Metabolic and gut microbiota effects of ketogenic diet and exogenous ketone salts in a rat model of metabolic syndrome.

PURPOSE: Metabolic syndrome (MetS) represents a significant public health challenge, with emerging evidence pointing to gut microbiota as a key player in its development and progression. This study explored the comparative effects of ketogenic diet (KD) and ketone salts supplementation (KS) on metabolic dysfunction and gut microbiota composition in ZSF1 obese rats, an established MetS rat model.

METHODS

ZSF1 obese and lean rats were allocated to a control diet, a ketogenic diet or ketone salts supplementation. Metabolic assessments and 16 S rRNA V4 region sequencing (Illumina Miseq) were performed to evaluate glucose metabolism and gut microbiota composition.

RESULTS

Our validation confirmed the MetS phenotype in this model, including increased body weight and adiposity, which were further amplified in rats receiving the ad libitum KD. Although both KD and KS effectively reduced fasting glucose levels, the KD, contrary to its typical weight-reducing effect in humans, significantly increased body weight and mesenteric fat, whereas KS did not alter adiposity relative to the control diet. Both interventions profoundly impacted the gut microbiota profile; KD reduced microbial richness and shifted community composition (including a lower Bacillota/Bacteroidota ratio and higher Akkermansia levels). In contrast, the intervention with KS resulted in a gut microbiota profile resembling the control rats fed with the control diet.

CONCLUSION

These results highlight the distinct effects of different ketogenic interventions (KD and KS) on host metabolism and gut microbiome, suggesting that while both can influence glucose control, KS may offer a more favorable metabolic and microbiota profile for managing MetS, without the strict dietary adherence required by KD.