Brain injury is the leading cause of death and disability in survivors of cardiac arrest, where neuroinflammation triggered by infiltrating macrophages plays a pivotal role. Here, we seek to elucidate the origin of macrophages infiltrating the brain and their mechanism of action after cardiac arrest/cardiopulmonary resuscitation (CA/CPR). Wild-type or photoconvertible Cd68-Cre:R26-LSL-KikGR mice were subjected to 10-min CA/CPR, and the migration of gut-derived macrophages into brain was assessed. Transcriptome sequencing was performed to identify the key proinflammatory signal of macrophages infiltrating the brain, triggering receptor expressed on myeloid cells 1 (TREM1). Upon drug intervention, the effects of TREM1 on post-CA/CPR brain injury were further evaluated. 16S rRNA sequencing was used to detect gut dysbiosis after CA/CPR. Through photoconversion experiments, we found that small intestine-derived macrophages infiltrated the brain and played a crucial role in triggering secondary brain injury after CA/CPR. The infiltrating peripheral macrophages showed upregulated TREM1 levels, and we further revealed the crucial role of gut-derived TREM1