Suppression of Clostridium difficile in the Gastrointestinal Tracts of Germfree Mice Inoculated with a Murine Isolate from the Family Lachnospiraceae

Abstract

The indigenous microbial community of the gastrointestinal (GI) tract determines susceptibility to Clostridium difficile colonization and disease. Previous studies have demonstrated that antibiotic-treated mice challenged with C. difficile either developed rapidly lethal C. difficile infection or were stably colonized with mild disease. The GI microbial community of animals with mild disease was dominated by members of the bacterial family Lachnospiraceae, while the gut community in moribund animals had a predominance of Escherichia coli. We investigated the roles of murine Lachnospiraceae and E. coli strains in colonization resistance against C. difficile in germfree mice. Murine Lachnospiraceae and E. coli isolates were cultured from wild-type mice. The ability of each of these isolates to interfere with C. difficile colonization was tested by precolonizing germfree mice with these bacteria 4 days prior to experimental C. difficile challenge. Mice precolonized with a murine Lachnospiraceae isolate, but not those colonized with E. coli, had significantly decreased C. difficile colonization, lower intestinal cytotoxin levels and exhibited less severe clinical signs and colonic histopathology. Infection of germfree mice or mice precolonized with E. coli with C. difficile strain VPI 10463 was uniformly fatal by 48 h, but only 20% mortality was seen at 2 days in mice precolonized with the Lachnospiraceae isolate prior to challenge with VPI 10463. These findings confirm that a single component of the GI microbiota, a murine Lachnospiraceae isolate, could partially restore colonization resistance against C. difficile. Further study of the members within the Lachnospiraceae family could lead to a better understanding of mechanisms of colonization resistance against C. difficile and novel therapeutic approaches for the treatment and prevention of C. difficile infection.

Clostridium difficile and the microbiota

“…Fidaxomicin was also shown to exert little effect on Bacteroides counts, which may be advantageous in preserving colonization resistance (85). Tigecycline has follow-up study based on these observations observed that mice colonized by Lachnospiraceae isolates, but not those colonized by E. coli isolates, exhibited decreased C. difficile colonization and less severe disease (69). Despite differences at lower taxonomic levels in the gut microbiota between humans and mice, murine models have provided a more testable way of identifying components protective in CDI development.…”

Intestinal Dysbiosis and Depletion of Butyrogenic Bacteria in Clostridium difficile Infection and Nosocomial Diarrhea

“…Interestingly, in 20 patients with asymptomatic C. difficile carriage, the gut microbial profile closely resembled that of healthy adults (19), suggesting that the normal gut microbiota may protect hosts from developing C. difficile infection. Two recent studies provided additional evidence that resistance against C. difficile colonization could be engineered in mice using a single Lachnospiraceae isolate or a defined cocktail of six murine gut isolates (20,21). Taken together, the data on fecal transplantation in clinical settings and experimental studies in animals suggest that it may be possible to manipulate the gut microbiota using defined human gut isolates as probiotics to treat and/or to prevent CDI.…”

Gastrointestinal dysbiosis and the use of fecal microbial transplantation inClostridium difficileinfection

“…Reeves et al [101] later demonstrated that, while germfree mice were extremely susceptible to CDI, the addition of multiple Lachnospiraceae family members suppressed the growth of C. difficile by 20fold, and decreased the toxin production by 25%. Only complete cecal microbiota transfer entirely inhibited CDI.…”