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

Abstract

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.

Adherent-invasive Escherichia coli in inflammatory bowel disease

“…Since bacteriophages are part of the human commensal microbiota and because they are highly specific, they are likely to have a better safety profile than antibiotic therapy. Galtier et al 210 found three virulent LF82 bacteriophages that were able to replicate in ileal and colon samples, and in faeces of murine specimens. A single day of oral treatment with these bacteriophages significantly decreased intestinal colonisation by LF82 AIEC strain.…”

“…A single day of oral treatment with these bacteriophages significantly decreased intestinal colonisation by LF82 AIEC strain. Promisingly, this single-dose bacteriophage cocktail reduced DSS-induced colitis symptoms over a 2-week period in mice colonised with LF82 210. Studies in human subjects are currently being planned in the USA for evaluating this treatment in patients with IBD.…”

Defined microbiota transplant restores Th17/RORγt+ regulatory T cell balance in mice colonized with inflammatory bowel disease microbiotas

“…In the majority of conditions, no consistent association between the disease and any specific commensal species or strain has been made, and the distinction between the microbiotas in the healthy and diseased states reflects broader differences in the community structure, diversity or density Durack and Lynch 2019). In the rare cases where specific species or strains are hypothesized to contribute to disease, for example adhesiveinvasive Escherichia coli (AIEC) in Crohn's disease (Darfeuille-Michaud et al 2004), targeted therapy using approaches such as phages may be possible (Galtier et al 2017). In other situations, rational therapeutic approaches are elusive and the foremost strategy to modulate the microbiota has been fecal microbiota transplantation (FMT).…”

The spatial heterogeneity of the gut limits bacteriophage predation leading to the coexistence of antagonist populations of bacteria and their viruses

“…Using phage-bacterial model systems, dynamics of the coexistence of predators (or parasites) and preys (or hosts) have been the subject of theoretical and experimental studies, mostly performed in vitro and in silico (Betts et al 2014, Brockhurst et al 2006, Hannigan et al 2018a, Lenski and Levin 1985, Weitz et al 2013. In vivo, the interaction of phages and bacteria in the mammalian gut has been explored in mice and pigs (Galtier et al 2016, Galtier et al 2017, Looft et al 2014, Maura et al 2012a, Maura et al 2012b, Weiss et al 2009. Studies in mice have shown that virulent phages have a limited effect on the targeted bacterial populations within the gut (Galtier et al 2017, Maura et al 2012a, Maura et al 2012b, Weiss et al 2009.…”