Administration of defined microbiota is protective in a murine Salmonella infection model

Abstract

Salmonella typhimurium is a major cause of diarrhea and causes significant morbidity and mortality worldwide, and perturbations of the gut microbiota are known to increase susceptibility to enteric infections. The purpose of this study was to investigate whether a Microbial Ecosystem Therapeutic (MET-1) consisting of 33 bacterial strains, isolated from human stool and previously used to cure patients with recurrent Clostridium difficile infection, could also protect against S. typhimurium disease. C57BL/6 mice were pretreated with streptomycin prior to receiving MET-1 or control, then gavaged with S. typhimurium. Weight loss, serum cytokine levels, and S. typhimurium splenic translocation were measured. NF-κB nuclear staining, neutrophil accumulation, and localization of tight junction proteins (claudin-1, ZO-1) were visualized by immunofluorescence. Infected mice receiving MET-1 lost less weight, had reduced serum cytokines, reduced NF-κB nuclear staining, and decreased neutrophil infiltration in the cecum. MET-1 also preserved cecum tight junction protein expression, and reduced S. typhimurium translocation to the spleen. Notably, MET-1 did not decrease CFUs of Salmonella in the intestine. MET-1 may attenuate systemic infection by preserving tight junctions, thereby inhibiting S. typhimurium from gaining access to the systemic circulation. We conclude that MET-1 may be protective against enteric infections besides C. difficile infection.

Embracing the gut microbiota: the new frontier for inflammatory and infectious diseases

“…Defined gut microbial species have been shown to maintain tight junction integrity, which in turn limits Salmonella typhimurium invasion. 88 Gut microbiota promote the secretory IgA response that inactivates rotavirus and neutralises cholera toxin, 87 and outcompete C. difficile colonisation thereby preventing infection. 47 Key gut microbial species also prime the development of cellular immune responses in the GI tract.…”

Gleaning Insights from Fecal Microbiota Transplantation and Probiotic Studies for the Rational Design of Combination Microbial Therapies

“…Intriguingly, the in vitro increase in keratinocyte transepithelial electrical resistance (TER) induced by a B. longum lysate, but not by an L. rhamnosus GG lysate, was abrogated in the presence of a TLR2-neutralizing antibody, suggesting that these bacteria act on different pathways to influence tight junction molecule expression (185). An in vivo infectious model recently demonstrated that a defined mixture of 33 probiotic bacterial strains pre- vented the Salmonella enterica serovar Typhimurium-induced disruption of ZO-1 and claudin-1 in mice and ameliorated disease severity (191).…”

A human gut ecosystem protects against C. difficile disease by targeting TcdA

“…MET-1 also attenuated TcdA-mediated apoptosis, another factor known to contribute to loss of gut barrier integrity [45], and enhanced tight junction protein expression. MET-1 has been shown to protect the expression of tight junction proteins important in the maintenance of host barrier function in an antibiotic-associated colitis animal model using Salmonella typhimurium [23], a pathogen that does not depend on toxin production for its pathogenicity. Of interest, MET-1 also preserves tight junction protein expression and attenuates systemic and local inflammation in a DSS mouse model of colitis [63].…”

“…A score between 1 and 3 was assigned for each parameter, and the overall score was the sum [22]. Immunofluorescence staining of myeloperoxidase (MPO) and claudin-1 was carried out on formalin-fixed cecal tissues as previously described [23]. …”