Galectin-3 as a Therapeutic Target for NSAID-Induced Intestinal Ulcers
Ah-Mee Park, Sundar Khadka, Fumitaka Sato, Seiichi Omura, Mitsugu Fujita, Daniel K Hsu, Fu-Tong Liu, Ikuo Tsunoda, Ah-Mee Park, Sundar Khadka, Fumitaka Sato, Seiichi Omura, Mitsugu Fujita, Daniel K Hsu, Fu-Tong Liu, Ikuo Tsunoda
Abstract
Non-steroidal anti-inflammatory drugs (NSAIDs) induce ulcers in the gastrointestinal tract, including the stomach and small intestine. NSAID-induced gastric ulcers can be prevented by taking acid-neutralizing/inhibitory drugs and cytoprotective agents. In contrast, there are no medicines to control NSAID-induced small intestinal ulcers, which are accompanied by a mucosal invasion of bacteria and subsequent activation of immune cells. Galectin-3 (Gal3), an endogenous lectin, has anti-microbial and pro-inflammatory functions. In the small intestine, since Gal3 is highly expressed in epithelial cells constitutively and macrophages inducibly, the Gal3 level can affect microbiota composition and macrophage activation. We hypothesized that the modulation of Gal3 expression could be beneficial in NSAID-induced intestinal ulcers. Using Gal3 knockout (Gal3KO) mice, we determined whether Gal3 could be a therapeutic target in NSAID-induced intestinal ulcers. Following the administration of indomethacin, an NSAID, we found that small intestinal ulcers were less severe in Gal3KO mice than in wild-type (WT) mice. We also found that the composition of intestinal microbiota was different between WT and Gal3KO mice and that bactericidal antibiotic polymyxin B treatment significantly suppressed NSAID-induced ulcers. Furthermore, clodronate, a macrophage modulator, attenuated NSAID-induced ulcers. Therefore, Gal3 could be an exacerbating factor in NSAID-induced intestinal ulcers by affecting the intestinal microbiota population and macrophage activity. Inhibition of Gal3 may be a therapeutic strategy in NSAID-induced intestinal ulcers.
Clinical trial registration: www.ClinicalTrials.gov, identifier NCT03832946.
Keywords: 16S rRNA; PAS stain; adverse effect; animal model; cyclooxygenase-2 inhibitors; gastrointestinal flora; microbiome; small intestine.
Copyright © 2020 Park, Khadka, Sato, Omura, Fujita, Hsu, Liu and Tsunoda.
Figures
References
- Bjarnason I, Hayllar J, MacPherson AJ, Russell AS. Side effects of nonsteroidal anti-inflammatory drugs on the small and large intestine in humans. Gastroenterology. (1993) 104:1832–47. 10.1016/0016-5085(93)90667-2
- Lewis JD, Bilker WB, Brensinger C, Farrar JT, Strom BL. Hospitalization and mortality rates from peptic ulcer disease and GI bleeding in the 1990s: relationship to sales of nonsteroidal anti-inflammatory drugs and acid suppression medications. Am J Gastroenterol. (2002) 97:2540–9. 10.1111/j.1572-0241.2002.06037.x
- Davies NM, Saleh JY, Skjodt NM. Detection and prevention of NSAID-induced enteropathy. J Pharm Pharm Sci. (2000) 3:137–55.
- Barondes SH, Cooper DN, Gitt MA, Leffler H. Galectins. Structure and function of a large family of animal lectins. J Biol Chem. (1994) 269:20807–10.
- Sundblad V, Croci DO, Rabinovich GA. Regulated expression of galectin-3, a multifunctional glycan-binding protein, in haematopoietic and non-haematopoietic tissues. Histol Histopathol. (2011) 26:247–65. 10.14670/HH-26.247
- Hsu DK, Yang RY, Pan Z, Yu L, Salomon DR, Fung-Leung WP, et al. Targeted disruption of the galectin-3 gene results in attenuated peritoneal inflammatory responses. Am J Pathol. (2000) 156:1073–83. 10.1016/S0002-9440(10)64975-9
- Beatty WL, Rhoades ER, Hsu DK, Liu F-T, Russell DG. Association of a macrophage galactoside-binding protein with Mycobacterium-containing phagosomes. Cell Microbiol. (2002) 4:167–76. 10.1046/j.1462-5822.2002.00183.x
- Sano H, Hsu DK, Apgar JR, Yu L, Sharma BB, Kuwabara I, et al. Critical role of galectin-3 in phagocytosis by macrophages. J Clin Invest. (2003) 112:389–97. 10.1172/JCI17592
- Farnworth SL, Henderson NC, Mackinnon AC, Atkinson KM, Wilkinson T, Dhaliwal K, et al. Galectin-3 reduces the severity of pneumococcal pneumonia by augmenting neutrophil function. Am J Pathol. (2008) 172:395–405. 10.2353/ajpath.2008.070870
- Sato S, Ouellet N, Pelletier I, Simard M, Rancourt A, Bergeron MG. Role of galectin-3 as an adhesion molecule for neutrophil extravasation during streptococcal pneumonia. J Immunol. (2002) 168:1813–22. 10.4049/jimmunol.168.4.1813
- Fermino ML, Polli CD, Toledo KA, Liu F-T, Hsu DK, Roque-Barreira MC, et al. LPS-induced galectin-3 oligomerization results in enhancement of neutrophil activation. PLoS One. (2011) 6:e26004. 10.1371/journal.pone.0026004
- Park A-M, Hagiwara S, Hsu DK, Liu F-T, Yoshie O. Galectin-3 plays an important role in innate immunity to gastric infection by Helicobacter pylori. Infect Immun. (2016) 84:1184–93. 10.1128/IAI.01299-15
- Kohatsu L, Hsu DK, Jegalian AG, Liu F-T, Baum LG. Galectin-3 induces death of Candida species expressing specific beta-1,2-linked mannans. J Immunol. (2006) 177:4718–26. 10.4049/jimmunol.177.7.4718
- Mackinnon AC, Gibbons MA, Farnworth SL, Leffler H, Nilsson UJ, Delaine T, et al. Regulation of transforming growth factor-β1-driven lung fibrosis by galectin-3. Am J Respir Crit Care Med. (2012) 185:537–46. 10.1164/rccm.201106-0965OC
- Li L, Li J, Gao J. Functions of galectin-3 and its role in fibrotic diseases. J Pharmacol Exp Ther. (2014) 351:336–43. 10.1124/jpet.114.218370
- Harrison SA, Marri SR, Chalasani N, Kohli R, Aronstein W, Thompson GA, et al. Randomised clinical study: GR-MD-02, a galectin-3 inhibitor, vs. placebo in patients having non-alcoholic steatohepatitis with advanced fibrosis. Aliment Pharmacol Ther. (2016) 44:1183–98. 10.1111/apt.13816
- Eliaz I. The role of galectin-3 as a marker of cancer and inflammation in a stage IV ovarian cancer patient with underlying pro-inflammatory comorbidities. Case Rep Oncol. (2013) 6:343–9. 10.1159/000353574
- Dong R, Zhang M, Hu Q, Zheng S, Soh A, Zheng Y, et al. Galectin-3 as a novel biomarker for disease diagnosis and a target for therapy (Review). Int J Mol Med. (2018) 41:599–614. 10.3892/ijmm.2017.3311
- Takeuchi K, Tanaka A, Ohno R, Yokota A. Role of COX inhibition in pathogenesis of NSAID-induced small intestinal damage. J Physiol Pharmacol. (2003) 54(Suppl. 4):165–82.
- Takeuchi K, Satoh H. NSAID-induced small intestinal damage-roles of various pathogenic factors. Digestion. (2015) 91:218–32. 10.1159/000374106
- Delacour D, Koch A, Ackermann W, Eude-Le Parco I, Elsässer H-P, Poirier F, et al. Loss of galectin-3 impairs membrane polarisation of mouse enterocytes in vivo. J Cell Sci. (2008) 121:458–65. 10.1242/jcs.020800
- Weissenborn U, Maedge S, Buettner D, Sewing KF. Indometacin-induced gastrointestinal lesions in relation to tissue concentration, food intake and bacterial invasion in the rat. Pharmacology. (1985) 30:32–9. 10.1159/000138047
- Fukumoto K, Naito Y, Takagi T, Yamada S, Horie R, Inoue K, et al. Role of tumor necrosis factor-α in the pathogenesis of indomethacin-induced small intestinal injury in mice. Int J Mol Med. (2011) 27:353–9. 10.3892/ijmm.2011.602
- Dabek M, McCrae SI, Stevens VJ, Duncan SH, Louis P. Distribution of beta-glucosidase and beta-glucuronidase activity and of beta-glucuronidase gene gus in human colonic bacteria. FEMS Microbiol Ecol. (2008) 66:487–95. 10.1111/j.1574-6941.2008.00520.x
- Saitta KS, Zhang C, Lee KK, Fujimoto K, Redinbo MR, Boelsterli UA. Bacterial β-glucuronidase inhibition protects mice against enteropathy induced by indomethacin, ketoprofen or diclofenac: mode of action and pharmacokinetics. Xenobiotica. (2014) 44:28–35. 10.3109/00498254.2013.811314
- Watanabe T, Higuchi K, Kobata A, Nishio H, Tanigawa T, Shiba M, et al. Non-steroidal anti-inflammatory drug-induced small intestinal damage is Toll-like receptor 4 dependent. Gut. (2008) 57:181–7. 10.1136/gut.2007.125963
- Montalto M, Gallo A, Curigliano V, D’Onofrio F, Santoro L, Covino M, et al. Clinical trial: the effects of a probiotic mixture on non-steroidal anti-inflammatory drug enteropathy – a randomized, double-blind, cross-over, placebo-controlled study. Aliment Pharmacol Ther. (2010) 32:209–14. 10.1111/j.1365-2036.2010.04324.x
- Konaka A, Kato S, Tanaka A, Kunikata T, Korolkiewicz R, Takeuchi K. Roles of enterobacteria, nitric oxide and neutrophil in pathogenesis of indomethacin-induced small intestinal lesions in rats. Pharmacol Res. (1999) 40:517–24. 10.1006/phrs.1999.0550
- McCoy KD, Geuking MB, Ronchi F. Gut microbiome standardization in control and experimental mice. Curr Protoc Immunol. (2017) 117:23.1.1–23.1.13. 10.1002/cpim.25
- Emmelot CH, van der Waaij D. The dose at which neomycin and polymyxin B can be applied for selective decontamination of the digestive tract in mice. J Hyg (Lond). (1980) 84:331–40. 10.1017/s0022172400026851
- Mitsuoka T, Terada A, Watanabe K, Uchida K. Bacteroides multiacidus, a new species from the feces of humans and pigs. Int J Syst Bacteriol. (1974) 24:35–41. 10.1099/00207713-24-1-35
- Jayaraman A, Mansfeld FB, Wood TK. Inhibiting sulfate-reducing bacteria in biofilms by expressing the antimicrobial peptides indolicidin and bactenecin. J Ind Microbiol Biotechnol. (1999) 22:167–75. 10.1038/sj.jim.2900627
- Osaka T, Moriyama E, Arai S, Date Y, Yagi J, Kikuchi J, et al. Meta-analysis of fecal microbiota and metabolites in experimental colitic mice during the inflammatory and healing phases. Nutrients. (2017) 9:1329. 10.3390/nu9121329
- Huang Y-L, Chassard C, Hausmann M, von Itzstein M, Hennet T. Sialic acid catabolism drives intestinal inflammation and microbial dysbiosis in mice. Nat Commun. (2015) 6:8141. 10.1038/ncomms9141
- Grabinger T, Glaus Garzon JF, Hausmann M, Geirnaert A, Lacroix C, Hennet T. Alleviation of intestinal inflammation by oral supplementation with 2-fucosyllactose in mice. Front Microbiol. (2019) 10:1385. 10.3389/fmicb.2019.01385
- Bloom SM, Bijanki VN, Nava GM, Sun L, Malvin NP, Donermeyer DL, et al. Commensal Bacteroides species induce colitis in host-genotype-specific fashion in a mouse model of inflammatory bowel disease. Cell Host Microbe. (2011) 9:390–403. 10.1016/j.chom.2011.04.009
- Darnaud M, Dos Santos A, Gonzalez P, Augui S, Lacoste C, Desterke C, et al. Enteric delivery of regenerating family member 3 alpha alters the intestinal microbiota and controls inflammation in mice with colitis. Gastroenterology. (2018) 154:1009–23.e14. 10.1053/j.gastro.2017.11.003
- Magierowski M, Jasnos K, Kwiecien S, Drozdowicz D, Surmiak M, Strzalka M, et al. Endogenous prostaglandins and afferent sensory nerves in gastroprotective effect of hydrogen sulfide against stress-induced gastric lesions. PLoS One. (2015) 10:e0118972. 10.1371/journal.pone.0118972
- Kato Y, Hiasa M, Ichikawa R, Hasuzawa N, Kadowaki A, Iwatsuki K, et al. Identification of a vesicular ATP release inhibitor for the treatment of neuropathic and inflammatory pain. Proc Natl Acad Sci USA. (2017) 114:E6297–305. 10.1073/pnas.1704847114
- Bichara M, Attmane-Elakeb A, Brown D, Essig M, Karim Z, Muffat-Joly M, et al. Exploring the role of galectin 3 in kidney function: a genetic approach. Glycobiology. (2006) 16:36–45. 10.1093/glycob/cwj035
- Chan Y-C, Lin H-Y, Tu Z, Kuo Y-H, Hsu S-TD, Lin C-H. Dissecting the structure-activity relationship of galectin-ligand interactions. Int J Mol Sci. (2018) 19:392. 10.3390/ijms19020392
- Nair AB, Jacob S. A simple practice guide for dose conversion between animals and human. J Basic Clin Pharm. (2016) 7:27–31. 10.4103/0976-0105.177703
- Park A-M, Tsunoda I. Forensic luminol reaction for detecting fecal occult blood in experimental mice. BioTechniques. (2018) 65:227–30. 10.2144/btn-2018-0017
Source: PubMed