Abstract
The benefits of ketone production regimens remain controversial. Here, we hypothesized that the ketone-producing regimens modulated cognitive impairment, glucose metabolism, and inflammation while altering the gut microbiome. The hypothesis and the mechanism were explored in amyloid-β infused rats. Rats that received an amyloid-β(25-35) infusion into the hippocampus had either ketogenic diet (AD-KD), intermittent fasting (AD-IMF), 30 energy percent fat diet (AD-CON), or high carbohydrate (starch) diet (AD-CHO) for 8 weeks. AD-IMF and AD-CHO, but not AD-KD, lowered the hippocampal amyloid-β deposition compared to the AD-CON despite serum ketone concentrations being elevated in both AD-KD and AD-IMF. AD-IMF and AD-CHO, but not AD-KD, improved memory function in passive avoidance, Y maze, and water maze tests compared to the AD-CON. Hippocampal insulin signaling (pAkt→pGSK-3β) was potentiated and pTau was attenuated in AD-IMF and AD-CHO much more than AD-CON. AD-IMF and AD-CON had similar glucose tolerance results during OGTT, but AD-KD and AD-IMF exhibited glucose intolerance. AD-KD exacerbated gut dysbiosis by increasing Proteobacteria, and AD-CHO improved it by elevating Bacteriodetes. In conclusion, ketone production itself might not improve memory function, insulin resistance, neuroinflammation or the gut microbiome when induced by ketone-producing remedies. Intermittent fasting and a high carbohydrate diet containing high starch may be beneficial for people with dementia.