Hemorrhagic Transformation in Patients With Large-artery Atherosclerotic Stroke Is Associated With Gut Microbiota and LPS-TLR4 Signaling Pathway

Abstract Objective: Hemorrhagic transformation (HT) is a major complication of ischemic stroke that worsens outcomes and increases mortality. Disruption of gut microbiota is an important feature of stroke, and some special bacteria combined with bacterial metabolites may contribute to HT pathogenesis. we aimed to study the relationship between gut microbiota and HT of large-artery atherosclerotic stroke. Methods: From May-2020 through September-2021, the blood and fecal samples in patients with acute first-ever ischemic stroke and not undergoing intravenous thrombolysis or endovascular were obtained on admission, and gut microbiota was assessed by 16s ribosomal ribonucleic acid (rRNA) sequence. Stroke that developed HT (n=15) were compared to those without HT (n=17) and healthy controls (n=16). We also examined the key components of lipopolysaccharide (LPS) pathway: LPS, LPS-binding protein (LBP), and solube CD14 (sCD14). The role of gut microbiota in HT was evaluated using experimental stroke model. Results: We observed that bacterial diversity was decreased in both HT and non-HT group compared to the healthy controls. The patients of ischemic stroke that developed HT had differential composition of gut microbiota, in particular, an increase in the relative abundance and diversity of members belonging to the Enterobacteriaceae family. Plasma LPS and LBP levels were higher in HT group compared to non-HT group. The concentrations of LPS, LBP and sCD14 were associated with increased abundance of Enterobacteriaceae. In experimental study, the antibiotics treatment diminished HT-induced increase in the levels of LPS and LBP as well as upregulated expression of Toll-like receptor 4 (TLR4) and NF-κB in colon tissue. Transplant of microbiota from HT rats triggered higher level of LPS, LBP and sCD14 in plasma and increased expression of TLR4 and NF-κB in colon tissue.Conclusion: Stroke patients who developed with HT exhibit an obvious change in gut microbiota and LPS-induced inflammatory response. This suggests that maintaining a balance of gut microbiota may be an important factor in preventing HT after stroke.