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Clinically used broad-spectrum antibiotics compromise inflammatory monocyte-dependent antibacterial defense in the lung

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Item Type:Article
Title:Clinically used broad-spectrum antibiotics compromise inflammatory monocyte-dependent antibacterial defense in the lung
Creators Name:Dörner, P.J. and Anandakumar, H. and Röwekamp, I. and Fiocca Vernengo, F. and Millet Pascual-Leone, B. and Krzanowski, M. and Sellmaier, J. and Brüning, U. and Fritsche-Guenther, R. and Pfannkuch, L. and Kurth, F. and Milek, M. and Igbokwe, V. and Löber, U. and Gutbier, B. and Holstein, M. and Heinz, G.A. and Mashreghi, M.F. and Schulte, L.N. and Klatt, A.B. and Caesar, S. and Wienhold, S.M. and Offermanns, S. and Mack, M. and Witzenrath, M. and Jordan, S. and Beule, D. and Kirwan, J.A. and Forslund, S.K. and Wilck, N. and Bartolomaeus, H. and Heimesaat, M.M. and Opitz, B.
Abstract:Hospital-acquired pneumonia (HAP) is associated with high mortality and costs, and frequently caused by multidrug-resistant (MDR) bacteria. Although prior antimicrobial therapy is a major risk factor for HAP, the underlying mechanism remains incompletely understood. Here, we demonstrate that antibiotic therapy in hospitalized patients is associated with decreased diversity of the gut microbiome and depletion of short-chain fatty acid (SCFA) producers. Infection experiments with mice transplanted with patient fecal material reveal that these antibiotic-induced microbiota perturbations impair pulmonary defense against MDR Klebsiella pneumoniae. This is dependent on inflammatory monocytes (IMs), whose fatty acid receptor (FFAR)2/3-controlled and phagolysosome-dependent antibacterial activity is compromized in mice transplanted with antibiotic-associated patient microbiota. Collectively, we characterize how clinically relevant antibiotics affect antimicrobial defense in the context of human microbiota, and reveal a critical impairment of IM´s antimicrobial activity. Our study provides additional arguments for the rational use of antibiotics and offers mechanistic insights for the development of novel prophylactic strategies to protect high-risk patients from HAP.
Keywords:Anti-Bacterial Agents, Anti-Infective Agents, Klebsiella pneumoniae, Lung, Monocytes, Animals, Mice
Source:Nature Communications
Publisher:Nature Publishing Group
Page Range:2788
Date:30 March 2024
Official Publication:https://doi.org/10.1038/s41467-024-47149-z
PubMed:View item in PubMed

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