β-Hydroxybutyric acid impairs host antimicrobial defense by targeting the CEACAM1-NADPH-ROS axis to disrupt macrophage bactericidal activity.

During bacterial infections, the immune function of macrophages in the host is crucial for eliminating bacteria. Metabolic disturbances can directly interfere with the normal function of host immune cells. However, it is unknown whether β-hydroxybutyric acid (BHBA), an important nutrient metabolite in humans, affects the bactericidal capacity of macrophages and the overall bacterial load in the infected host. Our clinical data show that circulating BHBA levels are higher in septic patients upon admission and positively correlate with increased infection-related parameters, such as procalcitonin (PCT) and high-sensitivity C-reactive protein (hsCRP). A similar clinical phenomenon was observed in mice suffering from bacterial peritonitis. Further, animal and cell experiments confirmed that BHBA stimulation could impair the antibacterial defense response of hosts by disrupting the bactericidal activity of macrophages. Interestingly, BHBA could disrupt the nicotinamide adenine dinucleotide phosphate (NADPH)/reactive oxygen species (ROS)-mediated bactericidal activity of macrophages by binding to the membrane protein carcinoembryonic antigen-associated cell adhesion molecule 1 (CEACAM1), ultimately affecting the bacterial load in the host. In conclusion, we identify BHBA as an endogenous negative pharmacological ligand that directly targets CEACAM1 as a macrophage druggable receptor, thereby disrupting the NADPH-ROS bactericidal axis. This BHBA-CEACAM1-NADPH-ROS pharmacological cascade impairs host antimicrobial defense, providing a biochemically tractable target for the development of novel anti‑infective therapies.