Background and purposeCerebral ischemia-reperfusion injury disrupts the brain-gut axis, which involves the activation of the toll-like receptor 4 (TLR4)/myeloid differentiation factor 88 (MyD88)/nuclear factor-kappa B (NF-κB) pathway and gut microbiota dysregulation. Acorus tatarinowii Schott (AT) and Panax notoginseng saponins are traditional Chinese medicines with neuroprotective potential, yet the mechanism underlying their combined action remains elusive.Materials and methods144 Sprague-Dawley rats were divided into groups including: sham, model (transient middle cerebral artery occlusion/reperfusion, MCAO/R), and drug-treated groups receiving A. tatarinowii Schott (AT), P. notoginseng saponins (PNS), or their combination (PAT). To evaluate efficacy under heightened inflammatory conditions, parallel groups were pre-treated with lipopolysaccharide (LPS, a TLR4 pathway agonist) before MCAO/R and subsequent drug administration (e.g., LPS + MCAO/R, LPS + AT, LPS + PNS, LPS + PAT, etc.). Neurological deficits (Longa score), cerebral infarct volume (TTC staining), intestinal motility, and histopathology (Hematoxylin-eosin staining, transmission electron microscopy) were analyzed. Additionally, levels of tight junction proteins (ZO-1, claudin-5, occludin), TLR4 pathway components, and inflammatory cytokines (TNF-α, IL-6) were assessed using Western blot and/or immunohistochemistry. Gut microbiota composition was evaluated via 16S rDNA sequencing.ResultsCompared with either monotherapy, the combined AT–PNS treatment produced greater improvements in neurological function, reduced cerebral infarct volume, preserved blood-brain and intestinal barrier integrity, and attenuated TLR4/MyD88/NF-κB pathway activation. The combination was also associated with partial normalization of cecal microbiota composition, including an increased Firmicutes/Bacteroidota ratio and reduced Proteobacteria abundance. These effects were attenuated but remained detectable under LPS-induced inflammatory challenge.ConclusionCombined AT–PNS treatment ameliorated brain-gut axis dysfunction after cerebral ischemia-reperfusion injury and showed greater efficacy than either monotherapy in this fixed-dose experimental design. These effects were accompanied by suppression of TLR4/MyD88/NF-κB signaling, improved barrier integrity, and associated changes in gut microbiota composition. Because the present study did not include dose-response matrices, a formal dose-response interaction profile and a causal microbiota-TLR4 mechanism remain to be established in future studies.