2. Academic Validation
  3. (R,R)-BD-AcAc2 Mitigates Chronic Colitis in Rats: A Promising Multi-Pronged Approach Modulating Inflammasome Activity, Autophagy, and Pyroptosis

(R,R)-BD-AcAc2 Mitigates Chronic Colitis in Rats: A Promising Multi-Pronged Approach Modulating Inflammasome Activity, Autophagy, and Pyroptosis

  • Pharmaceuticals (Basel). 2023 Jul 3;16(7):953. doi: 10.3390/ph16070953.
Sameh Saber 1,  Mohannad Mohammad S Alamri 2,  Jaber Alfaifi 3,  Lobna A Saleh 4,  Sameh Abdel-Ghany 5,  Adel Mohamed Aboregela 6 7,  Alshaimaa A Farrag 8 9,  Abdulrahman H Almaeen 10,  Masoud I E Adam 11,  AbdulElah Al Jarallah AlQahtani 12,  Ali M S Eleragi 13,  Mustafa Ahmed Abdel-Reheim 14 15,  Heba A Ramadan 16,  Osama A Mohammed 4 17
Affiliations

Affiliations

  • 1 Department of Pharmacology, Faculty of Pharmacy, Delta University for Science and Technology, Gamasa 11152, Egypt.
  • 2 Department of Family Medicine, College of Medicine, University of Bisha, Bisha 61922, Saudi Arabia.
  • 3 Department of Child Health, College of Medicine, University of Bisha, Bisha 61922, Saudi Arabia.
  • 4 Department of Clinical Pharmacology, Faculty of Medicine, Ain Shams University, Cairo 11566, Egypt.
  • 5 Department of Clinical Pharmacology, Faculty of Medicine, Mansoura University, Mansoura 35516, Egypt.
  • 6 Human Anatomy and Embryology Department, Faculty of Medicine, Zagazig University, Zagazig 44519, Egypt.
  • 7 Basic Medical Sciences Department, College of Medicine, University of Bisha, Bisha 61922, Saudi Arabia.
  • 8 Department of Histology and Cell Biology, Faculty of Medicine, Assiut University, Assiut 71515, Egypt.
  • 9 Department of Anatomy, College of Medicine, University of Bisha, Bisha 61922, Saudi Arabia.
  • 10 Department of Pathology, College of Medicine, Jouf University, Sakaka 72388, Saudi Arabia.
  • 11 Department of Medical Education and Internal Medicine, College of Medicine, University of Bisha, Bisha 61922, Saudi Arabia.
  • 12 Department of Internal Medicine, Division of Dermatology, College of Medicine, University of Bisha, Bisha 61922, Saudi Arabia.
  • 13 Department of Microbiology, College of Medicine, University of Bisha, Bisha 61922, Saudi Arabia.
  • 14 Department of Pharmaceutical Sciences, College of Pharmacy, Shaqra University, Shaqra 11961, Saudi Arabia.
  • 15 Department of Pharmacology and Toxicology, Faculty of Pharmacy, Beni-Suef University, Beni Suef 62521, Egypt.
  • 16 Department of Microbiology and Immunology, Faculty of Pharmacy, Delta University for Science and Technology, Gamasa 11152, Egypt.
  • 17 Department of Clinical Pharmacology, College of Medicine, University of Bisha, Bisha 61922, Saudi Arabia.
PMID: 37513865 DOI: 10.3390/ph16070953
Abstract

Ulcerative colitis is a chronic and incurable form of inflammatory bowel disease that can increase the risk of colitis-associated Cancer and mortality. Limited treatment options are available for this condition, and the existing ones often come with non-tolerable adverse effects. This study is the first to examine the potential benefits of consuming (R,R)-BD-AcAc2, a type of ketone ester (KE), and intermittent fasting in treating chronic colitis induced by dextran sodium sulfate (DSS) in rats. We selected both protocols to enhance the levels of β-hydroxybutyrate, mimicking a state of nutritional ketosis and early ketosis, respectively. Our findings revealed that only the former protocol, consuming the KE, improved disease activity and the macroscopic and microscopic features of the colon while reducing inflammation scores. Additionally, the KE counteracted the DSS-induced decrease in the percentage of weight change, reduced the colonic weight-to-length ratio, and increased the survival rate of DSS-insulted rats. KE also showed potential antioxidant activities and improved the gut microbiome composition. Moreover, consuming KE increased the levels of tight junction proteins that protect against leaky gut and exhibited anti-inflammatory properties by reducing proinflammatory cytokine production. These effects were attributed to inhibiting NFκB and NLRP3 inflammasome activation and restraining Pyroptosis and Apoptosis while enhancing Autophagy as revealed by reduced p62 and increased BECN1. Furthermore, the KE may have a positive impact on maintaining a healthy microbiome. To conclude, the potential clinical implications of our findings are promising, as (R,R)-BD-AcAc2 has a greater safety profile and can be easily translated to human subjects.

Keywords

(R,R)-BD-AcAc2; NLRP3 inflammasome; autophagy; gut dysbiosis; ketone esters; pyroptosis; ulcerative colitis.

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