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

Area of Science:

• Microbiology
• Immunology
• Gastroenterology

Background:

• Hospital-acquired pneumonia (HAP) presents significant mortality and economic burdens, often driven by multidrug-resistant (MDR) bacteria.
• Prior antimicrobial therapy is a known risk factor for HAP, yet the precise mechanisms remain unclear.

Purpose of the Study:

• To investigate how antibiotic therapy impacts the gut microbiome and subsequent pulmonary defense mechanisms against MDR pathogens.
• To elucidate the role of inflammatory monocytes (IMs) and their signaling pathways in antibiotic-associated HAP.

Main Methods:

• Analysis of gut microbiome diversity and short-chain fatty acid (SCFA) producer populations in hospitalized patients receiving antibiotics.
• Murine infection models using fecal microbiota transplantation from antibiotic-treated patients to assess pulmonary defense against MDR Klebsiella pneumoniae.

Main Results:

• Antibiotic therapy led to reduced gut microbiome diversity and depletion of SCFA producers.
• Antibiotic-induced microbiota alterations in mice impaired pulmonary defense against MDR K. pneumoniae.
• The antibacterial activity of inflammatory monocytes (IMs), regulated by fatty acid receptors (FFAR)2/3, was compromised in mice with antibiotic-associated microbiota.

Conclusions:

• Clinically relevant antibiotics can impair antimicrobial defense by altering the human gut microbiota.
• A critical impairment of IM antibacterial activity is identified as a mechanism linking antibiotic use to increased HAP risk.
• Findings support the rational use of antibiotics and suggest novel prophylactic strategies for HAP prevention in high-risk individuals.