Abstract
BackgroundInfections with multi-drug resistant (MDR) Gram-negative bacteria including Pseudomonas aeruginosa (PA) have become a serious threat particularly in hospitalized patients with immunopathological co-morbidities. The well-balanced interplay between immune cells, pattern recognition receptors such as Toll-like receptor (TLR)-4 sensing lipopolysaccharide from Gram-negative bacteria including PA, and evolving pathways is crucial to prevent the host from invading (opportunistic) pathogens. Information regarding the molecular mechanisms underlying the interactions between intestinal carriage of MDR PA and host immunity during chronic large intestinal inflammation is scarce, however.Methods and resultsWe therefore perorally challenged conventionally colonized TLR4-deficient IL10−/− mice and IL10−/− counterparts displaying comparably severe chronic colitis with a clinical MDR PA strain. PA could more sufficiently establish in the intestinal tract of TLR4-deficient IL10−/− mice until day 14 postinfection (p.i.), whereas within 48 h the majority of IL10−/− mice had already expelled the opportunistic pathogen from their guts. Intestinal colonization properties of PA in TLR4-deficient IL10−/− mice were associated with distinct genotype-dependent differences in gut microbiota compositions before challenge given that TLR4-deficient IL10−/− mice harbored more fecal enterobacteria and enterococci, but lower Clostridium/Eubacterium burdens. At day 14 p.i., PA-induced increases in colonic immune cells such as macrophages, monocytes and T-lymphocytes could be observed in TLR4-deficient IL10−/− mice, but not IL10−/− counterparts, that were accompanied by a more distinct secretion of IFN-γ in the colon and TNF in the mesenteric lymph nodes (MLN) of the former as compared to the latter. Conversely, splenic TNF levels were lower in TLR4-deficient IL10−/− mice as compared to IL10−/− controls at day 14 p.i. Interestingly, more pronounced apoptotic responses could be assessed in colonic epithelia of PA-challenged IL10−/− mice only. This was paralleled by enhanced pro-inflammatory cytokine secretion not only in the intestines, but also in extra-intestinal compartments of IL10−/− mice as indicated by increased concentrations of nitric oxide in the colon, IFN-γ in the MLN and IL-12p70 in the spleen at day 14 p.i.ConclusionsUnder chronic intestinal inflammatory conditions including IL10−/− colitis MDR PA-association results in well-orchestrated TLR4-dependent immune responses both in intestinal and extra-intestinal compartments. Further studies should unravel the underlying molecular mechanisms in more detail.
Highlights
Infections with multi-drug resistant (MDR) Gram-negative bacteria including Pseudomonas aeruginosa (PA) have become a serious threat in hospitalized patients with immunopathological co-morbidities
Intestinal colonization properties of multi‐drug resistant P. aeruginosa following peroral association of TLR4 deficient IL10−/− mice In order to address the impact of TLR4 in MDR PA colonization and subsequent intestinal as well as extraintestinal immune responses in murine IL10−/− colitis, we perorally challenged 11–14 months old conventionally colonized TLR4 deficient IL10−/− mice and IL10−/− counterparts with 109 colony forming units (CFU) of a clinical MDR PA isolate by gavage
As early as 48 h p.i., more than 50% of mice had already expelled the opportunistic pathogen from their intestinal tract, whereas later on, PA could be isolated from fecal samples in single cases only (Fig. 1a)
Summary
Infections with multi-drug resistant (MDR) Gram-negative bacteria including Pseudomonas aeruginosa (PA) have become a serious threat in hospitalized patients with immunopathological co-morbidities. The well-balanced interplay between immune cells, pattern recognition receptors such as Toll-like receptor (TLR)-4 sensing lipopolysaccharide from Gram-negative bacteria including PA, and evolving pathways is crucial to prevent the host from invading (opportunistic) pathogens. More pronounced apoptotic responses could be assessed in colonic epithelia of PA-challenged IL10−/− mice only This was paralleled by enhanced pro-inflammatory cytokine secretion in the intestines, and in extra-intestinal compartments of IL10−/− mice as indicated by increased concentrations of nitric oxide in the colon, IFN-γ in the MLN and IL-12p70 in the spleen at day 14 p.i. Conclusions: Under chronic intestinal inflammatory conditions including IL10−/− colitis MDR PA-association results in well-orchestrated TLR4-dependent immune responses both in intestinal and extra-intestinal compartments. Even though not considered as being part of the human commensal intestinal microbiota, intestinal PA colonization is a prerequisite of infection later on, given that rectally colonized individuals harbored a 15 times higher risk for development of a PA infection when admitted to an ICU [15]
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