Ketogenic Diet Mechanisms of Action
The ketogenic diet is best known as a high-fat, low-carbohydrate diet commonly used to treat drug-resistant epilepsy in children. Despite a ketogenic diet therapy’s ability to suppress refractory epilepsies for over a century, the underlying mechanisms of the ketogenic diet remain enigmatic. While the exact ketogenic diet mechanisms of action are not yet known, several hypotheses have been proposed to explain its anticonvulsant effects.
Keywords: Epilepsy, ketogenic diet, metabolic hypotheses, gut microbiome hypothesis.
1. Introduction
The ketogenic diet is a high-fat, low-carbohydrate diet used to treat drug-resistant epilepsy, particularly in children. The Ketogenic diet was first formulated in the early 1920s, falling out of favor following the invention of phenytoin in 1938. However, renewed interest surged in the 1990s when it became evident that the diet could control seizures resistant to anticonvulsant drugs [1].
Since the early 1920s, several hypotheses have been proposed to explain the anticonvulsant effects of the ketogenic diet. The pH hypothesis, metabolic hypotheses, amino acid hypotheses (including the GABA shunt hypothesis), ketone hypotheses, caloric restriction hypothesis, brain lipids hypothesis, gut microbiome hypothesis, and noradrenaline hypothesis are among these [2].
This article discusses variations of the metabolic hypotheses, and the gut microbiome hypothesis.
2. Metabolic Hypotheses
The “metabolic” hypotheses posit that the ketogenic diet mechanisms of action causes the brain to switch from a glucose-based to a ketone-based metabolism which produces the anticonvulsant effects.
INCREASED BRAIN ENERGY
DeVivo was possibly the first researcher to propose a “metabolic” hypothesis (i.e., Appleton and DeVivo [3] and Nordi and DeVivo[4]). He hypothesized that the ketogenic diet provided additional energy to the brain.
DeVivo noted that ketone bodies are a more efficient energy source than glucose because they generate more ATP per unit [3,5]. Thus, an individual following a ketogenic diet would have more readily available energy in the form of ATP. It was suggested that this increase in available energy would have anticonvulsant effects [5]. The corollary of this hypothesis is that the epileptic brain is deficient in energy. DeVivo suggests that this deficiency causes seizures [5]. However, this still needs to be determined.
It should also be considered that the metabolic shift in patients on a ketogenic diet is incomplete. Patients on a ketogenic diet still have glucose in their blood, typically in the low normal range [6, 7]. Presumably, this glucose is entering the brain and providing energy. Even after several weeks of complete starvation, only about 60 percent of the brain’s energy supply comes from fats [8].
INCREASE IN THE NUMBER OF MITOCHONDRIA
A recent report that supports the DeVivo hypothesis relates to the mitochondrial effects of the ketogenic diet. According to Bough et al.[9], rats on a ketogenic diet produce more mitochondria than rats on standard rodent food. Presumably, more mitochondria would result in more energy for the brain and, consequently, reduce the frequency of seizures.
However, data is unclear whether an epileptic brain is energy deficient or that increased energy would reduce excitability.
“FAST” ENERGY
The availability of “fast” energy is the subject of a very different metabolic hypothesis. To simplify a rather complex argument, the essence of this hypothesis is that glucose is required to provide the “fast” energy required for seizure activity and that seizures cannot occur without glucose [10,11].
The concept behind this hypothesis is that the glucose levels in people with a standard diet generate “fast” energy through glycolysis and “slow” energy via the Krebs cycle. Seizures requiring “fast” energy can occur in patients who are not on a diet because glucose is readily available. However, ketone bodies (present in ketogenic diet individuals) do not undergo glycolysis. Consequently, they can only produce “slow” energy through the Krebs cycle. This hypothesis suggests that this is the reason why the ketogenic diet is anticonvulsant.
It should be noted that in this hypothesis, decreased glucose levels are believed to correlate with increased ketone body levels. Therefore, this hypothesis is consistent with the ketone hypotheses discussed below.
Several recent studies support the notion that decreasing glucose metabolism has anticonvulsant properties. In clinical studies, a diet consisting of foods that produce little increase in blood glucose levels has anticonvulsant effects, despite increasing ketone bodies and limiting glucose [12].
However, there are some significant shortcomings of this hypothesis. For example, both fructose-1,6-bisphosphate and 2-deoxyglucose have demonstrated anticonvulsant effects in acute animal seizure models [13], and 2-deoxyglucose has been shown to increase seizure thresholds and slow the rate of seizure development in newly-infected rats [14]. This hypothesis also is limited in its ability to account for the fact that normal glucose levels are low in patients on other non-ketogenic diets [15, 16 ], as well as the fact that hypoglycemia is also a known cause of seizures.
3. Gut Microbiome Hypothesis
The dysregulation of the gut-brain axis has been linked to neurological disorders, including depression, anxiety [17], schizophrenia [18], Alzheimer’s disease, [19] autism [20], and Parkinson’s disease [21]. However, research into the relationship between dysbiosis and epilepsy has been limited, focusing primarily on the microbiome as a target for the ketogenic diet [22,23].
While the precise mechanism by which a ketogenic diet contributes to reduced seizure activity is unknown, animal studies have implicated the gut microbiota composition and functions, in the seizure-reducing effects of a ketogenic diet. [24, 25].
Although the nature of gut microbiome disturbances suggests their relevance to the epileptic process, it has not been thoroughly investigated whether gut microbiome disturbances can be linked directly to epilepsy. Examples include dysregulation of bioactive peptides relevant to epilepsy (such as galanin and neuropeptide Y) [ 26, 27], vagal afferents [28] (which may provide a link to the anticonvulsant effects of vagus nerve stimulation), inflammation [29], and the stress hormone axis [30].
Recent studies on animals indicate that transplanting feces from stressed animals to naive animals worsens the duration and severity of epileptic seizures. However, when fecal material from naive animals was transplanted into stressed animals, the proepileptic effects of stress were effectively counteracted. This data indicates that the gut microbiota plays a much more crucial role as a potential mechanism of action than was previously understood [25].
Stress induces intricate alterations in the intestinal microbiota (e.g., increased or decreased Bacteroides, increased Clostridiales, and decreased Bifidobacterium and Lactobacillales) [31, 32, 33]. In addition, stress increases intestinal permeability, which permits a microbiota-driven proinflammatory state with implications for neuroinflammation, such as activation of circulating and brain inflammatory cytokines, microglia, and increased blood-brain barrier permeability [34]. Moreover, inflammation’s proepileptic properties have been well established.
Additional mouse studies [24, 35, 36] shed light on how the gut microbiota contributes to the anticonvulsant effects of a ketogenic diet. Compared to the control group, mice fed a ketogenic diet were less susceptible to seizures. After a course of broad-spectrum antibiotics, however, the protective effects of the ketogenic diet diminished.
In addition, the authors discovered that a ketogenic diet decreased alpha diversity overall while increasing the relative abundance of Akkermansia muciniphila. This is noteworthy because reduced alpha diversity is generally associated with worsened metabolic outcomes [37]. In contrast, a relatively higher abundance of A. muciniphila, a known producer of short-chain fatty acids, is associated with improved metabolic health [38, 39].
Short-chain fatty acids are metabolites of the gut microbiota that contribute to metabolic health. Propionate, acetate, and butyrate are the most studied short-chain fatty acids; however, they are primarily produced by the fermentation of fiber by bacterium [40, 41]. Short-chain fatty acids are frequently associated with improved metabolic health and play a crucial role in the gut–brain axis [40, 41].
While these microbiome studies are necessary to objectively confirm specific changes from stress and microbiome transplants from a mechanistic perspective, they need to be more comprehensive to provide a complete explanation of the ketogenic diet mechanisms of action, however compelling.
4. Discussion
Of the hypotheses discussed, the gut microbiota likely plays a more significant role in the ketogenic diet mechanism of action than previously recognized. More research is certainly warranted to elucidate these relationships fully.
5. Ketogenic Diet Mechanisms of Action Summary
•The ketogenic diet is a high-fat, low-carbohydrate diet used to treat drug-resistant epilepsy in children.
• Several hypotheses have been proposed to explain the ketogenic diet mechanisms of action, including metabolic hypotheses (increased brain energy and increased number of mitochondria), amino acid hypothesis (GABA shunt hypothesis), and gut microbiome hypothesis.
• Metabolic hypotheses suggest that the ketogenic diet provides additional energy to the brain, which reduces seizures while decreasing glucose metabolism has anticonvulsant properties.
• The gut microbiome hypothesis suggests that dysregulation of bioactive peptides relevant to epilepsy may be linked directly with the epileptic process due to stress-induced alterations in intestinal microbiota composition & functions, which increases inflammation & blood-brain barrier permeability leading towards proepileptic effects on stressed animals but counteracted by transplanting fecal material from naive animals into stressed ones.
6. References
[2] Statstrom CE, Rho JM, eds. Epilepsy and Ketogenic Diet, 1st ed. Totowa (NJ): Humana Press 2004.
[3] Appleton DB, DeVivo DC. An animal model for the ketogenic diet. Epilepsia 1974;15:211–227.
[7] Vining EPG. Clinical efficacy of the ketogenic diet. Epilepsy Res 1999;37:181–190.
[10] Greene AE, Todorova MT, Seyfried TN. Perspectives on the metabolic management of epilepsy through dietary reduction of glucose and elevation of ketone bodies. J Neurochem 2003;86:529– 537.
[11] Seyfried TN, Greene AE, Todorova MT. Caloric restriction and epilepsy: historical perspectives, relationship to the ketogenic diet, and analysis in epileptic EL mice. In: Stafstrom CE, Rho JM, eds. Epilepsy and the ketogenic diet, 1st ed. Totowa (NJ): Humana Press, 2004:247–264.
[12] Pfeifer HH, Thiele EA. Low-glycemic index treatment: a liberalized ketogenic diet for treatment of intractable epilepsy. Neurology 2005;65:1810 –1812.
[13] Lian X, Khan FA, Stringer JL. Fructose-1,6-bisphosphate has anticonvulsant activity in models of acute seizures in adult rats. J Neurosci 2007;27:1207–1211.
[14] Garriga-Canut M, Schoenke B, Qazi R, et al. 2-deoxyglucose reduces epilepsy progression by NRSF-CtBP-dependent metabolic regulation of chromatin structure. Nature Neurosci 2006;9:1382–1387.
[15] Huttenlocher PR. Ketonemia and seizures: metabolic and anticonvulsant effects of two ketogenic diets in childhood epilepsy. Pe- diatr Res 1976;10:536–540.
[16] Vining EPG. Clinical efficacy of the ketogenic diet. Epilepsy Res 1999;37:181–190.
[17] Foster JA, McVey Neufeld KA. Gut-brain axis: how the microbiome influences anxiety and depression. Trends Neurosci 2013;36:305–312.
[18] Nemani K, Hosseini Ghomi R, McCormick B, et al. Schizophrenia and the gut-brain axis. Prog Neuropsychopharmacol Biol Psychiatry 2015;56:155–160.
[19] Kohler CA, Maes M, Slyepchenko A, et al. The gut-brain axis, including the microbiome, leaky gut and bacterial translocation: mechanisms and pathophysiological role in Alzheimer’s disease. Curr Pharm Des 2016;22:6152–6166.
[20] VuongHE,HsiaoEY.Emergingrolesforthegutmicrobiomeinautism spectrum disorder. Biol Psychiatry 2017;81:411–423.
21] Perez-Pardo P, Hartog M, Garssen J, et al. Microbes tickling your tummy: the importance of the gut-brain axis in Parkinson’s disease. Curr Behav Neurosci Rep 2017;4:361–368.
[22] Olson C, Vuong HE, Yano JM, et al. Indigenous bacteria of the gut microbiota mediate antiseizure effects of the ketogenic diet. Neuroscience Meeting Planner 2017;Annual Meeting of Society for Neuroscience:Program # 124.105.
[23] Tagliabue A, Ferraris C, Uggeri F, et al. Short-term impact of a classical ketogenic diet on gut microbiota in GLUT1 deficiency syndrome: a 3-month prospective observational study. Clin Nutr ESPEN 2017;17:33–37.
[24] Olson, C.A.; Vuong, H.E.; Yano, J.M.; Liang, Q.Y.; Nusbaum, D.J.; Hsiao, E.Y. The Gut Microbiota Mediates the Anti-Seizure Effects of the Ketogenic Diet. Cell 2018, 173, 1728–1741.e13.
[25] Medel-Matus, J.-S.; Shin, D.; Dorfman, E.; Sankar, R.; Mazarati, A. Facilitation of Kindling Epileptogenesis by Chronic Stress May Be Mediated by Intestinal Microbiome. Epilepsia Open 2018, 3, 290–294.
[26] Lach G, Schellekens H, Dinan TG, et al. Anxiety, depression, and the microbiome: a role for gut peptides. Neurotherapeutics 2018;15:36– 59.
[27] Dockray GJ. Gastrointestinal hormones and the dialogue between gut and brain. J Physiol 2014;592:2927–2941.
[28] Dinan TG, Cryan JF. Regulation of the stress response by the gut microbiota: implications for psychoneuroendocrinology. Psychoneu- roendocrinology 2012;37:1369–1378.
[29] Kelly JR, Kennedy PJ, Cryan JF, et al. Breaking down the barriers: the gut microbiome, intestinal permeability and stress-related psychiatric disorders. Front Cell Neurosci 2015;9:392.
[30] Sudo N, Chida Y, Aiba Y, et al. Postnatal microbial colonization pro- grams the hypothalamic-pituitary-adrenal system for stress response in mice. J Physiol 2004;558:263–275.
[31] Murakami T, Kamada K, Mizushima K, et al. Changes in intestinal motility and gut microbiota composition in a rat stress model. Digestion 2017;95:55–60.
[32] Murakami T, Kamada K, Mizushima K, et al. Changes in intestinal motility and gut microbiota composition in a rat stress model. Digestion 2017;95:55–60.
[33] Bailey MT, Dowd SE, Galley JD, et al. Exposure to a social stressor alters the structure of the intestinal microbiota: implications for stressor-induced immunomodulation. Brain Behav Immun 2011;25:397– 407. Stress, Microbiome, and Epilepsy
[34] Doherty FD, O’Mahony SM, Peterson VL, et al. Post-weaning social isolation of rats leads to long-term disruption of the gut microbiota- immune-brain axis. Brain Behav Immun 2018;68:261–273.
[35] Kelly JR, Kennedy PJ, Cryan JF, et al. Breaking down the barriers: the gut microbiome, intestinal permeability and stress-related psychiatric disorders. Front Cell Neurosci 2015;9:392.
[36] Eor, J.Y.; Tan, P.L.; Son, Y.J.; Kwak, M.J.; Kim, S.H. Gut Microbiota Modulation by Both Lactobacillus Fermentum MSK 408 and Ketogenic Diet in a Murine Model of Pentylenetetrazole-Induced Acute Seizure. Epilepsy Res. 2021, 169, 106506.
[37] Kim, M.-H.; Yun, K.E.; Kim, J.; Park, E.; Chang, Y.; Ryu, S.; Kim, H.-L.; Kim, H.-N. Gut Microbiota and Metabolic Health among Overweight and Obese Individuals. Sci. Rep. 2020, 10, 19417.
[38] Dao, M.C.; Everard, A.; Aron-Wisnewsky, J.; Sokolovska, N.; Prifti, E.; Verger, E.O.; Kayser, B.D.; Levenez, F.; Chilloux, J.; Hoyles, L.; et al. Akkermansia Muciniphila and Improved Metabolic Health during a Dietary Intervention in Obesity: Relationship with Gut Microbiome Richness and Ecology. Gut 2016, 65, 426–436.
[39] Macchione, I.G.; Lopetuso, L.R.; Ianiro, G.; Napoli, M.; Gibiino, G.; Rizzatti, G.; Petito, V.; Gasbarrini, A.; Scaldaferri, F.Akkermansia Muciniphila: Key Player in Metabolic and Gastrointestinal Disorders. Eur. Rev. Med. Pharmacol. Sci. 2019, 23, 8075–8083.
[40] Blaak, E.E.; Canfora, E.E.; Theis, S.; Frost, G.; Groen, A.K.; Mithieux, G.; Nauta, A.; Scott, K.; Stahl, B.; van Harsselaar, J.; et al.Short Chain Fatty Acids in Human Gut and Metabolic Health. Benef. Microbes 2020, 11, 411–455.
[41] Silva, Y.P.; Bernardi, A.; Frozza, R.L. The Role of Short-Chain Fatty Acids from Gut Microbiota in Gut-Brain Communication. Front. Endocrinol. 2020, 11, 25.
