Unveiling the therapeutic potential of exogenous β-hydroxybutyrate for chronic colitis in rats: novel insights on autophagy, apoptosis, and pyroptosis

Abstract

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.

Ketogenic Diet Protects from Experimental Colitis in a Mouse Model Regardless of Dietary Fat Source

“…KDs, especially LA-KD, protected the mice from these changes. This is in line with the findings of Kong et al [10] and Abdelhady et al [9] who reported less inflammatory cell infiltration in DSS-treated rodents fed KDs with unknown fat sources. On the other hand, Li et al [11] showed LA-rich KD to promote immune cell infiltration and epithelial damage in DSS colitis.…”

“…Overall, our results align with the observations of Kong et al [10] who reported KD to alleviate DSS-induced colitis via microbiota-dependent reduction in colonic group 3 innate lymphoid cells, and Abdelhady et al [9] who observed benefits associated with NLRP3 inflammasome inhibition, decreased apoptosis, and increased autophagy. Thus, our findings contradict those of Li et al [11] who reported KD to worsen outcomes in the same model of colitis.…”

“…In our previous research, BHB levels were not different between healthy mice on SFA-KD or LA-KD [14], whereas in the present study, we saw significantly higher plasma concentrations in DSS-LA-KD than in DSS-SFA-KD. BHB administered either orally [9,25] or rectally [26] has been reported to alleviate DSS-induced colitis, and it is possible that, in our setting, the greater protective effect from LA-KD is partly a result of higher BHB availability. However, in these studies, plasma BHB levels were not reported, and it is unclear whether the magnitude of the difference in our study is large enough to produce a physiologically meaningful effect.…”

“…KD has shown efficacy in preclinical models of intestinal diseases. In experimental settings, the diet can protect from colon cancer [7], improve irritable bowel syndrome [8], and ameliorate dextran sodium sulfate (DSS)-induced colonic inflammation [9,10]. However, the results are not entirely uniform.…”