Backgrounds and Objective <p>Angiopoietin-2 (Ang-2) is a promising biomarker and therapeutic target for gastrointestinal angiodysplasia (GIAD). We hypothesized that the lncRNA-HIF1A-AS2/miR-153-3p/HIF-1α/Ang-2 axis plays a critical role in small bowel angiodysplasia (SBAD)-associated angiogenesis, which can be blocked by rifaximin. The purpose of this study was to investigate the expression and pro-angiogenic effects of the lncRNA-HIF1A-AS2/miR-153-3p/HIF-1α/Ang-2 in SBAD and to evaluate the therapeutic potential of rifaximin on SBAD by targeting this axis.</p> Methods <p>The expression and pro-angiogenic effects of lncRNA-HIF1A-AS2/miR-153-3p/HIF-1α/Ang-2 were analysed in SBAD tissues and human umbilical vein endothelial cells (HUVECs). The anti-angiogenic effect of rifaximin and its impact on the lncRNA-HIF1A-AS2/miR-153-3p/HIF-1α/Ang-2 axis were evaluated in HUVECs.</p> Results <p>Increased expression of lncRNA-HIF1A-AS2 and decreased expression of miR-153-3p were detected in SBAD tissues. LncRNA-HIF1A-AS2/miR-153-3p /HIF-1α were upstream regulators of Ang-2, and this axis was involved in angiogenesis in HUVECs. Rifaximin exerted antiangiogenic effects on HUVECs by blocking this axis.</p> Conclusions <p>The lncRNA-HIF1A-AS2/miR-153-3p/HIF-1α/Ang-2 axis is critically involved in SBAD-associated angiogenesis. Rifaximin is a potential therapeutic option for SBAD via blockade of this axis.</p>