Rifaximin Inhibits Small Bowel Angiodysplasia-Associated Angiogenesis by Attenuating LncRNA-HIF1A-AS2/miR-153-3p/HIF-1 α/Ang-2 Axis

Shuai Peng , An-ning Yin , Fei Liao , Liang Zhao

Current Medical Science ›› 2025, Vol. 45 ›› Issue (3) : 574 -584.

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Current Medical Science ›› 2025, Vol. 45 ›› Issue (3) : 574 -584. DOI: 10.1007/s11596-025-00061-z
Original Article
research-article

Rifaximin Inhibits Small Bowel Angiodysplasia-Associated Angiogenesis by Attenuating LncRNA-HIF1A-AS2/miR-153-3p/HIF-1 α/Ang-2 Axis

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Abstract

Backgrounds and Objective

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.

Methods

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.

Results

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.

Conclusions

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.

Keywords

Rifaximin / Small bowel / Gastrointestinal angiodysplasia / LncRNA-HIF1A-AS2

Cite this article

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Shuai Peng, An-ning Yin, Fei Liao, Liang Zhao. Rifaximin Inhibits Small Bowel Angiodysplasia-Associated Angiogenesis by Attenuating LncRNA-HIF1A-AS2/miR-153-3p/HIF-1 α/Ang-2 Axis. Current Medical Science, 2025, 45(3): 574-584 DOI:10.1007/s11596-025-00061-z

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References

[1]

RegulaJ, WronskaE, PachlewskiJ. Vascular lesions of the gastrointestinal tract. Best Pract Res Clin Gastroenterol., 2008, 22(2): 313-328.

[2]

SamiSS, Al-ArajiSA, RagunathK. Review article: gastrointestinal angiodysplasia–pathogenesis, diagnosis and management. Aliment Pharmacol Ther., 2014, 39(1): 15-34.

[3]

JacksonCS, StrongR. Gastrointestinal Angiodysplasia: Diagnosis and Management. Gastrointest Endosc Clin N Am., 2017, 27(1): 51-62.

[4]

BegS, RagunathK. Review on gastrointestinal angiodysplasia throughout the gastrointestinal tract. Best Pract Res Clin Gastroenterol., 2017, 31(1): 119-125.

[5]

LecleireS, Iwanicki-CaronI, Di-FioreA, et al.. Yield and impact of emergency capsule enteroscopy in severe obscure-overt gastrointestinal bleeding. Endoscopy., 2012, 44(4): 337-342.

[6]

GersonLB, FidlerJL, CaveDR, et al.. ACG Clinical Guideline: Diagnosis and Management of Small Bowel Bleeding. Am J Gastroenterol., 2015, 110(9): 1265-1287.

[7]

HolleranG, McNamaraD. An overview of angiodysplasia: management and patient prospects. Expert Rev Gastroenterol Hepatol., 2018, 12(9): 863-872.

[8]

KhanA, GuptaK, ChowdryM, et al.. Thirty-day readmission rates, reasons, and costs for gastrointestinal angiodysplasia-related bleeding in the USA. Eur J Gastroenterol Hepatol., 2021, 34(1): 11-17.

[9]

GkolfakisP, FostierR, TziatziosG, et al.. Efficacy of pharmacologic treatment for treating gastrointestinal angiodysplasias-related bleeding: a systematic review and meta-analysis. Eur J Gastroenterol Hepatol., 2022, 34(10): 1021-1030

[10]

RomagnuoloJ, BrockAS, RanneyN. Is Endoscopic Therapy Effective for Angioectasia in Obscure Gastrointestinal Bleeding ?: A Systematic Review of the Literature. J Clin Gastroenterol., 2015, 49(10): 823-830.

[11]

LewisBS, SalomonP, Rivera-MacMurrayS, et al.. Does hormonal therapy have any benefit for bleeding angiodysplasia?. J Clin Gastroenterol., 1992, 15(2): 99-103.

[12]

JunqueraF, FeuF, PapoM, et al.. A multicenter, randomized, clinical trial of hormonal therapy in the prevention of rebleeding from gastrointestinal angiodysplasia. Gastroenterology, 2001, 121(5): 1073-1079.

[13]

HodgsonH. Hormonal therapy for gastrointestinal angiodysplasia. Lancet Lond Engl., 2002, 359(9318): 1630-1631.

[14]

SzilagyiA, GhaliMP. Pharmacological therapy of vascular malformations of the gastrointestinal tract. Can J Gastroenterol., 2006, 20(3): 171-178.

[15]

BlichM, FruchterO, EdelsteinS, et al.. Somatostatin therapy ameliorates chronic and refractory gastrointestinal bleeding caused by diffuse angiodysplasia in a patient on anticoagulation therapy. Scand J Gastroenterol., 2003, 38(7): 801-803.

[16]

BowersM, McNultyO, MayneE. Octreotide in the treatment of gastrointestinal bleeding caused by angiodysplasia in two patients with von Willebrand's disease. Br J Haematol., 2000, 108(3): 524-527.

[17]

MolinaIJ, PNultyO, MayneE. Octreotide in the et al. Octreotide long-acting release for severe obscure gastrointestinal haemorrhage in elderly patients with serious comorbidities. Med Clin., 2009, 133(17): 667-670

[18]

OrsiP, Guatti-ZulianiC, OkolicsanyiL. Long-acting octreotide is effective incontrolling rebleeding angiodysplasia of the gastrointestinal tract. Digest Liver Dis., 2001, 33(4): 330-334.

[19]

BonC, AparicioT, VincentM, et al.. Long-acting somatostatin analogues decrease blood transfusionrequirements in patients with refractory gastrointestinal bleeding associated with angiodysplasia. Aliment Pharmacol Ther., 2012, 36(6): 587-593.

[20]

IannoneA, PrincipiM, BaroneM, et al.. Gastrointestinal bleeding from vascular malformations: Is octreotide effective to rescue difficult-to-treat patients?. Clin Res Hepatol Gastroenterol., 2016, 40(4): 373-377.

[21]

MarluR, BarthelonJ, DurandA, et al.. Longterm therapy with bevacizumab in a patient with Glanzmann’s thrombasthenia and recurrent digestive bleeding due to gastrointestinal angiodysplastic lesions. Am J Gastroenterol., 2015, 110(2): 352-353.

[22]

BarréA, DréanicJ, FlaujacC, et al.. Is there a role for antiangiogenic therapy, bevacizumab, in the treatment of recurrent digestive bleeding due to angiodysplasia in Glanzmann’s thrombasthenia?. Haemophilia., 2016, 22(4): e347-348.

[23]

D'AmatoRJ, LoughnanMS, FlynnE, et al.. Thalidomide is an inhibitor of angiogenesis. Proc Natl Acad Sci U S A., 1994, 91(9): 4082-4085.

[24]

FranksME, MacphersonGR. Thalidomide FWD. Lancet., 2004, 363(8): 1802-1811.

[25]

McFarlaneM, O'FlynnL, VentreR, et al.. Emerging role of thalidomide in the treatment of gastrointestinal bleeding. Frontline Gastroenterol., 2018, 9(2): 98-104.

[26]

ShurafaM, KambojG. Thalidomide for the treatment of bleeding angiodysplasias. Am J Gastroenterol., 2003, 98(1): 221-222.

[27]

BauditzJ, LochsH, VoderholzerW. Macroscopic appearance of intestinal angiodysplasias under antiangiogenic treatment with thalidomide. Endoscopy., 2006, 38(10): 1036-1039.

[28]

DabakV, KuriakoseP, KambojG, et al.. A pilot study of thalidomide in recurrent GI bleeding due to angiodysplasias. Dig Dis Sci., 2008, 53(6): 1632-1635.

[29]

KamalapornP, SaravananR, CiroccoM, et al.. Thalidomide for the treatment of chronic gastrointestinal bleeding from angiodysplasias: a case series. Eur J Gastroenterol Hepatol., 2009, 21(12): 1347-1350.

[30]

GarridoA, SayagoM, LópezJ, et al.. Thalidomide in refractory bleeding due to gastrointestinal angiodysplasias. Rev Esp Enferm Dig., 2012, 104(2): 69-71.

[31]

ChenH, FuS, FengN, et al.. Bleeding recurrence in patients with gastrointestinal vascular malformation after thalidomide. Medicine (Baltimore)., 2016, 9533. e4606

[32]

GeZZ, ChenHM, GaoYJ, et al.. Efficacy of thalidomide for refractory gastrointestinal bleeding from vascular malformation. Gastroenterology., 2011, 141(5): 1629-1637.e1-e4.

[33]

ChenH, WuS, TangM, et al.. Thalidomide for recurrent bleeding due to small-intestinal angiodysplasia. N Engl J Med., 2023, 389(18): 1649-1659.

[34]

LiY, FuS, ChenH, et al.. Inhibition of endothelial Slit2/Robo1 signaling by thalidomide restrains angiogenesis by blocking the PI3K/Akt pathway. Dig Dis Sci., 2014, 59(12): 2958-2966.

[35]

JunqueraF, SaperasE, de TorresI, et al.. Increased expression of angiogenic factors in human colonic angiodysplasia. Am J Gastroenterol., 1999, 94(4): 1070-1076.

[36]

FujitaH, MomoiM, ChuganjiY, et al.. Increased plasma vascular endothelial growth factor levels in patients with angiodysplasia. J Intern Med., 2000, 248(3): 268-269.

[37]

HolleranG, HallB, O'ReganM, et al.. Expression of Angiogenic Factors in Patients with Sporadic Small Bowel Angiodysplasia. J Clin Gastroenterol., 2015, 49(10): 831-836.

[38]

TanH, ChenH, XuC, et al.. Role of vascular endothelial growth factor in angiodysplasia: an interventional study with thalidomide. J Gastroenterol Hepatol., 2012, 27(6): 1094-1101.

[39]

TanHH, GeZZ, GaoYJ, et al.. The role of HIF-1, angiopoietin-2, Dll4 and Notch1 in bleeding gastrointestinal vascular malformations and thalidomide-associated actions: a pilot in vivo study. J Dig Dis., 2011, 12(5): 349-356.

[40]

FengQ, TanHH, GeZZ, et al.. Thalidomide-induced angiopoietin 2, Notch1 and Dll4 downregulation under hypoxic condition in tissues with gastrointestinal vascular malformation and human umbilical vein endothelial cells. J Dig Dis., 2014, 15(2): 85-95.

[41]

FengN, ChenH, FuS. HIF-1α and HIF-2α induced angiogenesis in gastrointestinal vascular malformation and reversed by thalidomide. Sci Rep., 2016, 1627280.

[42]

LiL, WangM, MeiZ, et al.. lncRNAs HIF1A-AS2 facilitates the up-regulation of HIF-1alpha by sponging to miR-153-3p, whereby promoting angiogenesis in HUVECs in hypoxia. Biomed Pharmacother., 2017, 96(1): 165-172.

[43]

TangCT, ZhangQW, WuS, et al.. Thalidomide targets EGFL6 to inhibit EGFL6/PAX6 axis-driven angiogenesis in small bowel vascular malformation. Cell Mol Life Sci., 2020, 77(24): 5207-5221.

[44]

DescombeJJ, DubourgD, PicardM, et al.. Pharmacokinetic study of rifaximin after oral administration in healthy volunteers. Int J Clin Pharmacol Res., 1994, 14(2): 51-56

[45]

BakerDE. Rifaximin: a nonabsorbed oral antibiotic. Rev Gastroenterol Disord., 2005, 5(1): 19-30

[46]

ShaytoRH, Abou MradR, ShararaAI. Use of rifaximin in gastrointestinal and liver diseases. World J Gastroenterol., 2016, 22(29): 6638-6651.

[47]

SartorRB. Review article: the potential mechanisms of action of rifaximin in the management of inflammatory bowel diseases. Aliment Pharmacol Ther., 2016, 43(1): 27-36.

[48]

SchoenfeldP, PimentelM, ChangL, et al.. Safety and tolerability of rifaximin for the treatment of irritable bowel syndrome without constipation: a pooled analysis of randomised, double-blind, placebo-controlled trials. Aliment Pharmacol Ther., 2014, 39(10): 1161-1168.

[49]

RobinsGW, WellingtonK. Rifaximin: a review of its use in the management of traveller’s diarrhoea. Drugs., 2005, 65(12): 1697-1713.

[50]

MattilaE, ArkkilaP, MattilaPS, et al.. Rifaximin in the treatment of recurrent Clostridium difficile infection. Aliment Pharmacol Ther., 2013, 37(1): 122-128.

[51]

PimentelM. Review article: potential mechanisms of action of rifaximin in the management of irritable bowel syndrome with diarrhoea. Aliment Pharmacol Ther., 2016, 43(1): 37-49.

[52]

IbrahimES, AlsebaeyA, ZaghlaH, et al.. Long-term rifaximin therapy as a primary prevention of hepatorenal syndrome. Eur J Gastroenterol Hepatol., 2017, 29(11): 1247-1250.

[53]

GattaL, ScarpignatoC. Systematic review with meta-analysis: rifaximin is effective and safe for the treatment of small intestine bacterial overgrowth. Aliment Pharmacol Ther., 2017, 45(5): 604-616.

[54]

CuomoR, BarbaraG, AnnibaleB. Rifaximin and diverticular disease: Position paper of the Italian Society of Gastroenterology (SIGE). Dig Liver Dis., 2017, 49(6): 595-603.

[55]

MaconiG. Diagnosis of symptomatic uncomplicated diverticular disease and the role of Rifaximin in management. Acta Biomed., 2017, 88(1): 25-32

[56]

MarianiM, ZuccaroV, PatrunoSF, et al.. The impact of rifaximin in the prevention of bacterial infections in cirrhosis. Eur Rev Med Pharmacol Sci., 2017, 21(5): 1151-1158

[57]

BruyneelM, SerstéT, LibertW, et al.. Improvement of sleep architecture parameters in cirrhotic patients with recurrent hepatic encephalopathy with the use of rifaximin. Eur J Gastroenterol Hepatol., 2017, 29(3): 302-308.

[58]

EspositoG, GigliS, SeguellaL, et al.. Rifaximin, a non-absorbable antibiotic, inhibits the release of pro-angiogenic mediators in colon cancer cells through a pregnane X receptor-dependent pathway. Int J Oncol., 2016, 49(2): 639-645.

[59]

ZhuQ, ZouL, JagaveluK, et al.. Intestinal decontamination inhibits TLR4 dependent fibronectin mediated crosstalk between stellate cells and endothelial cells in liver fibrosis in mice. J Hepatol., 2012, 56(4): 893-889.

[60]

MuniyappaP, GulatiR, MohrF, et al.. Use and safety of rifaximin in children with inflammatory bowel disease. J Pediatr Gastroenterol Nutr., 2009, 49(4): 400-404.

[61]

YangC, SinghP, SinghH, et al.. Systematic review: thalidomide and thalidomide analogues for treatment of inflammatory bowel disease. Aliment Pharmacol Ther., 2015, 41(11): 1079-1093.

[62]

SherbetGV. Therapeutic Potential of Thalidomide and Its Analogues in the Treatment of Cancer. Anticancer Res., 2015, 35(11): 5767-5772

[63]

WangX, ShenY, LiS, et al.. Importance of the interaction between immune cells and tumor vasculature mediated by thalidomide in cancer treatment (Review). Int J Mol Med., 2016, 38(4): 1021-1029.

[64]

HolsteinSA, McCarthyPL. Immunomodulatory Drugs in Multiple Myeloma: Mechanisms of Action and Clinical Experience. Drugs., 2017, 77(5): 505-520.

[65]

ZhangX, LuoH. Effects of thalidomide on growth and VEGF-A expression in SW480 colon cancer cells. Oncol Lett., 2018, 15(3): 3313-3320

[66]

ZengX, ShengX, WangPQ, et al.. Low-dose rifaximin prevents complications and improves survival in patients with decompensated liver cirrhosis. Hepatol Int., 2021, 15(1): 155-165.

Funding

Natural Science Foundation of Hubei Province(2022CFC010)

RIGHTS & PERMISSIONS

The Author(s), under exclusive licence to Huazhong University of Science and Technology

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