Tracking the therapeutic efficacy of a ketone mono ester and β-hydroxybutyrate for ulcerative colitis in rats: New perspectives

Osama A Mohammed; Sameh Saber; Mustafa Ahmed Abdel-Reheim; Mohannad Mohammad S Alamri; Jaber Alfaifi; Masoud I E Adam; Muffarah Hamid Alharthi; Ali M S Eleragi; Hanan B Eltahir; Mohamed Osama Abdalla; Emad Bahashwan; Elwathiq Khalid Ibrahim; Assad Ali Rezigalla; Sameh Abdel-Ghany; Amany A Alzokaky; Ahmed S Doghish; Hussein M El-Husseiny; Mushabab Alghamdi; Mahmoud E Youssef

doi:10.1016/j.taap.2024.116943

Tracking the therapeutic efficacy of a ketone mono ester and β-hydroxybutyrate for ulcerative colitis in rats: New perspectives

Toxicol Appl Pharmacol. 2024 Apr 26:486:116943. doi: 10.1016/j.taap.2024.116943. Online ahead of print.

Authors

Osama A Mohammed¹, Sameh Saber², Mustafa Ahmed Abdel-Reheim³, Mohannad Mohammad S Alamri⁴, Jaber Alfaifi⁵, Masoud I E Adam⁶, Muffarah Hamid Alharthi⁴, Ali M S Eleragi⁷, Hanan B Eltahir⁸, Mohamed Osama Abdalla⁹, Emad Bahashwan¹⁰, Elwathiq Khalid Ibrahim¹¹, Assad Ali Rezigalla¹¹, Sameh Abdel-Ghany¹², Amany A Alzokaky¹³, Ahmed S Doghish¹⁴, Hussein M El-Husseiny¹⁵, Mushabab Alghamdi¹⁶, Mahmoud E Youssef¹⁷

Affiliations

¹ Department of Pharmacology, College of Medicine, University of Bisha, Bisha 61922, Saudi Arabia.
² Department of Pharmacology, Faculty of Pharmacy, Delta University for Science and Technology, Gamasa 11152, Egypt. Electronic address: sameh.saber@deltauniv.edu.eg.
³ Department of Pharmaceutical Sciences, College of Pharmacy, Shaqra University, Shaqra 11961, Saudi Arabia; Department of Pharmacology and Toxicology, Faculty of Pharmacy, Beni-Suef University, Beni Suef 62521, Egypt. Electronic address: m.ahmed@su.edu.sa.
⁴ Department of Family and Community Medicine, College of Medicine, University of Bisha, Bisha 61922, Saudi Arabia.
⁵ Department of Child Health, College of Medicine, University of Bisha, Bisha 61922, Saudi Arabia.
⁶ Department of Medical Education and Internal Medicine, College of Medicine, University of Bisha, Bisha 61922, Saudi Arabia.
⁷ Department of Microorganisms and Clinical Parasitology, University of Bisha, Bisha 61922, Saudi Arabia.
⁸ Department of Clinical Biochemistry, College of Medicine, University of Bisha, Bisha 61922, Saudi Arabia.
⁹ Department of Clinical Pathology, Faculty of Medicine, Suez Canal University, Ismailia 41522, Egypt.
¹⁰ Department of Internal Medicine, Division of Dermatology, College of Medicine, University of Bisha, Bisha 61922, Saudi Arabia.
¹¹ Department of Anatomy, College of Medicine, University of Bisha, Bisha 61922, Saudi Arabia.
¹² Department of Clinical Pharmacology, Faculty of Medicine, Mansoura University, Mansoura 35516, Egypt; Department of basic medical sciences, Ibn Sina University for Medical Sciences, Amman 16197, Jordan.
¹³ Pharmacology and Toxicology Department, Faculty of Pharmacy (Girls), Al-Azhar University, Cairo 11754, Egypt; Department of Pharmacology and Biochemistry, Faculty of Pharmacy, Horus University, New Damietta 34518, Egypt.
¹⁴ Department of Biochemistry, Faculty of Pharmacy, Badr University in Cairo (BUC), Cairo 11829, Egypt; Department of Biochemistry and Molecular Biology, Faculty of Pharmacy (Boys), Al-Azhar University, Cairo 11231, Egypt. Electronic address: ahmed.soliman2@buc.edu.eg.
¹⁵ Cooperative Department of Veterinary Medicine, Faculty of Agriculture, Tokyo University of Agriculture and Technology, 3-5-8 Saiwai Cho, Fuchu-shi, Tokyo 183-8509, Japan; Department of Surgery, Anesthesiology, and Radiology, Faculty of Veterinary Medicine, Benha University, Al Qalyubia 13736, Egypt.
¹⁶ Department of Internal Medicine, Division of Rheumatology, College of Medicine, University of Bisha, Bisha 61922, Saudi Arabia.
¹⁷ Department of Pharmacology, Faculty of Pharmacy, Delta University for Science and Technology, Gamasa 11152, Egypt.

PMID: 38677600
DOI: 10.1016/j.taap.2024.116943

Abstract

Ulcerative colitis (UC) is an inflammatory condition that affects the colon's lining and increases the risk of colon cancer. Despite ongoing research, there is no identified cure for UC. The recognition of NLRP3 inflammasome activation in the pathogenesis of UC has gained widespread acceptance. Notably, the ketone body β-hydroxybutyrate inhibits NLRP3 demonstrating its anti-inflammatory properties. Additionally, BD-AcAc 2 is ketone mono ester that increases β-hydroxybutyrate blood levels. It has the potential to address the constraints associated with exogenous β-hydroxybutyrate as a therapeutic agent, including issues related to stability and short duration of action. However, the effects of β-hydroxybutyrate and BD-AcAc 2 on colitis have not been fully investigated. This study found that while both exogenous β-hydroxybutyrate and BD-AcAc 2 produced the same levels of plasma β-hydroxybutyrate, BD-AcAc 2 demonstrated superior effectiveness in mitigating dextran sodium sulfate-induced UC in rats. The mechanism of action involves modulating the NF-κB signaling, inhibiting the NLRP3 inflammasome, regulating antioxidant capacity, controlling tight junction protein expression and a potential to inhibit apoptosis and pyroptosis. Certainly, BD-AcAc 2's anti-inflammatory effects require more than just increasing plasma β-hydroxybutyrate levels and other factors contribute to its efficacy. Local ketone concentrations in the gastrointestinal tract, as well as the combined effect of specific ketone bodies, are likely to have contributed to the stronger protective effect observed with ketone mono ester ingestion in our experiment. As a result, further investigations are necessary to fully understand the mechanisms of BD-AcAc 2 and optimize its use.

Keywords: Apoptosis/pyroptosis; BD-AcAc 2 ketone mono ester; NF-κB/NLRP3; Ulcerative colitis; β-hydroxybutyrate.