Gut Microbiota–Derived Lipopolysaccharides and Short‐Chain Fatty Acids Regulate Immune Responses via FFAR2/FFAR3 in Lung Ischemia–Reperfusion Injury

ABSTRACT Lung ischemia–reperfusion (IR) injury is a sterile inflammatory process seen in conditions such as hemorrhage‐resuscitation and pulmonary embolism. Our previous work suggests that alveolar macrophages (AMs) drive the inflammatory cascade via NLRP3 inflammasome activation, and that gut‐derived lipopolysaccharides (LPS) and short‐chain fatty acids (SCFAs) influence these responses. However, the precise mechanisms by which gut microbiota signals govern AM function during lung IR remain unclear. Here, we show that germ‐free mice exhibit reduced inflammatory responses compared to specific pathogen‐free mice following lung IR injury in vivo . In contrast, mice lacking free fatty acid receptor (FFAR)2 or FFAR3—receptors for SCFAs—display heightened inflammation relative to wild‐type controls. Ex vivo and in vitro nutritional IR experiments further demonstrate that AMs, primed with LPS, produce IL‐1 β via NLRP3 inflammasome and caspase‐1 activation. Notably, SCFAs significantly diminish IR‐induced IL‐1β release, indicating a protective effect. These findings support a gut–lung axis in which gut microbiota modulate baseline lung immune capacity or lung immune tone through the transmission of LPS and SCFAs, thereby shaping the lung's response to sterile injury. Gut microbiota–based therapies, including dietary fiber interventions, may thus represent a promising therapeutic strategy for regulating inflammatory processes in the lung.