Animals : an Open Access Journal from MDPI · 4 authors, 2 centres
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This study in 32 dogs found that dietary betaine and L-carnitine, especially in combination, altered the blood metabolome and modulated immune cell cytokine release: reducing unstimulated cytokine levels while enhancing the response to LPS stimulation. The findings suggest that combined betaine and L-carnitine supplementation may support healthy immune function by lowering basal inflammation and improving pathogen defense.
**Background:** Betaine and L-carnitine are dietary components with independent effects on metabolism and immune function. Betaine acts as a methyl donor in one-carbon metabolism and as an osmolyte, while L-carnitine is involved in fatty acid oxidation and has antioxidant properties. Both have been shown to modulate inflammatory cytokines in various cell types. This study aimed to evaluate their independent and combined effects on the metabolome and immune response in dogs, hypothesizing that they would provide immune system support.
**Methods:** Thirty-two healthy adult dogs (7 beagles and 1 mixed-breed per group) were assigned to one of four foods for 90 days: control (no added betaine or L-carnitine), control + 0.5% betaine, control + 300 ppm L-carnitine, or control + 0.5% betaine + 300 ppm L-carnitine. Blood samples were collected at day 0 and day 90. Untargeted metabolomic analysis (723 plasma metabolites) was performed by Metabolon. Immune function was assessed ex vivo using the TruCulture system: whole blood was incubated with or without lipopolysaccharide (LPS) for 24 hours, and the supernatant was analyzed for cytokines (IL-6, IL-7, IL-8, IL-10, IL-15, TNF-α, MCP-1) using a multiplex ELISA. The sum of molar concentrations of these cytokines was used as the response variable. Statistical analysis used mixed models with betaine, carnitine, time, and LPS stimulation as fixed effects; p < 0.05 was considered significant.
**Key Results:** Metabolomics: Compared to control, betaine alone changed 84 metabolites, carnitine alone changed 63, and the combination changed 26 (p < 0.05, q < 0.1). Betaine increased one-carbon metabolites (e.g., methionine fold change 7.13, S-adenosylhomocysteine 3.76, dimethylglycine 2.49) and decreased many carnitine-containing compounds (e.g., acetylcarnitine 0.52, propionylcarnitine 0.65). Carnitine alone increased many carnitine metabolites (e.g., propionylcarnitine 1.78, isovalerylcarnitine 1.79). The combination maintained increased one-carbon metabolites and normalized most carnitine metabolites to control levels. Taurine increased in all treatment groups (fold changes 1.30–1.40).
There was a significant three-way interaction between betaine, carnitine, time, and LPS stimulation (p < 0.01). In unstimulated cells, the betaine + carnitine group showed a decrease in cytokine release (LSMean change −0.31 ± 0.13) compared to control (0.00 ± 0.13) and carnitine alone (0.04 ± 0.13). In LPS-stimulated cells, the betaine + carnitine group showed an increase (0.13 ± 0.09) versus control (−0.07 ± 0.09). The ratio (stimulated minus unstimulated) was significantly higher for the combination (0.44 ± 0.14) than control (−0.07 ± 0.14) and carnitine alone (0.00 ± 0.14).
**Clinical Implications:** The combination of dietary betaine and L-carnitine produced a dual beneficial effect on immune function: reducing basal cytokine release (suggesting lower chronic inflammation) while enhancing the cytokine response to bacterial stimulation (indicating improved pathogen defense). These changes were associated with alterations in one-carbon metabolism, carnitine trafficking, and increases in taurine, methionine, serine, and choline. The findings suggest that combined betaine and L-carnitine supplementation may help attenuate immunosenescence and support healthy aging in dogs by modulating inflammation and immune responsiveness. Further research is needed to explore effects on specific immune cell subsets and in disease models.