocktails (10) and examined the Russian E. coli-Proteus phage cocktail (13) for its phage composition and gene content. In the present study, we investigated the amplification and purification of T4-like coliphages for phage therapy purposes.…”

mentioning

confidence: 99%

Amplification and Purification of T4-Like Escherichia coli Phages for Phage Therapy: from Laboratory to Pilot Scale

Bourdin

Schmitt

Guy

et al. 2014

Appl Environ Microbiol

Self Cite

115

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We investigated the amplification and purification of phage preparations with respect to titer, contamination level, stability, and technical affordability. Using various production systems (wave bags, stirred-tank reactors, and Erlenmeyer flasks), we obtained peak titers of 10 9 to 10 10 PFU/ml for T4-like coliphages. Phage lysates could be sterilized through 0.22-m membrane filters without titer loss. Phages concentrated by differential centrifugation were not contaminated with cellular debris or bacterial proteins, as assessed by electron microscopy and mass spectrometry, respectively. Titer losses occurred by high-speed pelleting of phages but could be decreased by sedimentation through a sucrose cushion. Alternative phage concentration methods are prolonged medium-speed centrifugation, strong anion-exchange chromatography, and ultrafiltration, but the latter still allowed elevated lipopolysaccharide contamination. T4-like phages could not be pasteurized but maintained their infectivity titer in the cold chain. In the presence of 10 mM magnesium ions, phages showed no loss of titer over 1 month at 30°C.

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Safety analysis of a Russian phage cocktail: From MetaGenomic analysis to oral application in healthy human subjects

Cited by 220 publications

References 47 publications

A bacteriophage cocktail targetingEscherichia colireducesE. coliin simulated gut conditions, while preserving a non-targeted representative commensal normal microbiota

A bacteriophage cocktail targetingEscherichia colireducesE. coliin simulated gut conditions, while preserving a non-targeted representative commensal normal microbiota

Bacteriophages targeting adherent invasive Escherichia coli strains as a promising new treatment for Crohn's disease

Amplification and Purification of T4-Like Escherichia coli Phages for Phage Therapy: from Laboratory to Pilot Scale

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