Friday, May 17, 2019

Fecal microbiota in ketogenic diet and epilepsy

Inspired by a patient.

We know that our intestines hold over 100 trillion microbes, including approximately 1,000 different species of bacteria. Our own DNA is overwhelmed in a way by the DNA of these bacteria living happily along with us! Probiotics, as well as bacteria in yogurts and other supplements, are very popular nowadays to improve “gut health.” But what does this mean for epilepsy in general and the ketogenic diet in specific?

What have studies found?

Two recent papers have raised awareness and excitement that maybe a part of the ketogenic diet’s mechanism of action may rest in changes in the population of several key bacteria in our intestines.

The first paper from UCLA was published in Cell in June. In mice, it appeared that two bacteria, Akkermansia and Parabacteroides, were important for protection from seizures. These mice did not have seizure control when on the ketogenic diet if they were treated with antibiotics (which would kill these bacteria) or were raised in a germ-free environment. Similarly, putting (transplanting) these bacteria into the intestines of other mice would protect them from seizures. The theory is that GABA (an inhibitory neurotransmitter) goes up when these bacteria are in the gut. These results were presented in a TEDx talk. Of note, a study from 2016 in Molecular Autism from Calgary found that Akkermansia decreased in mice treated with the ketogenic diet (the opposite finding).

In another study published in Epilepsy Research from Fudan University in China, researchers looked at the fecal samples of 20 children treated with the ketogenic diet. Again, there were changes in the gut microbiota, with increased Bacteroidetes and decreased Firmicutes, with perhaps hints of differences in those children who responded to the ketogenic diet. These findings were actually very different from published work from Italy in Clinical Nutrition ESPEN back in February 2017. These authors found NO changes in 6 children with Glut1 Deficiency on the ketogenic diet in amounts of Bacteroidetes and Firmicutes.

How do we interpret these often contradictory results?

Right now, we can say there is growing evidence that the ketogenic diet appears to affect the bacteria in your intestines. Yet, we are not certain if improving bacterial strains that affect seizures or possibly reducing those that could have a negative effect could make a difference. For now, it is too early to change probiotics or try to ingest any bacteria intentionally.

More Study Needed

Absolutely this line of research is fascinating and begs for more studies of children and adults on (and off) ketogenic diets. These studies could help us learn

If there are definite trends in larger numbers of people after many months
What these bacteria may be producing that could affect epilepsy
If changes correlate with seizure control (or may only just show a change based on the foods we eat that isn’t relevant for epilepsy)

Xie G, Zhou Q, Qiu CZ, Dai WK, Wang HP, Li YH, Liao JX, Lu XG, Lin SF, Ye JH, Ma ZY, Wang WJ. Ketogenic diet poses a significant effect on imbalanced gut microbiota in infants with refractory epilepsy. World J Gastroenterol. 2017 Sep 7;23(33):6164-6171.


To investigate whether patients with refractory epilepsy and healthy infants differ in gut microbiota (GM), and how ketogenic diet (KD) alters GM.

A total of 14 epileptic and 30 healthy infants were recruited and seizure frequencies were recorded. Stool samples were collected for 16S rDNA sequencing using the Illumina Miseq platform. The composition of GM in each sample was analyzed with MOTHUR, and inter-group comparison was conducted by R software.

After being on KD treatment for a week, 64% of epileptic infants showed an obvious improvement, with a 50% decrease in seizure frequency. GM structure in epileptic infants (P1 group) differed dramatically from that in healthy infants (Health group). Proteobacteria, which had accumulated significantly in the P1 group, decreased dramatically after KD treatment (P2 group). Cronobacter predominated in the P1 group and remained at a low level both in the Health and P2 groups. Bacteroides increased significantly in the P2 group, in which Prevotella and Bifidobacterium also grew in numbers and kept increasing.

GM pattern in healthy infants differed dramatically from that of the epileptic group. KD could significantly modify symptoms of epilepsy and reshape the GM of epileptic infants.

Zhang Y, Zhou S, Zhou Y, Yu L, Zhang L, Wang Y. Altered gut microbiome composition in children with refractory epilepsy after ketogenic diet. Epilepsy Res. 2018 Sep;145:163-168.


The aim of this study was to investigate the characteristics and composition of intestinal microbiota in children with refractory epilepsy after ketogenic diet (KD) therapy and to explore the bacterial biomarkers related to clinical efficacy.

We prospectively analyzed 20 patients (14 males, 6 females) treated with KD. Clinical efficacy, electroencephalogram (EEG) changes, and laboratory tests were evaluated, and fecal specimens were obtained prior to and 6 months after therapy. The composition of gut microbiota was analyzed by 16S rDNA sequencing, and we screened the possible flora associated with efficacy of the KD.

After 6 months of treatment, 2 patients were seizure free, 3 had ≥ 90% seizure reduction, 5 had a reduction of 50-89%, and 10 had < 50% reduction. All 10 responders showed an improvement in EEG. Compared with baseline, fecal microbial profiles showed lower alpha diversity after KD therapy and revealed significantly decreased abundance of Firmicutes and increased levels of Bacteroidetes. We also observed that Clostridiales, Ruminococcaceae, Rikenellaceae, Lachnospiraceae, and Alistipes were enriched in the non-responsive group.

The results show that the KD can reduce the species richness and diversity of intestinal microbiota. The changes of gut microbiota may be associated with different efficacy after KD, and specific gut microbiota may serve as an efficacy biomarker and a potential therapeutic target in patients with refractory epilepsy.

Tagliabue A, Ferraris C, Uggeri F, Trentani C, Bertoli S, de Giorgis V, Veggiotti P, Elli M. 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 Feb;17:33-37.


The classical ketogenic diet (KD) is a high-fat, very low-carbohydrate normocaloric diet used for drug-resistant epilepsy and Glucose Transporter 1 Deficiency Syndrome (GLUT1 DS). In animal models, high fat diet induces large alterations in microbiota producing deleterious effects on gut health. We carried out a pilot study on patients treated with KD comparing their microbiota composition before and after three months on the diet.

Six patients affected by GLUT1 DS were asked to collect fecal samples before and after three months on the diet. RT - PCR analysis was performed in order to quantify Firmicutes, Bacteroidetes, Bifidobacterium spp., Lactobacillus spp., Clostridium perfringens, Enterobacteriaceae, Clostridium cluster XIV, Desulfovibrio spp. and Faecalibacterium prausnitzii.

Compared with baseline, there were no statistically significant differences at 3 months in Firmicutes and Bacteroidetes. However fecal microbial profiles revealed a statistically significant increase in Desulfovibrio spp. (p = 0.025), a bacterial group supposed to be involved in the exacerbation of the inflammatory condition of the gut mucosa associated to the consumption of fats of animal origin.

A future prospective study on the changes in gut microbiota of all children with epilepsy started on a KD is warranted. In patients with dysbiosis demonstrated by fecal samples, it my be reasonable to consider an empiric trial of pre or probiotics to potentially restore the «ecological balance» of intestinal microbiota.

He Z, Cui BT, Zhang T, Li P, Long CY, Ji GZ, Zhang FM. Fecal microbiota transplantation cured epilepsy in a case with Crohn's disease: The first report. World J Gastroenterol. 2017 May 21;23(19):3565-3568.


Fecal microbiota transplantation (FMT) is a promising strategy that involves reconstruction of gut microbiota. Recently, it has been considered as a treatment of Crohn's disease (CD) and certain neurological diseases. Here, to the best of our knowledge, we report the first case that used FMT to achieve remission of intestinal and neurological symptoms in a girl with CD and a 17-year history of epilepsy. During the 20 mo of follow-up, FMT has proved its efficacy in preventing relapse of seizures after withdrawing the antiepileptic drugs. Furthermore, this finding highlights the role of microbiota-gut-brain axis and inspires a novel treatment for epilepsy through remodeling gut microbiota.

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