Although the ketogenic (or keto) diet was initially used for treating childhood refractory epilepsy in the 1920s, fasting has been used to treat epilepsy since 500 BC. Later on, variations of the ketogenic diet (such as the Atkins diet) have appeared and its use has extended into adults for purposes other than reducing seizure frequency. They include treating weight loss, metabolic syndrome, certain cancers and psychiatric disorders such as Alzheimers disease.

This high-fat diet resembles the physiological effects of fasting by restricting carbohydrate intake to between 20g and 50g non-fiber carbohydrate per day (an average person in an industrialized country consumes 200g carbohydrate per day). This means replacing grains, fruit, starchy vegetables, legumes and sweets with carb-free or very low-carb foods such as non-starchy vegetables, cheese, avocados, nuts and seeds, eggs, meat, seafood and olive or coconut oil for cooking and dressing. That fat is then turned into ketone bodies in the liver, which can be taken up and used to fuel the bodys cells.

While scientists still struggle with figuring out which mechanisms underlie the keto diets therapeutic benefits, the gut microbiota, epigenetic changes and metabolic reprogramming appear to be involved in the response to diet.

Elaine Hsiao and her colleagues found that the microbiome is required for the anti-seizure effects of the keto diet. When germ-free mice received stool from mice on a keto diet, seizures were reduced, with Akkermansia muciniphila and Parabacteroides being involved in reducing electrical activity in the brain.

This has led scientists to explore whether the keto diet might be worth considering in gastrointestinal disease.

A new study in mice and humans, led by Peter J. Turnbaugh from UC San Francisco, breaks down the effects of the keto diet on the gut microbiome involving a reduction in bifidobacteria levels and pro-inflammatory Th17 immune cells.

First, Ang and colleagues assigned 17 men who were overweight or obese (but non-diabetic) to a control diet for 4 weeks, followed by the keto diet for 4 weeks. Metagenomic sequencing revealed bifidobacteria speciesin particular Bifidobacterium adolescentisdecreased the most on the keto diet.

The authors were also interested in exploring whether these changes were specific to the keto diet or were also observed in the high-fat and high-carbohydrate diet that is known to promote metabolic disease in mice by inducing shifts in the gut microbiome. To this end, Ang and colleagues fed groups of mice with high-fat diets formulated with graded levels of carbohydrates. It turned out that Bifidobacterium levels decreased with increasing carbohydrate restriction, thus highlighting that carbohydrate restriction, rather than high-fat intake, is the main contributor to the keto diets impact on the gut microbiome.

The mucus layer was maintained in the absence of dietary carbohydrates and bile acid metabolism was not affected. This led the authors to test whether ketone bodies themselves could be directly responsible for the progressive decreasing of Bifidobacterium as carbohydrates decreased.

Feeding mice with the high-fat diet and high-carbohydrate diet or the keto diet supplemented with a synthetic ketone esterdeveloped for mimicking ketosis without modifying dietled to increased levels of beta-hydroxybutyrate ketone bodies in the intestinal lumen and less adiposity. That can be explained by the fact that, beyond the liver, intestinal epithelial cells are also a source of ketone bodies.

Interestingly, in vitro experiments in human stool samples and work in rodents showed that ketone bodies selectively inhibited bifidobacterial growth in a dose- and pH-dependent mechanism. While other members of the gut microbiota were also affected to a lesser extent, the selective inhibitory effects of ketone bodies on Bifidobacterium may involve changes at the gut ecosystems ecological level and warrants further research.

Finally, both mono-colonization of germ-free mice with B. adolescentisthe most abundant species in the baseline diet that experienced the most marked decrease after going on the keto diet and human microbiome transplantations into germ-free mice showed that the keto diet mediates the lack of intestinal pro-inflammatory Th17 induction by reducing colonization levels of B. adolescentis. The observed differences in the gut were also detected on Th17 cells in the visceral adipose tissue.

To sum up, this study shows that the keto diet induces changes in the gut microbiome characterized by marked suppression of bifidobacteria coupled with a decrease in intestinal Th17. Said reduction would be worth considering in the context of improving obesity and immune-related diseases with increased Th17 activation.

The results reported here regarding changes in beneficial bifidobacteria, together with gut-related side effects and the nutritional safety of the keto diet due to the exclusion of major food groups, warrants caution on the use of this diet for managing gut symptoms or gastrointestinal disease progression.

References:

Kossoff EH, Zupec-Kania BA, Auvin S, et al. Optimal clinical management of children receiving dietary therapies for epilepsy: updated recommendations of the international ketogenic diet study group. Epilepsia Open. 2018; 3(2):175-92. doi: 10.1002/epi4.12225.

Wheless JW. History of the ketogenic diet. Epilepsia. 2008; 49(Suppl. 8):3-5. doi: 10.1111/j.1528-1167.2008.01821.x.

Tuck CJ, Staudacher HM. The keto diet and the gut: cause for concern? Lancet Gastroenterol Hepatol. 2019; 4(12):908-9. doi: 10.1016/S2468-1253(19)30353-X.

Cabrera-Mulero A, Tinahones A, Bandera B, et al. Keto microbiota: a powerful contributor to host disease recovery. Rev Endocr Metab Disord. 2019; 20(4):415-25. doi: 10.1007/s11154-019-09518-8.

Olson CA, Vuong HE, Yano JM, et al. The gut microbiota mediates the anti-seizure effects of the ketogenic diet. Cell. 2018; 173(7):1728-41. doi: 10.1016/j.cell.2018.04.027.

Ang QY, Alexander M, Newman JC, et al. Ketogenic diets alter the gut microbiome resulting in decreased intestinal Th17 cells. Cell. 2020. doi: 10.1016/j.cell.2020.04.027.

Turnbaugh PJ, Backhed F, Fulton L, et al. Diet-induced obesity is linked to marked but reversible alterations in the mouse distal gut microbiome. Cell Host Microbe. 2008; 3:213-23. doi: 10.1016/j.chom.2008.02.015.

Newport MT, Vanltallie TB, Kashiwaya Y, et al. A new way to produce hyperketonemia: use of ketone ester in a case of Alzheimers disease. Alzheimers Dement. 2015; 11(1):99-103. doi: 10.1016/j.jalz.2014.01.006.

Reddel S, Putignani L, Del Chierico F. The impact of low-FODMAPs, gluten-free, and ketogenic diets on gut microbiota modulation in pathological conditions. Nutrients. 2019; 11(2):373. doi: 10.3390/nu11020373.

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Could the keto diet's benefits be linked to changes in the gut microbiota? - Gut Microbiota for Health