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

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.

SUBMITTER: Dorner PJ

PROVIDER: S-EPMC10981692 | biostudies-literature | 2024 Mar

REPOSITORIES: biostudies-literature

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

Dörner Patrick J PJ Anandakumar Harithaa H Röwekamp Ivo I Fiocca Vernengo Facundo F Millet Pascual-Leone Belén B Krzanowski Marta M Sellmaier Josua J Brüning Ulrike U Fritsche-Guenther Raphaela R Pfannkuch Lennart L Kurth Florian F Milek Miha M Igbokwe Vanessa V Löber Ulrike U Gutbier Birgitt B Holstein Markus M Heinz Gitta Anne GA Mashreghi Mir-Farzin MF Schulte Leon N LN Klatt Ann-Brit AB Caesar Sandra S Wienhold Sandra-Maria SM Offermanns Stefan S Mack Matthias M Witzenrath Martin M Jordan Stefan S Beule Dieter D Kirwan Jennifer A JA Forslund Sofia K SK Wilck Nicola N Bartolomaeus Hendrik H Heimesaat Markus M MM Opitz Bastian B

Nature communications 20240330 1

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 ...[more]

PMID: 38555356

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Project description:The phagocytic clearance of apoptotic cells, termed efferocytosis, is essential for both tissue homeostasis and tissue health during cell death-inducing treatments. Failure to efficiently clear apoptotic cells augment the risk of pathological inflammation and has been linked to a myriad of autoimmune and inflammatory diseases. Although past studies have elucidated local molecular signals that regulate homeostatic efferocytosis in a tissue, whether signals arising distally also regulate homeostatic efferocytosis remains elusive. Interestingly, clinical evidence suggests that prolonged use of broad-spectrum antibiotics is associated with an increased risk of autoimmune and inflammatory disease development. We therefore hypothesized that intestinal microbes produce molecular signals that regulate efferocytotic ability in tissue phagocytes beyond the intestines. Here, we find that macrophages, the body’s professional phagocyte, display impaired efferocytosis in the peritoneum of broad-spectrum antibiotics (ABX)-treated, vancomycin-treated, and germ-free mice in vivo, the latter of which could be rescued by fecal microbiota transplantation. Mechanistically, the microbiota-derived short-chain fatty acid butyrate directly boosted efferocytosis efficiency and capacity in mouse and human macrophages, with both intestinal and local delivery of butyrate capable of rescuing ABX-induced large peritoneal macrophage (LPM) efferocytosis defects. Bulk mRNA sequencing of butyrate-treated primary macrophages in vitro and single cell mRNA sequencing of LPMs isolated from ABX-treated and butyrate-rescued mice revealed specific regulation of efferocytosis-supportive transcriptional programs. Specifically, we found that the efferocytosis receptor T-cell immunoglobulin and mucin domain containing 4 (TIM-4, Timd4) was downregulated in LPMs of ABX-treated mice which was rescued by oral butyrate and that TIM-4 was required for the butyrate-induced enhancement of LPM efferocytosis capacity in vivo. Strikingly, LPM efferocytosis was impaired well-beyond withdrawal of ABX and, importantly, ABX-treated mice exhibited significantly worse disease in a mouse model of system lupus erythematosus. Collectively, our results demonstrate that homeostatic efferocytosis relies on distal molecular signals and suggest that a defect in homeostatic efferocytosis may contribute to the clinically observed link between broad-spectrum antibiotics use and inflammatory disease.

Dataset Information

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

Publications

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

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