Enterococcus faecalis (EF) is both a common commensal of the human gastrointestinal tract (GI) and a leading cause of hospital acquired infections1. Systemic infections with multi-drug resistant enterococci occur subsequent to GI colonization2. Preventing colonization by multi-drug resistant EF could therefore be a valuable approach to limiting infection. However, little is known about mechanisms EF uses to colonize and compete for stable gastrointestinal niches. Pheromone-responsive, conjugative plasmids encoding bacteriocins are common among enterococcal strains3, and could modulate niche competition among enterococci or between enterococci and the intestinal microbiota. We developed a model of mouse gut colonization with EF without disrupting the microbiota, to evaluate the role of the conjugative plasmid pPD1 expressing bacteriocin 214 on enterococcal colonization. Here we show that EF harboring pPD1 replaces indigenous enterococci and outcompetes EF lacking pPD1. Furthermore, in the intestine, pPD1 is transferred to other EF strains by conjugation, enhancing their survival. Moreover, colonization with an EF strain carrying a conjugation-defective pPD1 mutant resulted in clearance of vancomycin-resistant enterococci, without plasmid transfer. Therefore bacteriocin expression by commensal bacteria can influence niche-competition in the GI tract, and bacteriocins, delivered by commensals that occupy a precise intestinal bacterial niche, may be an effective therapeutic approach to specifically eliminate intestinal colonization by multi-drug resistant bacteria, without profound disruption of the indigenous microbiota.
Enterococci are Gram-positive commensals of the mammalian intestinal tract and harbor intrinsic resistance to broad-spectrum cephalosporins. Disruption of colonization resistance in humans by antibiotics allows enterococci to proliferate in the gut and cause disseminated infections. In this study, we used (EF)-colonized mice to study the dynamics of enterococci, commensal microbiota, and the host in response to systemic ceftriaxone administration. We found that the mouse model recapitulates intestinal proliferation and dissemination of enterococci seen in humans. Employing a ceftriaxone-sensitive strain of enterococci ( JL308), we showed that increased intestinal abundance is critical for the systemic dissemination of enterococci. Investigation of the impact of ceftriaxone on the mucosal barrier defenses and integrity suggested that translocation of enterococci across the intestinal mucosa was not associated with intestinal pathology or increased permeability. Ceftriaxone-induced alteration of intestinal microbial composition was associated with transient increase in the abundance of multiple bacterial operational taxonomic units (OTUs) in addition to enterococci, for example, lactobacilli, which also disseminated to the extraintestinal organs. Collectively, these results emphasize that ceftriaxone-induced disruption of colonization resistance and alteration of mucosal homeostasis facilitate increased intestinal abundance of a limited number of commensals along with enterococci, allowing their translocation and systemic dissemination in a healthy host.
The Salton Sea is a drying salt lake in an arid region with high aerosol particulate-matter concentrations. This region is plagued by a high incidence of asthma, attributed in part to the aerosols surrounding the Sea. But the connection between the Sea and asthma may be more than simple calculations of dust concentrations. While dusts might contain toxic substances that impact the lungs of residents, the complex dynamics related to the environmental degradation of the Salton Sea may be generating additional toxins relevant to public health, such as microcystins produced by algal blooms. This collection of pollutants may be driving inflammatory responses in the lungs of residents through multiple mechanisms. As such, examination of the full range of potential environmental triggers of lung inflammation promises to yield a better understanding of key mechanisms driving the high incidence of asthma in local residents. Our discussion provides a perspective aiming to re-frame the issue in the context of the historical theory of “miasma” and the linkages between environmental change and health impacts.
Background and Aims Crohn’s disease is a debilitating chronic inflammatory disorder of the mammalian gastrointestinal tract. Current interventions using anti-TNF biologics show long term benefit in only half of patients. This study focused on the role of the TNF receptor 1 (TNFR1) in pathogenesis in a TNF-driven model of ileitis. Methods We studied TNF ΔAU-rich element (ARE)/+ (TNFdARE) mice, which develop progressive ileitis similar to Crohn’s ileitis. Histopathological analysis and gene expression profiling were used to characterize disease progression from 5 to 16 weeks. Mice with TNFR1 hemizygosity (TNFdARE/R1het) allowed us to assess gene dosage effects. Transcriptional profiling established inflection points in disease progression; inflammatory gene expression increased at 8 weeks with a plateau by 10 weeks, so these were selected as end points of treatment using the TNF biologic Infliximab and the TNFR1-specific XPro1595. Differences in recruitment of cells in the lamina propria were assessed using flow cytometry. Results TNFdARE/R1het mice displayed stable long term protection from disease, associated with decreased recruitment of CD11b hiF4/80lo monocytes and CD11b hiLy6Ghi neutrophils, suggesting an important role of TNFR1 signaling in pathogenesis, and indicating potential benefit from TNFR1-specific intervention. Treatment with Infliximab and XPro1595 both showed similar impact on disease in TNFdARE mice. Importantly, these beneficial effects were greatly surpassed by hemizygosity at the TNFR1 locus. Conclusions Treatment with either Infliximab or XPro1595 produced moderate protection from ileitis in TNFdARE mice. However, hemizygosity at the TNFR1 locus in TNFdARE mice showed far better protection, implicating TNFR1 signaling as a key mediator of TNF-driven disease.
Enterococci are gram-positive commensals of the mammalian intestinal tract and intrinsically resistant to broad-spectrum cephalosporin antibiotics. They proliferate in the gut and disseminate systemically causing infections in immunocompromised individuals and hospitalized patients undergoing cephalosporin therapy. Using a unique mouse model with stable intestinal colonization with a lab strain of Enterococcus faecalis (EF), we investigated the role of the immune system in EF dissemination and clearance from mice treated with cephalosporins. Ceftriaxone mediated depletion of indigenous microbiota was associated with expansion of EF throughout the gut, reduced levels of gut mucosal barrier components and eventually EF dissemination to peripheral organs. We observed that EF was not associated with the FACS sorted populations of lamina propria mononuclear phagocytes suggesting that these immune cells did not actively translocate EF across the intestinal mucosa. Mice cleared EF systemically by 2 weeks post-antibiotic treatment without evidence of adaptive immune response. Studies in Rag1−/− mice suggested that adaptive immune system was not essential in EF clearance or containment. Our observations support that intestinal containment and systemic clearance of EF are mediated by innate immune mechanisms. We predict that this reflects general mechanisms for host containment and management of the intestinal commensal microbiota.
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