FIGURE 2.

Impact of ketogenic diet ameliorating abnormalities in microbiome-gut-brain axis. The figure illustrates the effect of the ketogenic diet (KD) on alleviating brain injury and modulating the microbiome. With ischemic and traumatic acute brain injury, the energetic demands of the brain are compromised due to injury-provoked low cerebral blood flow and hence glucose supply to the brain- leading to lower production of ATP, exacerbation of brain parenchymal damage and propagating neuroinflammation, including microglial macrophage-like activity and cytokine (i.e., IL-1β, IL-6, TNF) release. Also depicted in the injured brain state is a baseline number of monocarboxylic acid transporters (MCTs) on the blood brain barrier (BBB), receptors that determine cerebral uptake of ketone bodies (KB). When KD is ingested and converted to its component ketone bodies (KB) through liver metabolism, the KBs lead to changes in the brain as well as the gut microbiome. In the microbiome, several studies note beneficial changes in taxa in both animal and human models, including a decrease in Proteobacteria (Medel-Matus et al., 2018), Actinobacteria (De Caro et al., 2019; Zilberter and Zilberter, 2020), and a rise in SCFA levels (Nagpal et al., 2019). In the brain, with increases of systemic KB supply, there is increase of synthesis of MCT receptors on the BBB, leading to enhanced cerebral uptake of KBs. KBs have been proposed to act as efficient alternative cerebral fuel, reinstating the energetic demands of the brain by increasing ATP production, as well as mitigating neuroinflammation by decreasing the pro-inflammatory activation of NLRP3 Inflammasome, and decreasing microglial activation and cytokine and chemokine release. There is growing evidence that KB has the potential of improving the injured and diseased brain states.