Modulating the gut microbiota with a synthetic stool “MET-1”: protective effects in animal models of antibiotic associated colitis
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Antibiotics disrupt the normal balance of the gut microbiota and may subsequently reduce colonization resistance, allowing pathogenic bacteria to colonize and cause disease. By re-introducing normal microbiota from a donor, colonization resistance can be restored. Based on this premise, a complex mixture, “microbial ecosystem therapeutic-1” (MET-1) containing 33 strains of commensal bacteria was derived from the stool of a healthy human donor. This gut microbial ecosystem has been successfully used to treat two patients infected with C. difficile, but mechanisms of action of the beneficial effects of MET-1 were undefined. An infectious antibiotic-associated mouse model of S. typhimurium and a germ free mouse model of C. difficile infection were utilized to determine the therapeutic effect of MET-1. In the S. typhimurium model, female C57BL/6 mice were pretreated with oral streptomycin prior to receiving MET-1 or vehicle control. When S. typhimurium infected mice were pretreated with MET-1, weight loss was attenuated (-3.5% vs. -6.8%; p<0.05). Serum cytokine levels of TNF-α, MIP-1β, IL-3 and GM-CSF were all significantly reduced. The S. typhimurium bacterial loads in the spleen were decreased in mice pretreated with MET-1 (9190 CFU/g vs. 25,438 CFU/g; p<0.05). Verified using a time-kill assay, MET-1 was bactericidal against S. typhimurium. These results showed that MET-1 could have attenuated the infection by inhibiting the growth of S. typhimurium. Germ-free, female Swiss Webster mice were pretreated with MET-1 or vehicle control prior to infection with C. difficile strain 027. In infected mice that were pretreated with MET-1 weight loss was attenuated, (-2.43% vs. -13.35%; p<0.05) and serum cytokine levels of TNF-α, IL-1β, IL-6, GM-CSF, MCP-1, MIP-1α and MIP-1β were all significantly reduced. The C. difficile bacterial loads in the cecum were reduced in mice pretreated with MET-1 (1.1x106 CFU/g vs. 1.9x108 CFU/g; p<0.05). In this model MET-1 was able to restore colonization resistance and therefore attenuate the C. difficile infection. Therefore, using a complex microbial community could restore colonization resistance against two different pathogens, S. typhimurium and C. difficile. In the future, MET-1 could be used as a prophylactic in conjunction with antibiotics to ensure colonization resistance is maintained against pathogenic bacteria.