article · Frontiers in Pharmacology
Exogenous beta-hydroxybutyrate and a ketogenic diet alleviate dextran sodium sulfate-induced ulcerative colitis in rats. Both interventions reduce overall disease activity, improve the colon weight-to-length ratio, and restore damaged intestinal structures. At the molecular level, these regimens suppress aberrant NLRP3 inflammasome activation and inhibit pyroptosis mediated by NLRP3 and NGSDMD. They also reduce caspase-1 activity and associated inflammatory cytokines, whilst mitigating apoptosis through the inactivation of caspase-3. In addition to curbing markers such as NF-kB, IL-6, and TNF-alpha, both treatments demonstrate antioxidant effects by decreasing reactive oxygen species and boosting protective enzymes. Epithelial barrier integrity is renovated through the correction of tight junction proteins. Exogenous beta-hydroxybutyrate further modulates autophagy via the upregulation of BECN-1 and downregulation of p62, which may explain its superior effectiveness over the ketogenic diet.
Ulcerative colitis is an increasingly common and debilitating inflammatory condition affecting the lower bowel. Demonstrating that a ketone body or a ketogenic diet can resolve inflammation, restore the intestinal epithelial barrier, and prevent cell death provides valuable biological insights. These findings establish a foundation for examining whether metabolic and nutritional strategies could eventually help manage chronic relapsing gut disorders.
The findings highlight early-stage opportunities for developing ketone-based therapeutics or specialised medical nutrition products for inflammatory bowel diseases. Potential users include pharmaceutical developers and clinical nutrition companies formulating metabolic adjunct therapies. Because the evidence is derived entirely from an animal model, the concept remains at a preclinical stage and is distant from real-world clinical application until human safety and efficacy trials are conducted.
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Ulcerative colitis (UC) is a chronic relapsing inflammatory disease of the colorectal area that demonstrates a dramatically increasing incidence worldwide. This study provides novel insights into the capacity of the exogenous β-hydroxybutyrate and ketogenic diet (KD) consumption to alleviate dextran sodium sulfate (DSS)-induced UC in rats. Remarkably, both interventions attenuated disease activity and colon weight-to-length ratio, and improved macro and microstructures of the damaged colon. Importantly, both β-hydroxybutyrate and KD curbed the DSS-induced aberrant NLRP3 inflammasome activation as observed in mRNA and protein expression analysis. Additionally, inhibition of the NLRP3/NGSDMD-mediated pyroptosis was detected in response to both regimens. In parallel, these modalities attenuated caspase-1 and its associated consequences of IL-1β and IL-18 overproduction. They also mitigated apoptosis as indicated by the inactivation of caspase-3. The anti-inflammatory effects of BHB and KD were confirmed by the reported decline in the levels of inflammatory markers including MPO, NFκB, IL-6, and TNF-α. Moreover, these interventions exhibited antioxidative properties by reducing ROS production and improving antioxidative enzymes. Their effectiveness in mitigating UC was also evident in the renovation of normal intestinal epithelial barrier function, as shown by correcting the discrepancies in the levels of tight junction proteins ZO-1, OCLN, and CLDN5. Furthermore, their effects on the intestinal microbiota homeostasis were investigated. In terms of autophagy, exogenous β-hydroxybutyrate upregulated BECN-1 and downregulated p62, which may account for its superiority over KD in attenuating colonic damage. In conclusion, this study provides experimental evidence supporting the potential therapeutic use of β-hydroxybutyrate or β-hydroxybutyrate-boosting regimens in UC.
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DOI: 10.3389/fphar.2023.1239025
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