Beta-Hydroxybutyrate: A Dual Function Molecular and Immunological Barrier Function Regulator

Abstract

Ketone bodies are crucial intermediate metabolites widely associated with treating metabolic diseases. Accumulating evidence suggests that ketone bodies may act as immunoregulators in humans and animals to attenuate pathological inflammation through multiple strategies. Although the clues are scattered and untrimmed, the elevation of these ketone bodies in the circulation system and tissues induced by ketogenic diets was reported to affect the immunological barriers, an important part of innate immunity. Therefore, beta-hydroxybutyrate, a key ketone body, might also play a vital role in regulating the barrier immune systems. In this review, we retrospected the endogenous ketogenesis in animals and the dual roles of ketone bodies as energy carriers and signal molecules focusing on beta-hydroxybutyrate. In addition, the research regarding the effects of beta-hydroxybutyrate on the function of the immunological barrier, mainly on the microbiota, chemical, and physical barriers of the mucosa, were outlined and discussed. As an inducible endogenous metabolic small molecule, beta-hydroxybutyrate deserves delicate investigations focusing on its immunometabolic efficacy. Comprehending the connection between ketone bodies and the barrier immunological function and its underlining mechanisms may help exploit individualised approaches to treat various mucosa or skin-related diseases.

Short chain fatty acids prime colorectal cancer cells to activate antitumor immunity

“…We did not detect differential gene expression of these between our MSI OVA and CIN OVA CRC variants either at baseline or upon treatment of the cells ( Figure 1C ). To functionally examine the role of the receptors in CD8+ T cell activation, we repeated the stimulation above following pretreatment of the CRC cells with the GPR41 blocking agent beta-hydroxybutyrate (BHB) ( 36 – 38 ). This significantly suppressed OTI T cell activation by the treated CRCs, indicating that butyrate and propionate increase the immunogenicity of CRC cells via a GPR-dependent mechanism ( Figure 1D ).…”

“…Central to resolving this complex picture is undoubtedly to better understand the mechanisms by which SCFAs such as butyrate and propionate mediate their immune-regulating effects directly on the CRCs. While we have used BHB to show that the main butyrate and propionate receptors contribute to the process, BHB exerts many other effects on cells besides GPR41 inhibition ( 36 ). In the absence of more specific inhibitors for the highly homologous SCFA receptors, it is difficult to show conclusively that signaling via these receptors directly induces DNA damage and drives the first step in the feedback loop ( 35 , 69 ).…”

Supplementation with medium-chain fatty acids increases body weight loss during very low-calorie ketogenic diet: a retrospective analysis in a real-life setting

“…Indeed, VLCKD has shown to reduce inflammation through several mechanisms, i.e.by inhibiting activation of the nuclear factor kappa-light-chain-enhancer of activated B cells, and the inflammatory nucleotide-binding, leucine-rich-containing family, pyrin domain-containing-3, and inhibiting histone deacetylases [ 56 ]. Notably, the earlyMCTs group experienced the greatest reduction as compared to the other groups, likely due to the overflow of ketone bodies [ 57 ]. Unfortunately, we did not perform a quantitative measurement of ketone bodies and we were not able to test this hypothesis.…”

Free triiodothyronine levels and age influences the metabolic profile and COVID-19 severity parameters in euthyroid and levothyroxine-treated patients

“…However, acetone and 3-hydroxybutyrate, two ketogenic metabolites, showed a negative correlation with FT3 levels and also with age in non-critical hospitalized patients, but showed a positive correlation with FT3 levels not associated with age, in critical patients. The ketone bodies, acetoacetate, and , a spontaneous breakdown product of acetoacetate, are products of the fatty acid metabolism serving during states of energy deficit as an alternative source of ATP ( 45 ), which is required for a proper activation of the host immune response ( 46 ). 3-Hydroxybutyrate is generated in different scenarios such as low food intake ( ), , and prolonged intense ( 11 , 47 ).…”