A Novel Combination Therapy Using Rosuvastatin and <i>Lactobacillus</i> Combats Dextran Sodium Sulfate-Induced Colitis in High-Fat Diet-Fed Rats by Targeting the TXNIP/NLRP3 Interaction and Influencing Gut Microbiome Composition

Inflammasome targeting and controlling dysbiosis are promising therapeutic approaches to control ulcerative colitis. This report is the first to investigate the mechanisms underlying the coloprotective effects of rosuvastatin and <i>Lactobacillus</i> and their combined therapy on dextran...

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Main Authors: Sameh Saber, Eslam E. Abd El-Fattah, Galal Yahya, Naglaa A. Gobba, Abdalkareem Omar Maghmomeh, Ahmed E. Khodir, Ahmed A. E. Mourad, Ahmed S. Saad, Hager G. Mohammed, Nehal A. Nouh, Ahmed Shata, Noha A. Amin, Magdy Abou El-Rous, Samuel Girgis, Eman El-Ahwany, Eman M. Khalaf, Attalla F. El-Kott, Ahmed M. El-Baz
Format: Article
Language:English
Published: MDPI AG 2021-04-01
Series:Pharmaceuticals
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Online Access:https://www.mdpi.com/1424-8247/14/4/341
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author Sameh Saber
Eslam E. Abd El-Fattah
Galal Yahya
Naglaa A. Gobba
Abdalkareem Omar Maghmomeh
Ahmed E. Khodir
Ahmed A. E. Mourad
Ahmed S. Saad
Hager G. Mohammed
Nehal A. Nouh
Ahmed Shata
Noha A. Amin
Magdy Abou El-Rous
Samuel Girgis
Eman El-Ahwany
Eman M. Khalaf
Attalla F. El-Kott
Ahmed M. El-Baz
author_facet Sameh Saber
Eslam E. Abd El-Fattah
Galal Yahya
Naglaa A. Gobba
Abdalkareem Omar Maghmomeh
Ahmed E. Khodir
Ahmed A. E. Mourad
Ahmed S. Saad
Hager G. Mohammed
Nehal A. Nouh
Ahmed Shata
Noha A. Amin
Magdy Abou El-Rous
Samuel Girgis
Eman El-Ahwany
Eman M. Khalaf
Attalla F. El-Kott
Ahmed M. El-Baz
author_sort Sameh Saber
collection DOAJ
description Inflammasome targeting and controlling dysbiosis are promising therapeutic approaches to control ulcerative colitis. This report is the first to investigate the mechanisms underlying the coloprotective effects of rosuvastatin and <i>Lactobacillus</i> and their combined therapy on dextran sodium sulfate (DSS)-induced colitis in high-fat diet (HFD)-fed rats. Our results demonstrate the aggravation of intestinal inflammation as a consequence of an HFD following DSS administration. An association between dyslipidemia, LDL oxidation, CD36 expression, ROS generation, thioredoxin-interacting protein (TXNIP) upregulation, and NLRP3 inflammasome activation was demonstrated by DSS exposure in HFD-fed rats. We demonstrated that rosuvastatin/<i>Lactobacillus</i> significantly suppressed the DSS/HFD-induced increase in colon weight/length ratio, DAI, MDI, and myeloperoxidase, as well as corrected dysbiosis and improved histological characteristics. Additionally, caspase-1 activity and IL-1β-driven pyroptotic activity was significantly reduced. Rosuvastatin/<i>Lactobacillus</i> showed prominent anti-inflammatory effects as revealed by the IL-10/IL-12 ratio and the levels of TNF-α and IL-6. These latter effects may be attributed to the inhibition of phosphorylation-induced activation of NF-κB and a concomitant reduction in the expression of NLRP3, pro-IL-1β, and pro-IL-18. Furthermore, rosuvastatin/<i>Lactobacillus</i> reduced Ox-LDL-induced TXNIP and attenuated the inflammatory response by inhibiting NLRP3 inflammasome assembly. To conclude, rosuvastatin/Lactobacillus offers a safe and effective strategy for the management of ulcerative colitis.
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spelling doaj.art-8ec2dda160bc4147b50f5a6b97896fe42023-11-21T14:41:53ZengMDPI AGPharmaceuticals1424-82472021-04-0114434110.3390/ph14040341A Novel Combination Therapy Using Rosuvastatin and <i>Lactobacillus</i> Combats Dextran Sodium Sulfate-Induced Colitis in High-Fat Diet-Fed Rats by Targeting the TXNIP/NLRP3 Interaction and Influencing Gut Microbiome CompositionSameh Saber0Eslam E. Abd El-Fattah1Galal Yahya2Naglaa A. Gobba3Abdalkareem Omar Maghmomeh4Ahmed E. Khodir5Ahmed A. E. Mourad6Ahmed S. Saad7Hager G. Mohammed8Nehal A. Nouh9Ahmed Shata10Noha A. Amin11Magdy Abou El-Rous12Samuel Girgis13Eman El-Ahwany14Eman M. Khalaf15Attalla F. El-Kott16Ahmed M. El-Baz17Department of Pharmacology, Faculty of Pharmacy, Delta University for Science and Technology, Gamasa 11152, EgyptDepartment of Biochemistry, Faculty of Pharmacy, Delta University for Science and Technology, Gamasa 11152, EgyptDepartment of Microbiology and Immunology, Faculty of Pharmacy, Zagazig University, Al Sharqia 44519, EgyptDepartment of Pharmacology and Toxicology, College of Pharmacy, Misr University for Science and Technology, Giza 12411, EgyptDepartment of Biochemistry, Faculty of Pharmacy, Arab Private University for Science and Technology, Hama 1293400, SyriaDepartment of Pharmacology, Faculty of Pharmacy, Horus University-Egypt, New Damietta 34518, EgyptDepartment of Pharmacology and Toxicology, Faculty of Pharmacy, Port-Said University, Port-Said 42511, EgyptDepartment of Pharmacology and Toxicology, Faculty of Pharmacy, Port-Said University, Port-Said 42511, EgyptGeneral Administration of Pharmacy, Mansoura 11001, EgyptDepartment of Microbiology, Albatterjee Medical College, Jeddah 6231, Saudi ArabiaDepartment of Clinical Pharmacology, Faculty of Medicine, Mansoura University, Mansoura 35516, EgyptDepartment of Haematology, Theodor Bilharz Research Institute, Giza 12411, EgyptDepartment of Biochemistry, Faculty of Pharmacy, Helwan University, Cairo 11795, EgyptDepartment of Pharmaceutics, Faculty of Pharmacy, Alsalam University, Kafr El-Zayat 31612, EgyptDepartment of Immunology, Theodor Bilharz Research Institute, Giza 12411, EgyptDepartment of Microbiology and Immunology, Faculty of Pharmacy, Damanhour University, Damanhour 22511, EgyptDepartment of Biology, College of Science, King Khalid University, Abha 61421, Saudi ArabiaDepartment of Microbiology and Biotechnology, Faculty of Pharmacy, Delta University for Science and Technology, Gamasa 11152, EgyptInflammasome targeting and controlling dysbiosis are promising therapeutic approaches to control ulcerative colitis. This report is the first to investigate the mechanisms underlying the coloprotective effects of rosuvastatin and <i>Lactobacillus</i> and their combined therapy on dextran sodium sulfate (DSS)-induced colitis in high-fat diet (HFD)-fed rats. Our results demonstrate the aggravation of intestinal inflammation as a consequence of an HFD following DSS administration. An association between dyslipidemia, LDL oxidation, CD36 expression, ROS generation, thioredoxin-interacting protein (TXNIP) upregulation, and NLRP3 inflammasome activation was demonstrated by DSS exposure in HFD-fed rats. We demonstrated that rosuvastatin/<i>Lactobacillus</i> significantly suppressed the DSS/HFD-induced increase in colon weight/length ratio, DAI, MDI, and myeloperoxidase, as well as corrected dysbiosis and improved histological characteristics. Additionally, caspase-1 activity and IL-1β-driven pyroptotic activity was significantly reduced. Rosuvastatin/<i>Lactobacillus</i> showed prominent anti-inflammatory effects as revealed by the IL-10/IL-12 ratio and the levels of TNF-α and IL-6. These latter effects may be attributed to the inhibition of phosphorylation-induced activation of NF-κB and a concomitant reduction in the expression of NLRP3, pro-IL-1β, and pro-IL-18. Furthermore, rosuvastatin/<i>Lactobacillus</i> reduced Ox-LDL-induced TXNIP and attenuated the inflammatory response by inhibiting NLRP3 inflammasome assembly. To conclude, rosuvastatin/Lactobacillus offers a safe and effective strategy for the management of ulcerative colitis.https://www.mdpi.com/1424-8247/14/4/341ulcerative colitisNLRP3 inflammasomerosuvastatin<i>Lactobacillus</i>gut microbiomeTXNIP
spellingShingle Sameh Saber
Eslam E. Abd El-Fattah
Galal Yahya
Naglaa A. Gobba
Abdalkareem Omar Maghmomeh
Ahmed E. Khodir
Ahmed A. E. Mourad
Ahmed S. Saad
Hager G. Mohammed
Nehal A. Nouh
Ahmed Shata
Noha A. Amin
Magdy Abou El-Rous
Samuel Girgis
Eman El-Ahwany
Eman M. Khalaf
Attalla F. El-Kott
Ahmed M. El-Baz
A Novel Combination Therapy Using Rosuvastatin and <i>Lactobacillus</i> Combats Dextran Sodium Sulfate-Induced Colitis in High-Fat Diet-Fed Rats by Targeting the TXNIP/NLRP3 Interaction and Influencing Gut Microbiome Composition
Pharmaceuticals
ulcerative colitis
NLRP3 inflammasome
rosuvastatin
<i>Lactobacillus</i>
gut microbiome
TXNIP
title A Novel Combination Therapy Using Rosuvastatin and <i>Lactobacillus</i> Combats Dextran Sodium Sulfate-Induced Colitis in High-Fat Diet-Fed Rats by Targeting the TXNIP/NLRP3 Interaction and Influencing Gut Microbiome Composition
title_full A Novel Combination Therapy Using Rosuvastatin and <i>Lactobacillus</i> Combats Dextran Sodium Sulfate-Induced Colitis in High-Fat Diet-Fed Rats by Targeting the TXNIP/NLRP3 Interaction and Influencing Gut Microbiome Composition
title_fullStr A Novel Combination Therapy Using Rosuvastatin and <i>Lactobacillus</i> Combats Dextran Sodium Sulfate-Induced Colitis in High-Fat Diet-Fed Rats by Targeting the TXNIP/NLRP3 Interaction and Influencing Gut Microbiome Composition
title_full_unstemmed A Novel Combination Therapy Using Rosuvastatin and <i>Lactobacillus</i> Combats Dextran Sodium Sulfate-Induced Colitis in High-Fat Diet-Fed Rats by Targeting the TXNIP/NLRP3 Interaction and Influencing Gut Microbiome Composition
title_short A Novel Combination Therapy Using Rosuvastatin and <i>Lactobacillus</i> Combats Dextran Sodium Sulfate-Induced Colitis in High-Fat Diet-Fed Rats by Targeting the TXNIP/NLRP3 Interaction and Influencing Gut Microbiome Composition
title_sort novel combination therapy using rosuvastatin and i lactobacillus i combats dextran sodium sulfate induced colitis in high fat diet fed rats by targeting the txnip nlrp3 interaction and influencing gut microbiome composition
topic ulcerative colitis
NLRP3 inflammasome
rosuvastatin
<i>Lactobacillus</i>
gut microbiome
TXNIP
url https://www.mdpi.com/1424-8247/14/4/341
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