Rhubarb ameliorates ischemic stroke-induced tryptophan-kynurenine metabolic reprogramming and neuroinflammation via modulation of the IDO-1/TREM-1 pathway

BACKGROUND: Ischemic stroke (IS) elicits intertwined metabolic derangements and neuroinflammatory responses that propagate pathogenic cascades. Rhubarb (RR) is widely applied to treat IS in the clinic. However, its underlying pharmacological mechanisms remain incompletely elucidated. PURPOSE: To dissect the mechanism and pharmacological basis of RR's ability to ameliorate IS from the side of modulating tryptophan-kynurenine (TRP-KYN) metabolism and neuroinflammation. METHODS: An embolic middle cerebral artery occlusion (MCAO) model was employed in rats to simulate human IS. Neurological deficit scores, hematoxylin-eosin, 2,3,5-triphenyltetrazolium chloride, alcian blue-periodic acid-Schiff staining, Western blotting, targeted metabolomics, immunofluorescence, and enzyme-linked immunosorbent assay were utilized to evaluate the efficacy of RR against cerebral ischemic injury, gut permeability, TRP-KYN metabolism levels, and neuroinflammation. Surface plasmon resonance and cell-based assays were further utilized to screen and validate potential bioactive ingredients of RR for the treatment of IS. RESULTS: In addition to mitigating cerebral ischemic damage, RR treatment substantially restored intestinal barrier function in IS rats by reducing leaky gut biomarkers, ameliorating histopathological alterations, and upregulating colonic tight junction proteins. Moreover, RR modulated TRP-KYN metabolism, concomitant with regulated expression and enzymatic activity of indoleamine 2,3-dioxygenase 1 (IDO-1) and the triggering receptor expressed on myeloid cells-1 (TREM-1) levels in both colon tissue and serum. Within the central nervous system, RR attenuated neuroinflammation triggered by MCAO through orchestrating microglial polarization and cytokine levels, accompanied by suppression of the TREM-1-mediated inflammatory signaling cascade. Chrysophanol 8-O-β-d-glucoside, rutinum, lindleyin, and (-)-catechin gallate from RR were identified as potential IDO-1 inhibitors, while rhein, lindleyin, methyl gallate, and chrysophanol 8-O-β-d-glucoside were identified as potential TREM-1 inhibitors, capable of attenuating the overexpression of IDO-1 and TREM-1 or TREM-1 and NOD-like receptor protein 3 (NLRP3). CONCLUSION: This study demonstrates that RR exerts therapeutic effects in IS by improving the intestinal barrier function, reprogramming the IDO-1-dependent TRP-KYN pathway, and attenuating neuroinflammation. These effects are attributed to its bioactive components, including rutinum, chrysophanol 8-O-β-d-glucoside, lindleyin, (-)-catechin gallate, rhein, and methyl gallate.