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Wednesday 11 July 2018

Ketones and Autism Part 1 - Ketones, Epilepsy, GABA and Gut Bacteria




Today’s post is the first in a short series about ketones, that looks into very specific areas of the science.
There was an earlier post on the Ketogenic Diet (KD).

The Clever Ketogenic Diet for some Autism


We already know, anecdotally, that some people with autism respond well to the Ketogenic Diet (KD) and some to just ketone supplements. We also know from some very small clinical trials that a minority of those with autism benefit from the KD. 

What percentage of people with autism respond to ketones?
This is the important question and the simple answer appears to be a minority, albeit a significant minority. A lot depends on what you mean by autism and what you judge to be a response. From reading up on the subject I would estimate that about 20% respond well, but which 20%?

Why do some people with autism respond to ketones and how do you maximize the effect?
There is quite a lot of useful information in the literature, but it is clear that most people do not respond to ketones, so you really need to know if your case is one of the minority that do respond, before getting too carried away with changing diet. From research on people wanting to lose weight there are plenty of practical tips to maximize ketones, even drinking coffee produces more ketones; increasing the hours you fast each day also helps. 
If you have a healthy, sporty, child with autism you might want more ketones but you do not want to lose weight.

Do you have a responder? 
There does not yet appear to be a way to predict who will respond well to ketones, other than those people who have seizures. 
You can read all about ketones or just try them out. To try them out, a good place to start is with the exogenous ketone supplements mainly sold to people trying to lose weight. It looks like 10ml of C8 oil and 10ml of BHB ester is a good place to start and soon you may produce enough ketones to establish if someone is a responder, then you just have to figure out why they are a responder and then to maximize this effect, which might involve things other than ketone supplements.  
You can measure ketones in urine and so you can see whether you have reached the level found in trials that produces a positive effect in some people. If you can establish that you have indeed produced this level of ketones and you see no effect, then it is time to cross ketones and the ketogenic diet off your to-do list.  
If you are fortunate to find a responder, then you can move forward with trying to maximize the benefit. 

Ketone supplements
Ketone supplements can be extremely expensive when you use the recommended dosage and may contain quite large amounts of things that you might not want (sodium, potassium and calcium for example).  Always read the labels.
It is clear that some of these products are much more effective at producing ketones than others. For a change, you can measure their effectiveness and avoid wasting your money. Ketone testing strips are inexpensive. 

Ketone Posts 

·        Part1 - Ketones, epilepsy, GABA and gut bacteria

·        Ketones as a fuel, Alzheimer’s and GLUT1 deficiency

·        Ketones and microglia

·        Ketones as HDAC inhibitors and epigenetic modifiers

·        Ketones, exercise and BDNF

·        Maximizing ketones through diet, fasting, exercise, coffee and supplementation


Ketones, epilepsy, GABA and gut bacteria
Today’s post just looks at the effect of ketones on the neurotransmitter GABA, which should be inhibitory, but in much autism is actually excitatory. The GABA switch failed to flip just after birth and neurons remain in an immature state, due to too many NKCC1 chloride transporters and too few KCC2 chloride transporters. With too much chloride inside neurons GABA has an excitatory effect on neurons causing them to fire when they should not.
In epilepsy, too much excitation from Glutamate and too little inhibition from GABA may lead to seizures. So, in some types of epilepsy you want to increase GABA and reduce Glutamate, i.e. you want to increase the GABA/Glutamate ratio.
In autism it is not clear that increasing the GABA/Glutamate ratio is going to help, it all depends on the kind of autism. Much of this blog is about changing the effect of GABA (flipping the GABA switch) and not changing the amount of it.
In some people with autism and epilepsy ketones resolve the seizures but do not improve the autism.
In other people with autism and no seizures, ketones improve their autism. This may, or may not, be due to the effect ketones have on GABA.  
Two issues are looked into in this post: -
·        Do ketones affect NKCC1/KCC2 expression and hence the effect of GABA in the brain?

·        Do ketones affect the amount of GABA and Glutamate in key parts of the brain?
The good news is that research into epilepsy shows that ketones do indeed have an effect on GABA, but it is highly disputed whether they modify NKCC1/KCC2 expression and the GABA switch from immature to mature neurons. 

The KD and Epilepsy
The KD has been used to treat epilepsy for almost a century, but until very recently nobody really knew why it worked.
A recent very thoughtful study at UCLA has shown that the KD mediates its anti-seizure effects via changes to the bacteria in the gut. The researchers identified the two bacteria and then showed that, at least in mice, the same anti-seizure effect provided by the KD could be provided just by adding these two bacteria (i.e. no need to follow the ketogenic diet).

UCLA scientists have identified specific gut bacteria that play an essential role in the anti-seizure effects of the high-fat, low-carbohydrate ketogenic diet. The study, published today in the journal Cell, is the first to establish a causal link between seizure susceptibility and the gut microbiota — the 100 trillion or so bacteria and other microbes that reside in the human body’s intestines.

The ketogenic diet has numerous health benefits, including fewer seizures for children with epilepsy who do not respond to anti-epileptic medications, said Elaine Hsiao, UCLA assistant professor of integrative biology and physiology in the UCLA College, and senior author of the study. However, there has been no clear explanation for exactly how the diet aids children with epilepsy.
Researchers in Hsiao’s laboratory hypothesized that the gut microbiota is altered through the ketogenic diet and is important for the diet’s anti-seizure effects. Hsiao’s research team conducted a comprehensive investigation into whether the microbiota influences the ability of the diet to protect against seizures and if so, how the microbiota achieves these effects.
In a study of mice as a model to more thoroughly understand epilepsy, the researchers found that the diet substantially altered the gut microbiota in fewer than four days, and mice on the diet had significantly fewer seizures.
To test whether the microbiota is important for protection against seizures, the researchers analyzed the effects of the ketogenic diet on two types of mice: those reared as germ-free in a sterile laboratory environment and mice treated with antibiotics to deplete gut microbes.
“In both cases, we found the ketogenic diet was no longer effective in protecting against seizures,” said lead author Christine Olson, a UCLA graduate student in Hsiao’s laboratory. “This suggests that the gut microbiota is required for the diet to effectively reduce seizures.”
The biologists identified the precise order of organic molecules known as nucleotides from the DNA of gut microbiota to determine which bacteria were present and at what levels after the diet was administered. They identified two types of bacteria that were elevated by the diet and play a key role in providing this protection: Akkermansia muciniphila and Parabacteroides species.
With this new knowledge, they studied germ-free mice that were given these bacteria.
“We found we could restore seizure protection if we gave these particular types of bacteria together,” Olson said. “If we gave either species alone, the bacteria did not protect against seizures; this suggests that these different bacteria perform a unique function when they are together.”
The researchers measured levels of hundreds of biochemicals in the gut, blood and hippocampus, a region of the brain that plays an important role in spreading seizures in the brain. They found that the bacteria that were elevated by the ketogenic diet alter levels of biochemicals in the gut and the blood in ways that affect neurotransmitters in the hippocampus.
How do the bacteria do this? “The bacteria increased brain levels of GABA — a neurotransmitter that silences neurons — relative to brain levels of glutamate, a neurotransmitter that activates neurons to fire,” said co-author Helen Vuong, a postdoctoral scholar in Hsiao’s laboratory.
“This study inspires us to study whether similar roles for gut microbes are seen in people that are on the ketogenic diet,” Vuong said.
“The implications for health and disease are promising, but much more research needs to be done to test whether discoveries in mice also apply to humans,” said Hsiao, who is also an assistant professor of medicine in the David Geffen School of Medicine at UCLA.
On behalf of the Regents of the University of California, the UCLA Technology Development Group has filed a patent on Hsiao’s technology that mimics the ketogenic diet to provide seizure protection. It has exclusively licensed it to a start-up company Hsiao has helped to launch that will examine the potential clinical applications of her laboratory’s findings.
Here is Hsiao’s new start-up:

“We are hacking the ketogenic diet to identify microbes that have therapeutic potential for the treatment of epilepsy,” says Bloom CEO Tony Colasin.
The San Diego-based start-up isn’t announcing how much seed funding it raised, but Colasin plans to move fast and get a product on the market in a mere two to three years. That’s because Bloom will first develop a medical food based on the two kinds of bacteria identified in Hsiao’s study. Bloom also has plans to optimize the bacterial strains for specific kinds of epilepsy to develop a traditional approved drug.

The way the bacteria help control seizures actually appears to be similar to the mechanism of many commercial ant epilepsy drugs. The microbes’ metabolism increases the ratio of inhibitory to excitatory neurotransmitters in the brain—specifically, higher levels of gamma-aminobutyric acid (GABA) relative to levels of glutamate.
Bloom is also considering how the microbiome benefits of the ketogenic diet could be helpful in other neurological conditions, including autism, depression, and Parkinson’s disease. “It is early days, but we are excited about the potential,” Colasin says.

Here is the full paper: -

The ketogenic diet (KD) is used to treat refractory epilepsy, but the mechanisms underlying its neuroprotective effects remain unclear. Here, we show that the gut microbiota is altered by the KD and required for protection against acute electrically induced seizures and spontaneous tonic-clonic seizures in two mouse models. Mice treated with antibiotics or reared germ free are resistant to KD-mediated seizure protection. Enrichment of, and gnotobiotic co-colonization with, KD-associated Akkermansia and Parabacteroides restores seizure protection. Moreover, transplantation of the KD gut microbiota and treatment with Akkermansia and Parabacteroides each confer seizure protection to mice fed a control diet. Alterations in colonic lumenal, serum, and hippocampal metabolomic profiles correlate with seizure protection, including reductions in systemic gamma-glutamylated amino acids and elevated hippocampal GABA/glutamate levels. Bacterial cross-feeding decreases gamma-glutamyltranspeptidase activity, and inhibiting gamma-glutamylation promotes seizure protection in vivo. Overall, this study reveals that the gut microbiota modulates host metabolism and seizure susceptibility in mice.











Achieving the Gut Bacteria changes of the KD without the diet

Since the ketogenic diet (KD) is very restrictive, it would be much more convenient to achieve the GABA/Glutamate effect in a simpler way. You cannot currently just buy these two bacteria as a supplement.  There would seem to be 2 other obvious options: -

·        Take exogenous ketone supplements and hope this causes the same gut bacterial changes produced by the KD. No evidence exists.

·        Use other known methods to increase to increase Akkermansia muciniphila and Parabacteroides species in a similar way to that likely being developed by Bloom Sciences in San Diego. Bloom are developing a medical food to achieve this, so it will require a prescription and it will be costly. 

Increasing Akkermansia muciniphila can be achieved using fructooligosaccharides (FOS). FOS is included in many types of formula milk for babies and is sold as a supplement.
Metformin, a drug used to treat type 2 diabetes, greatly increases Akkermansia muciniphila. Vancomycin, the antibiotic that stays in the gut, also greatly increases Akkermansia muciniphila, but it is also going to wipe out many bacteria.
The research shows you also need the second bacteria Parabacteroides, of which there are many types. These bacteria are found in high levels in people following a Mediterranean type diet but it can be increased using Resistant Starch Type 4. This type of starch has been chemically modified to resist digestion. This starch is sold as food ingredient to add to bakery products.




Viable A. muciniphila and fructooligosaccharides contently promote A. muciniphila. 
Metformin and vancomycin also significantly promote A. muciniphila.



“Akkermansia can also be increased by consuming polyphenol-rich foods, including:

·         pomegranate (attributed to ellagitannins and their metabolites)

·      grape polyphenols (grape seed extract) (proanthocyanidin-rich extracts may increase mucus secretion, therefore creating a favorable environment for Akkermansia to thrive) 

·   cranberries “ 


The abundance of Parabacteroides distasonis (P = .025) and Faecalibacterium prausnitzii (P = .020) increased after long-term consumption of the Med diet and the LFHCC diet, respectively.






Resistant starches types 2 and 4 have differential effects on the composition of the fecal microbiota in human subjects.


Abstract


BACKGROUND:


To systematically develop dietary strategies based on resistant starch (RS) that modulate the human gut microbiome, detailed in vivo studies that evaluate the effects of different forms of RS on the community structure and population dynamics of the gut microbiota are necessary. The aim of the present study was to gain a community wide perspective of the effects of RS types 2 (RS2) and 4 (RS4) on the fecal microbiota in human individuals.

METHODS AND FINDINGS:


Ten human subjects consumed crackers for three weeks each containing either RS2, RS4, or native starch in a double-blind, crossover design. Multiplex sequencing of 16S rRNA tags revealed that both types of RS induced several significant compositional alterations in the fecal microbial populations, with differential effects on community structure. RS4 but not RS2 induced phylum-level changes, significantly increasing Actinobacteria and Bacteroidetes while decreasing Firmicutes. At the species level, the changes evoked by RS4 were increases in Bifidobacterium adolescentis and Parabacteroides distasonis, while RS2 significantly raised the proportions of Ruminococcus bromii and Eubacterium rectale when compared to RS4. The population shifts caused by RS4 were numerically substantial for several taxa, leading for example, to a ten-fold increase in bifidobacteria in three of the subjects, enriching them to 18-30% of the fecal microbial community. The responses to RS and their magnitudes varied between individuals, and they were reversible and tightly associated with the consumption of RS.

CONCLUSION:


Our results demonstrate that RS2 and RS4 show functional differences in their effect on human fecal microbiota composition, indicating that the chemical structure of RS determines its accessibility by groups of colonic bacteria. The findings imply that specific bacterial populations could be selectively targeted by well-designed functional carbohydrates, but the inter-subject variations in the response to RS indicates that such strategies might benefit from more personalized approaches.


Ketones and NKCC1/KCC2  
The next part of this post does get complicated and so it will be of interest to a smaller number of readers; the question is whether ketones play a role in the (miss) expression of those two critical chloride transporters NKCC1 and KCC2. If ketones play a role, then they might have therapeutic potential in all those people with autism and Down Syndrome who respond to bumetanide.
Some researchers think ketones play such a role but the bumetanide for autism researchers disagree.
The ongoing disagreement in the research is about the role played by a lack of ketones in why in immature neurons GABA is excitatory. Regular readers will know that in a large group of autism the GABA switch never flips and so neurons remain in the immature state that was only supposed to last weeks after birth. The debate in the research is to what extent ketone bodies play a role.
We know that in much autism and indeed in those with other problems like neuropathic pain, there can be elevated chloride due to over-expression of NKCC1 (through which chloride enters) and under-expression of KCC2 (through which chloride ions exit neurons). 

GABA action in immature neocortical neurons directly depends on the availability of ketone bodies. 


Abstract


In the early postnatal period, energy metabolism in the suckling rodent brain relies to a large extent on metabolic pathways alternate to glucose such as the utilization of ketone bodies (KBs). However, how KBs affect neuronal excitability is not known. Using recordings of single NMDA and GABA-activated channels in neocortical pyramidal cells we studied the effects of KBs on the resting membrane potential (E(m)) and reversal potential of GABA-induced anionic currents (E(GABA)), respectively. We show that during postnatal development (P3-P19) if neocortical brain slices are adequately supplied with KBs, E(m) and E(GABA) are both maintained at negative levels of about -83 and -80 mV, respectively. Conversely, a KB deficiency causes a significant depolarization of both E(m) (>5 mV) and E(GABA) (>15 mV). The KB-mediated shift in E(GABA) is largely determined by the interaction of the NKCC1 cotransporter and Cl(-)/HCO3 transporter(s). Therefore, by inducing a hyperpolarizing shift in E(m) and modulating GABA signaling mode, KBs can efficiently control the excitability of neonatal cortical neurons.

In the early postnatal period, energy metabolism in the suckling rodent brain relies to a large extent on metabolic pathways alternate to glucose such as the utilization of ketone bodies (KBs). However, how KBs affect neuronal excitability is not known. Using recordings of single NMDA and GABA activated channels in neocortical pyramidal cells we studied the effects of KBs on the resting membrane potential (Em) and reversal potential of GABA-induced anionic currents (EGABA), respectively. We show that during postnatal development (P3–P19) if neocortical brain slices are adequately supplied with KBs, Em and EGABA are both maintained at negative

levels of about )83 and )80 mV, respectively. Conversely, a KB deficiency causes a significant depolarization of both Em (>5 mV) and EGABA (>15 mV). The KB-mediated shift in EGABA is largely determined by the interaction of the NKCC1 cotransporter and Cl)/HCO3 transporter(s). Therefore, by inducing a hyperpolarizing shift in Em and modulating GABA signaling mode, KBs can efficiently control the excitability of neonatal cortical neurons. Keywords: cortex, development, energy substrates, GABA, ketone bodies, resting potential.

showed that in the presence of KBs, values of EGABA in neocortical pyramidal neurons were close to Em, and did not change significantly during postnatal development, being maintained at about )80 mV (see Fig. 3). We cannot exclude the possibility that these values may differ in dendritic (Gulledge and Stuart 2003) or axonal (Price and Trussell 2006; Trigo et al. 2007; Khirug et al. 2008) compartments, an issue for future studies. Additionally, in this study we have limited our investigations to pyramidal cells, and the effects of KBs on interneurons remain to be explored. Nevertheless, the present observations suggest that energy substrates in the developing brain are an important issue to consider when studying neonatal neuronal excitability. Indeed, the most straightforward explanation for the difference between the results of the current study and those of previous studies of the development of neonatal GABA signaling lies in the fact that the brain of the suckling rodent relies strongly on KBs (Cremer and Heath 1974; Dombrowski et al. 1989; Hawkins et al. 1971; Lockwood and Bailey 1971; Lust et al. 2003; Page et al. 1971; Pereira de Vasconcelos and Nehlig 1987; Schroeder et al. 1991; Yeh and Zee 1976). Glucose utilization is limited at this age (Dombrowski et al. 1989; Nehlig, 1997; Nehlig et al. 1988; Prins 2008) because of the delayed maturation of the glycolytic enzymatic system (Dombrowski et al. 1989; Land et al. 1977; Leong and Clark 1984; Prins 2008). Use of glucose as the sole energy substrate caused an increase in neonatal neuronal [Cl)]i in our experiments, similar to that observed previously, while the addition of KBs resulted in a hyperpolarizing shift in both Em and EGABA. These results highlighted the need for caution in the interpretation of results obtained from neonatal brain slices superfused with standard ACSF. The cation chloride cotransporters NKCC1 and KCC2have been suggested to be the main regulators of neuronal Cl) homeostasis both during development (Farrant and Kaila 2007; Fiumelli and Woodin 2007) and in pathology (Galanopoulou, 2007; Kahle and Staley, 2008; Kahle et al. 2008).Although the possible contribution of anion exchangers to neuronal Cl) homeostasis has been noted previously (Farrant and Kaila 2007; Hentschke et al. 2006; Hubneret al. 2004; Pfeffer et al. 2009), they have not attracted the same degree of attention. Results from our study demonstrate, however, that the Cl)/HCO)3 transporter system is strongly involved in the KB-mediated regulation of [Cl)]i during postnatal development. Within this family, the Na-dependent Cl)/HCO)3 transporter (NDCBE), is of particular interest as it is expressed in the cortex (Chen et al. 2008) and has a strong dependence on ATP for its action (Chen et al. 2008; Davis et al. 2008; Romero et al. 2004). In addition, the sodium driven chloride bicarbonate exchanger(NCBE),(Giffardet al. 2003; Hubner et al. 2004; Lee et al. 2006) was expressed in the brain early during prenatal development and its expression preceded that of KCC2 (Hubner et al. 2004).

In neonatal neocortical neurons the interaction of NKCC1 and the Cl)/HCO3) transporter(s) maintained [Cl)]i, with KCC2 playing a less significant role at this stage. In the absence of KBs, when Cl)/HCO3) transporter(s) were less effective, the role of NKCC1 as a Cl) loader was especially noticeable and resulted in a depolarizing EGABA. During development the contribution of KCC2 to neocortical neuronal Cl) homeostasis is likely to increase (Stein et al. 2004; Zhang et al. 2006), and the balance between the actions of the different Cl) transporters in adults should be studied in the future. In humans, blood levels of KBs increase considerably during fasting, strenuous exercise, stress, or on the high-fat, low-carbohydrate ketogenic diet (KD) (Newburgh and Marsh 1920). A rapidly growing body of evidence indicates that the KD can have numerous neuroprotective effects (Gasior et al. 2006). During treatment with the KD, levels of KBs increase in both blood and brain, and cerebral metabolism adapts to preferentially use KBs as an alternate energy substrate to glucose (Kim do and Rho 2008). In children, the KD has been used as an effective treatment for medically refractory epilepsy (Freeman et al. 2007; Hartman and Vining 2007). However, despite nearly a century of use, the mechanisms underlying its clinical efficacy have proved elusive (Morris 2005; Bough and Rho 2007; Kim do and Rho 2008). Suckling rodents provide a natural model of the KD because of the high ketogenic ratio (Wilder and Winter 1922) of rodent milk (Page et al. 1971; Nehlig 1999). We propose that the KB-induced modulation of GABA-signaling may constitute a mechanism of anticonvulsive actions of the KD.

Now for the opposing views: -

Summary
Brain slices incubated with glucose have provided most of our knowledge on cellular, synaptic, and network driven mechanisms. It has been recently suggested that γ‐aminobutyric acid (GABA) excites neonatal neurons in conventional glucose‐perfused slices but not when ketone bodies metabolites, pyruvate, and/or lactate are added, suggesting that the excitatory actions of GABA are due to energy deprivation when glucose is the sole energy source. In this article, we review the vast number of studies that show that slices are not energy deprived in glucose‐containing medium, and that addition of other energy substrates at physiologic concentrations does not alter the excitatory actions of GABA on neonatal neurons. In contrast, lactate, like other weak acids, can produce an intracellular acidification that will cause a reduction of intracellular chloride and a shift of GABA actions. The effects of high concentrations of lactate, and particularly of pyruvate (4–5 mm), as used are relevant primarily to pathologic conditions; these concentrations not being found in the brain in normal “control” conditions. Slices in glucose‐containing medium may not be ideal, but additional energy substrates neither correspond to physiologic conditions nor alter GABA actions. In keeping with extensive observations in a wide range of animal species and brain structures, GABA depolarizes immature neurons and the reduction of the intracellular concentration of chloride ([Cl]i) is a basic property of brain maturation that has been preserved throughout evolution. In addition, this developmental sequence has important clinical implications, notably concerning the higher incidence of seizures early in life and their long‐lasting deleterious sequels. Immature neurons have difficulties exporting chloride that accumulates during seizures, leading to permanent increase of [Cl]i that converts the inhibitory actions of GABA to excitatory and hampers the efficacy of GABA‐acting antiepileptic drugs.  


GABA depolarizes immature neurons because of a high [Cl]i and orchestrates giant depolarizing potential (GDP) generation. Zilberter and coworkers (Rheims et al., 2009; Holmgren et al., 2010) showed recently that the ketone body metabolite dl-3-hydroxybutyrate (dl-BHB) (4 mm), lactate (4 mm), or pyruvate (5 mm) shifted GABA actions to hyperpolarizing, suggesting that the depolarizing effects of GABA are attributable to inadequate energy supply when glucose is the sole energy source. We now report that, in rat pups (postnatal days 4–7), plasma d-BHB, lactate, and pyruvate levels are 0.9, 1.5, and 0.12 mm, respectively. Then, we show that dl-BHB (4 mm) and pyruvate (200 μm) do not affect (i) the driving force for GABAA receptor-mediated currents (DFGABA) in cell-attached single-channel recordings, (2) the resting membrane potential and reversal potential of synaptic GABAA receptor-mediated responses in perforated patch recordings, (3) the action potentials triggered by focal GABA applications, or (4) the GDPs determined with electrophysiological recordings and dynamic two-photon calcium imaging. Only very high non physiological concentrations of pyruvate (5 mm) reduced DFGABA and blocked GDPs. Therefore, dl-BHB does not alter GABA signals even at the high concentrations used by Zilberter and colleagues, whereas pyruvate requires exceedingly high non-physiological concentrations to exert an effect. There is no need to alter conventional glucose enriched artificial CSF to investigate GABA signals in the developing brain.

Very recent research shows that ketones do not affect the expression of NKCC1 or KCC2. This would tend to support the argument of Ben Ari and Tyzio.


  
Nonetheless it seems that ketone bodies do indeed have an effect on GABA; they appear to change the hippocampal GABA/Glutamate ratio. 
So Tyzio might not be as right as he thought in his rebuttal paper when he said.
“suggesting, contrary to Zilberter and colleagues, that the antiepileptic actions of ketone bodies are not mediated by GABA signalling
Tyzio is thinking about the resting membrane potential (Em) and reversal potential of GABA-induced anionic currents (EGABA).
At the end of that day a reduction in gamma-glutamylated amino acids, caused by changes in gut microbiota cause an increase in hippocampal GABA/Glutamate ratio. If you happen to have epilepsy this may mean less seizures.  

Conclusion
I think we can say with a fair degree of certainty that we now know why the ketogenic diet, and indeed the modified Atkins diet, greatly reduce seizures in many people with epilepsy. The diet changes the gut microbiota by increasing the amount of Akkermansia muciniphila and Parabacteroides species, the end result is an increase in GABA, the inhibitory neurotransmitter, inside the brain. In much epilepsy, more inhibition to neurons firing results is far less seizures.
GABA plays a key role in autism, albeit a complex one.
The ketone driven changes to GABA might explain why some people with autism respond to the KD or just ketone supplements, but ketones have many other effects relevant to autism that will be reviewed in later posts.







16 comments:

  1. Hi Peter, we have been on Zarontin since 20 days.The rolling eyes almost disappeared and also excitability is much better.I discoverd thay my son has phenol intolerance.Last week his ear turned red and started to show strange behavior, meaningless laughing, crying and anger.If it wasnt for the red ear i would have thought that was a bad reaction to Zarontin. Do you think if adding resistant starch 4 and Metmorfin would be of additional benefit?
    Valentina

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    Replies
    1. Valentina, the research shows that absence seizures often do respond to the ketogenic diet. So increasing the 2 bacteria from the UCLA study might indeed be helpful.

      I think fructooligosaccharides (FOS) is a good choice since it is available as a supplement and is very safe. I am not sure resistant starch type 4 will be easy to find, but it also is very safe.

      Metformin has many other effects.

      Delete
    2. Ok Peter, I will use inulin to increase Akkermansia M.What could I use to increase the second bacteria? Mediterranean diet is based on food high in poliphenols and would be a problem,what other option would be?
      Valentina

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    3. Valentina, why not contact the company Ingredion and ask where you can buy their Resistant Starch Type 4 called VERSAFIBE 2470. They fund a lot of research and so should be interested that their product can be used to increase certain bacteria and reduce epilepsy.

      They have another product that has an FDA approved health claim that it reduces the risk of type 2 diabetes.

      They should be interested in their products reducing epilepsy.

      Delete
    4. Peter, I got in touch with Ingredion Argentina, will see if they answer and are interested.I have also the phone.
      Valentina

      Delete
  2. KETO//OS products (KetoForce/C8 oil) may cause a diuretic effect that can lead to water and mineral depletion.
    To drink more water and supplementing with magnesium, potassium, and sodium to replenish minerals and fluid levels etc are obvious, but not best solutions.
    Anyone has better suggestion?
    Yi

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  3. Yet another epic post (series)!
    Ketones looks very beneficial in so many areas - epilepsy, energy uptake, neuroinflammation... However, dealing with hypoNMDAr I have concerns regarding the glutamate decrease. Looking forward to read the rest!
    /Ling

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  4. I met a doctor that treats for autoimmune encephalopathies. She is trying to help me determine the cause of my sons inflammation. He has ASD, and epilepsy. I am very concerned about a test she wants to perform for many reasons. My son has been on a ketogenic diet for 3 years and has about 2 seizures a month. This new doc was wanting to look at Lyme. I am so fed up with doctors it is unreal. I couldn't get into CPAE clinic because despite the fact they thought something autoimmune was there, the seizures were something that didn't fit into there studies or work so they wanted me to look into UCLA and go to another doctor to get a referral there (So the doctor hopping is getting annoying.)

    My concern with Azithromycin use for 30 days to provoke Lyme DNA into urine is that I would be destroying a great deal of beneficial microbes, adversly impacting seizure control, hurting his liver etc. The thing that offended me was the recommendation to take some random probiotics with the antibiotic.

    Does anyone know of any Lyme test that isnt giving false positives?


    My sons seizures likely have to do with underdeveloped GABA process as I was told by a different doctor to try GABA and that completely backfired. I also noticed that products in foods that contain certain corn bi-products, MSG or compounds that synergistically act as MSG would trigger a seizure.

    Also if he is fighting an infection- the ketogenic diet helps minimize the severity and duration of a seizure most of the time depending on the body burdon of glutamate he has at any given time.

    His Viome result revealed the species of microbiota that Peter discussed as butyrate producing bacteria. It also revealed that the body was fighting an inflammatory process as analyzed by AI mRNA sequencing of the microbes.

    I have noticed benefits with using the diet in that my son tries to interact with people more with the diet than any AED he tried in the past.

    In terms of supplements for my son, I use Avocado's a lot, and KIWI's for potassium, I use salt in his food, and I always give Magnesium at night. I try to balance his water too and not use too much RO water.

    In runs in my family that we cannot really digest most of the grain group well. I believe that his Viome showed that a couple types of rice were ok. Rice is difficult to include on the 2:25:1 ratio he is on.

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  5. For increasing diversity try some of https://www.davincilabs.com/
    varieties of vegetable powders---Sometimes it seems that it is difficult to provide the correct food for the beneficial microbes to survive. We relocated to a different biome to see if it would make a difference in his autism and I still cannot believe it.

    Since relocating the intensity and severity of stimming has decreased and he is actually calmer and attending.

    Attending for him has been a challenge. I had a feeling this biome was going to be better here for many reasons--We left the humidity which was carrying lots of particulates of various agricultural chemicals, we increased our sunlight. Today was a difficult day because he did come down with a virus and fell and had a seizure in the middle of a grocery store at a busy time and also smacked his face on a spice rack and someone passing by laughed about it. Most tried to stay out of the way or offer help.

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  6. Also, I frequently run out of garlic powder. I make my own Mayo for the Keto diet. I wonder if the garlic powder that I use is bioavailable, it must be because he does have Akkermansia. The smell of garlic in the house can really start to stink if we use cloves too much. Just an idea - maybe add inulin or inulin containing foods to keto diet to assist with Cal/Mag absorption too. I think it is important to utilize and support the microbes.

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  7. I think it would be interesting to study a keto diet adapted with use of indigenous plants. I wonder if those plants in that biome would be better suited for its inhabitants, enabling increased function of the organism? These plants are adapted to there climate thus by consuming them ---could it be of greater benefit for the consumer but the entire planet --in terms of minimizing emissions, pollution, exploitation of resources, and body burden of pollutants across species? Could these plants have the potential to help those who experience allergies by providing adaptogens or communicating immunity within us via light or mRNA/miRNA?

    I wonder????

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  8. super interesting about the meformin and Akkermansia

    my boy has CP and i have been looking at ways to reduce Glutamate based on some brain slice research

    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6409919/

    Had a quick look around about metformin and wow:

    https://www.ncbi.nlm.nih.gov/pubmed/26235894

    https://www.ncbi.nlm.nih.gov/pubmed/29088867

    Looks like the group in Canada are going to work out if its legit as well:

    https://clinicaltrials.gov/ct2/show/NCT03710343

    Thanks for posting!!!

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  9. I am a mother with a fragile son and I have discovered the causes of his fragility and it has to do with NMDA-R's, microbiome, glia, and exposures. Recently I have discovered that the schools here are not a good fit as his central nervous system and functioning is severely altered when he attends school and I know it is due to the electrosmog levels in my son's case.

    Basically, I have these records that show this excess seizure activity, dermal activity, behavior, and changes in bowel and bladder function when he is at school. I knew he was sensitive to EMFs so when we lived in MN I had special accommodations for him to avoid these exposures. I knew it was there and I did not realize how bad it could get. We had not had wireless in the home since he was 4 because I wanted to see if it might help and at home it reduced a lot of the problems I was seeing. I knew that when I took him to certain places he would react with disorientation, slow motor activity, and red face and ears, and I was told it was the lighting early on when I brought it up with neurologist which is possible but I believe there was more too it because I would notice reactions when he would play next to the smart meter in our backyard in MN or when he was in the house on the other side of it. He gets a look on his face an aura like something overcame him after playing next to it and would go into a seizure. Sometimes I would notice these spots on his legs. I realized that this exposure did not seem to exist in medical literature so I found a toxicologist that knew about it and I began looking at the science. And I am pasting Dr. Martin Paul's lecture here: https://www.youtube.com/watch?v=fJsWkzi14vM

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  10. So we started the Nemecheck protocol a few months ago and I was seeing great success but still some problems and especially if he went to school. Magda Havas has a great deal of information on defining the types of electrosmog. I asked the school if I could get an engineer out there or be informed of some electrosmog readings at his school and they would not inform me of this information that I needed to make an informed decision about sending him to school. What I notice is that his CNS antioxidant defense, and his brain gut and gut brain axis completely shuts down and his functional health is severly altered when he is exposed. When he is not exposed his symptoms improve and the Nemecheck protocol seems helpful in reducing his gastric distention and SIBO symptoms. He is also on a low glutamate, grain free, keto diet which is helpful as long as he is not flooded by electrosmog. Electrosmog physics and Electrosmog electricity is an undertaking to understand so give yourself time if you go down that path.

    So there seems to be a dermal mast cell response as well, an autonomic response, and CNS responses to these exposures. I question what DeNovo mutations in the VGCC's he may have??? Where might I find this information out?? What I was seeing was he would be at school a day and then another day have a seizure or have a day where he was off or have a dermal reaction and he was having a difficult time with fighting off infections where normally he would not have such a difficult time. Pretty soon it was pretty obvious and I had him at school a total of 6 days in March and 2 seizures occurred at school and 1 occured at home 30 minutes after being at school. I am hoping to make changes in the schools and reach the local government on this because I believe it is impacting those with allergies as well as it seems to trigger Mast cell reactivity. Neuroglia are electric in nature as well. You can find a great deal of information on the toxic nature of these electrosmog fields at the Bioinitiative Report.

    Basically the NO/ONOO cycle is triggered by Ca2+ flooding in the body and CNS triggering NMDA-R effecting excitotoxicity and brain gut axis via cytokines. When the CNS antioxidant defense is shut down the bacteria in the small intestine and the bowel function or motility seem to be effected. Now that he has been home more in March and in April his motility is returning and his gastric distention is subsiding. We had the power company remove the smart meter and I will be investing in some testing equipment for electrosmog. This is an understanding in physics, engineering, and electricity that I have never had. Over time with increased and prolonged exposures I see changes in sleep where he will wake up in the middle of the night easier and after a longer week at school will be very fatigued appearance.

    I am writing you to hopefully help your team consider this in your microbiome studies, as well as further the understanding of the effects of EMFs on microbiome, brain dysfunction, and more. I consider this a severe exposure issue to many children with various conditions. This is a lot to review for those who haven't pursued this rabbit hole.

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  11. Hi Peter
    Thank you for all the info.
    Use with my 4 year old daughter- Now Foods, Sports, MCT Oil
    50% c8 y 30% c10.
    I noticed her challenging and did not increase. 10ml per day.

    Should I buy pure c8?

    I don't find it pure.

    thanks María

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  12. It seems there is a live Akkermansia municiphila product from Pendulum out now, for anyone who wants to pursue this path. It's expensive, but at least it exists.
    /Ling

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