Multidrug-resistant Pseudomonas aeruginosa induce systemic pro-inflammatory immune responses in colonized mice

Abstract

The World Health Organization has rated multidrug-resistant (MDR) Pseudomonas aeruginosa as a critical threat to human health. In the present study, we performed a survey of intestinal colonization, and local and systemic immune responses following peroral association of secondary abiotic mice with either a clinical MDR P. aeruginosa or a commensal murine Escherichia coli isolate. Depletion of the intestinal microbiota following antibiotic treatment facilitated stable intestinal colonization of both P. aeruginosa and E. coli that were neither associated with relevant clinical nor histopathological sequelae. Either stable bacterial colonization, however, resulted in distinct innate and adaptive immune cell responses in the intestines, whereas a pronounced increase in macrophages and monocytes could be observed in the small as well as large intestines upon P. aeruginosa challenge only, which also applied to colonic T lymphocytes. In addition, TNF secretion was exclusively elevated in large intestines of P. aeruginosa-colonized mice. Strikingly, association of secondary abiotic mice with MDR P. aeruginosa, but not commensal E. coli, resulted in pronounced systemic pro-inflammatory responses, whereas anti-inflammatory responses were dampened. Hence, intestinal carriage of MDR P. aeruginosa as compared to a mere commensal Gram-negative strain in otherwise healthy individuals results in distinct local and systemic pro-inflammatory sequelae.

Toll-like receptor-4 differentially mediates intestinal and extra-intestinal immune responses upon multi-drug resistant Pseudomonas aeruginosa association of IL10−/− mice with chronic colitis

“…It is under current debate whether mere intestinal carriage of the opportunistic pathogen PA does have any immunopathological impact in health and disease [ 20 , 29 ]. In a previous survey, we were able to show that following peroral challenge of clinically uncompromised microbiota-depleted mice with an identical clinical isolate, MDR PA was not only able to stably colonize the intestinal tract at high loads, but also to induce intestinal as well as even extra-intestinal (i.e.…”

“…In a previous survey, we were able to show that following peroral challenge of clinically uncompromised microbiota-depleted mice with an identical clinical isolate, MDR PA was not only able to stably colonize the intestinal tract at high loads, but also to induce intestinal as well as even extra-intestinal (i.e. splenic) pro-inflammatory immune responses [ 29 ]. Hence, mere intestinal carriage of MDR Gram-negative opportunistic pathogens such as PA by an antibiotic-pretreated, but otherwise asymptomatic individual might result in immunopathological sequelae that may even be aggravated by other comorbidities (and vice versa).…”

Multidrug-resistant Pseudomonas aeruginosa aggravates inflammatory responses in murine chronic colitis

“…Furthermore, a recent study revealed that a majority of intensive care unit (ICU) patients with a Psae infection displayed prior rectal colonization with the bacterial opportunistic pathogen 8 . Particularly a preceding antimicrobial treatment had been shown to disturb the complex intestinal microbiota composition and therefore to compromise the physiological colonization resistance 9 – 12 which, in turn, may enable invading (opportunistic) pathogens including MDR Psae to establish within the human gastrointestinal ecosystem 13 . However, valid scientific data concerning the pathogenic potential of Psae infection of the intestinal tract are scarce.…”

“…However, valid scientific data concerning the pathogenic potential of Psae infection of the intestinal tract are scarce. Our very recent study revealed for the first time that mere intestinal carriage of a clinical MDR Psae isolate by otherwise healthy microbiota-depleted wildtype (WT) mice resulted in distinct local as well as systemic pro-inflammatory immune responses 13 . We were further able to demonstrate that with intestinal inflammation associated gut microbiota shifts facilitated murine infection with the enteropathogen Campylobacter jejuni 14 – 17 .…”

Full Transcriptomic Response of Pseudomonas aeruginosa to an Inulin-Derived Fructooligosaccharide

“…Moreover, under continuous antibiotic treatment the intestinal microbiota integrity is compromised and bears depletion of the intestinal microbiota (Dysbiosis), hence, physiological colonization resistance subsequently facilitates the establishment of the Pseudomonas aeruginosa in the intestinal ecosystem which might be considered an important internal source for P. aeruginosa infection (Ohara and Itoh, 2003;Von Klitzing et al, 2017). It is important to note that pathological alterations of the intestinal microbiota (dysbiosis) is related with continuous antibiotic treatment, obesity, diabetes and fatty liver, and of course alterations of the intestinal barrier function (IBF) as in inflammatory bowel disease and metabolic syndrome (Cano et al, 2013;Miura and Ohnishi, 2014).…”