Abstract
Host defence against infection requires a range of innate and adaptive immune responses that may lead to tissue damage. Such immune-mediated pathologies can be controlled with appropriate T regulatory (Treg) activity. The aim of the present study was to determine the influence of gut microbiota composition on Treg cellular activity and NF-κB activation associated with infection. Mice consumed the commensal microbe Bifidobacterium infantis 35624 followed by infection with Salmonella typhimurium or injection with LPS. In vivo NF-κB activation was quantified using biophotonic imaging. CD4+CD25+Foxp3+ T cell phenotypes and cytokine levels were assessed using flow cytometry while CD4+ T cells were isolated using magnetic beads for adoptive transfer to naïve animals. In vivo imaging revealed profound inhibition of infection and LPS induced NF-κB activity that preceded a reduction in S. typhimurium numbers and murine sickness behaviour scores in B. infantis–fed mice. In addition, pro-inflammatory cytokine secretion, T cell proliferation, and dendritic cell co-stimulatory molecule expression were significantly reduced. In contrast, CD4+CD25+Foxp3+ T cell numbers were significantly increased in the mucosa and spleen of mice fed B. infantis. Adoptive transfer of CD4+CD25+ T cells transferred the NF-κB inhibitory activity. Consumption of a single commensal micro-organism drives the generation and function of Treg cells which control excessive NF-κB activation in vivo. These cellular interactions provide the basis for a more complete understanding of the commensal-host-pathogen trilogue that contribute to host homeostatic mechanisms underpinning protection against aberrant activation of the innate immune system in response to a translocating pathogen or systemic LPS.
Highlights
Mechanisms of host protection by commensal organisms against infection vary depending on the nature of the pathogenic challenge
It is unclear whether enhancement of T regulatory (Treg) activity by commensal organisms contributes to protection of the host from mucosal damage and systemic inflammation associated with infection by invasive pathogens
We and others have previously shown that non-pathogenic or commensal micro-organisms can protect the host from aberrant pro-inflammatory activity within the gut, but the influence of these microbes on regulatory T cells in the context of systemic infection has not been examined
Summary
Mechanisms of host protection by commensal organisms against infection vary depending on the nature of the pathogenic challenge. They range from mutual competition for nutrients and for microbial niches, to the production of specific antimicrobial peptides [1,2]. Encounter with specific experimental microbes within the murine gut, has been shown to drive the development of mucosal Tregs which is associated with attenuation of inflammation in a murine model of colitis [10] It is unclear whether enhancement of Treg activity by commensal organisms contributes to protection of the host from mucosal damage and systemic inflammation associated with infection by invasive pathogens
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