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

Patrick J. Dörner, Harithaa Anandakumar, Ivo Röwekamp, Facundo Fiocca Vernengo, Belén Millet Pascual-Leone, Marta Krzanowski, Josua Sellmaier, Ulrike Brüning, Raphaela Fritsche-Guenther, Lennart Pfannkuch, Florian Kurth, Miha Milek, Vanessa Igbokwe, Ulrike Löber, Birgitt Gutbier, Markus Holstein, Gitta Anne Heinz, Mir-Farzin Mashreghi, Leon N. Schulte, Ann-Brit Klatt, Sandra Caesar, Sandra-Maria Wienhold, Stefan Offermanns, Matthias Mack, Martin Witzenrath, Stefan Jordan, Dieter Beule, Jennifer A. Kirwan, Sofia K. Forslund, Nicola Wilck, Hendrik Bartolomaeus, Markus M. Heimesaat and Bastian Opitz ()
Additional contact information
Patrick J. Dörner: Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin
Harithaa Anandakumar: a cooperation of Charité – Universitätsmedizin Berlin and Max-Delbrück-Center for Molecular Medicine
Ivo Röwekamp: Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin
Facundo Fiocca Vernengo: Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin
Belén Millet Pascual-Leone: Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin
Marta Krzanowski: Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin
Josua Sellmaier: Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin
Ulrike Brüning: Berlin Institute of Health at Charité
Raphaela Fritsche-Guenther: Berlin Institute of Health at Charité
Lennart Pfannkuch: Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin
Florian Kurth: Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin
Miha Milek: Berlin Institute of Health at Charité
Vanessa Igbokwe: Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin
Ulrike Löber: a cooperation of Charité – Universitätsmedizin Berlin and Max-Delbrück-Center for Molecular Medicine
Birgitt Gutbier: Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin
Markus Holstein: Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin
Gitta Anne Heinz: a Leibniz Institute
Mir-Farzin Mashreghi: a Leibniz Institute
Leon N. Schulte: Philipps University Marburg
Ann-Brit Klatt: Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin
Sandra Caesar: Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin
Sandra-Maria Wienhold: Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin
Stefan Offermanns: Max-Planck-Institute for Heart and Lung Research
Matthias Mack: University Hospital Regensburg
Martin Witzenrath: Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin
Stefan Jordan: Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin
Dieter Beule: Berlin Institute of Health at Charité
Jennifer A. Kirwan: Berlin Institute of Health at Charité
Sofia K. Forslund: a cooperation of Charité – Universitätsmedizin Berlin and Max-Delbrück-Center for Molecular Medicine
Nicola Wilck: a cooperation of Charité – Universitätsmedizin Berlin and Max-Delbrück-Center for Molecular Medicine
Hendrik Bartolomaeus: a cooperation of Charité – Universitätsmedizin Berlin and Max-Delbrück-Center for Molecular Medicine
Markus M. Heimesaat: Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin
Bastian Opitz: Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin

Nature Communications, 2024, vol. 15, issue 1, 1-14

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-47149-z

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