The Ketone D-BHB as a Medical Food for Heart, Kidney and Brain Disease (Alzheimer’s, some Autism …)

 Nestle’s research centre in Lausanne, Switzerland

I did write extensively about the potential to treat some autism using the ketone BHB (beta hydroxybutyrate). This can be achieved either by following a strict ketogenic diet or just by eating medical foods that contain/produce BHB.

Some readers are now big consumers of BHB supplements and anyone taking BHB should be interested in today’s paper, that I assume was paid for by Nestlé.

Nestlé make everything from baby milk formula to George Clooney’s Nespresso.  You may not be aware that they also have a business selling medical food; they have been looking at ketones to treat Alzheimer’s for some time.  This is quite similar to Mars developing Cocoa flavanols to improve heart and brain health.

Most ketone supplements are sold to help you lose weight or boost athletic performance.  The military also uses ketones in survival rations. 

We saw that you can increase the level of ketones in your body by supplementing: -

·        MCT oil (medium chain triglyceride oil, which usually contains about 60% caprylic C8 acid and 40% capric C10 acid).  This is a product already sold by Nestlé

·        Neat caprylic acid, C8

·        BHB salts (potassium, sodium, calcium etc)

·        BHB esters (also called ketone esters KE)

These products range from expensive to very expensive.

People requiring ketones as an alternative fuel to glucose, like those with Alzheimer’s need quite large amounts of the supplements.  In Alzheimer’s a glucose transporter at the blood brain barrier is restricting the flow of glucose in blood and so the brain is starved of “fuel”.  Mitochondria in the brain can be powered by both ketones and glucose, so if not enough glucose cannot get through, you have the option to increase the amount of ketones.

Babies fed with mother’s milk are on a high ketone diet.  You can safely combine both glucose and ketones as a fuel for your body.

The news from today’s paper has already been translated to a usable therapy. 

Metabolism of Exogenous D-Beta-Hydroxybutyrate, an Energy Substrate Avidly Consumed by the Heart and Kidney

There is growing interest in the metabolism of ketones owing to their reported benefits in neurological and more recently in cardiovascular and renal diseases. As an alternative to a very high fat ketogenic diet, ketones precursors for oral intake are being developed to achieve ketosis without the need for dietary carbohydrate restriction. Here we report that an oral D-beta-hydroxybutyrate (D-BHB) supplement is rapidly absorbed and metabolized in humans and increases blood ketones to millimolar levels. At the same dose, D-BHB is significantly more ketogenic and provides fewer calories than a racemic mixture of BHB or medium chain triglyceride. In a whole body ketone positron emission tomography pilot study, we observed that after D-BHB consumption, the ketone tracer ¹¹C-acetoacetate is rapidly metabolized, mostly by the heart and the kidneys. Beyond brain energy rescue, this opens additional opportunities for therapeutic exploration of D-BHB supplements as a “super fuel” in cardiac and chronic kidney diseases.

One of the main benefits of ketones is their ability to act as an alternative energy source to glucose or fatty acids for production of ATP by mitochondria. Caloric restriction and intermittent fasting also produce transient mild-moderate ketosis (6, 7).

While a high dose of MCT can provide a moderate increase in blood ketones (+0.5–1.0 mM), gastrointestinal intolerance and high caloric load limit their use. Second, ketone esters (KE) made of a BHB ester linked to butanediol provide one molecule of D-BHB after digestion, with the butanediol being further metabolized by the liver to D-BHB (9). KE increase blood ketones above 1 mM but are also limited at high dose by their gastric tolerability and severe bitterness (10).

Third, perhaps the most physiologic way to raise blood ketones is via the oral intake of D-BHB itself. Exogenous D-BHB is directly absorbed into the circulation, with some of it being converted to AcAc by the liver, and both ketones being distributed throughout the body. Until recently, only racemic mixtures of dextro (D) and levo (L) BHB (D+L-BHB) were available and oral human studies with them have been reported (9, 11–14). As L-BHB is not metabolized significantly into energy intermediates and is slowly excreted in the urine (9, 15), D+L-BHB would be anticipated to be less ketogenic than pure D-BHB. 

Levo, Dextro and Racemic

When certain chemicals are manufactured, they usually contain an equal mixture of the left-handed and right-handed version, this is called a racemic mixture. These versions are called enantiomers.

One enantiomer is an optical stereoisomer of another enantiomer. The two molecules are mirror images of each other, which are not superimposable - much like your left and right hand.

In the case of the chemical BHB, only the right-handed version has an effect on your body.  If you take the salt potassium BHB, half of the product has no effect other than raise your level of potassium.

Zyrtec is an antihistamine made of Cetirizine, but it is a racemic mixture.  If you want pure L-Cetirizine, you would buy Xyzal not Zyrtec.

Arbaclofen/ R-baclofen is the right-handed version of baclofen

Rezular/R-verapamil is the right-handed version of verapamil.

Back to the study:

The study compared three therapies: -

D-BHB

14.1 g of pure salts of the D enantiomer of D-BHB were used. The D-BHB supplement tested was formulated as a mixture of three salts: sodium D-beta-hydroxybutyrate, magnesium (D-beta-hydroxybutyrate and calcium (D-beta-hydroxybutyrate). Each oral serving provided 12 g D-beta-hydroxybutyric acid, 0.78 g sodium, 0.42 g magnesium, and 0.88 g calcium, citrus flavouring and sweetener (Stevia), dissolved in 150 mL of drinking water.

D+L-BHB

14.5 g of an equimolar mixture of commercial D and L beta-hydroxybutyrate salt was used (KetoCaNa, KetoSports, USA). Each serving provided a mixture of 12 g D+L-Beta-hydroxybutyric acid, 1.3 g sodium, 1.2 g calcium, orange flavoring and stevia, dissolved in 150 mL of drinking water.

MCT oil

Fifteen grams of medium chain triglyceride (MCT) (60% caprylic C8 acid and 40% capric C10 acid) emulsified in 70 mL of a 5% aqueous milk protein solution.

This chart shows the concentration of ketones in your blood plasma after taking either of the three therapies.

This chart shows the concentration of just the ketone D-BHB in your blood plasma after taking either of the three therapies.

 This chart shows the concentration of the ketone ACAc in your blood plasma after taking either of the three therapies.

  

This chart shows where the ketones are going; the chart shows the distribution of the ketone “tracer” acetoacetate (AcAc) by organ after D-BHB oral intake.  The effect is greatest on the heart and kidney, but some does reach the brain.

From the dynamic brain scan, CMR_AcAc and K_AcAc could be determined for all main regions of the brain and compared to baseline values previously determined in healthy young adults. Overall and compared to baseline, each region demonstrated an increase in CMR_AcAc and K_AcAc of ~4.7 and 2.3-fold, respectively, about 1 h after taking D-BHB. This indicated that AcAc is effectively taken by the brain and by other organs particularly the heart and the kidney.

Ketone production from an exogenous dietary source has been traditionally achieved by MCT. This requires a bolus intake to saturate the liver with MCFA, producing excess acetyl-CoA which is then transformed to AcAc and BHB, which are released into systemic circulation. The C_max achieved with MCT is usually between 300 and 600 μM, with higher values being difficult to reach due to GI side effects and liver saturation. Here we show that D-BHB, a natural and biologically active ketone isomer, raises blood ketone C_max above 1 mM without noticeable side effects. In comparison, an equivalent dose of D+L-BHB or MCT only achieved half this ketone level, with similar T_max at 1 h. Thus, compared to D+L-BHB, D-BHB significantly reduces the salt intake needed to achieve the same plasma ketone response.

Results from a previous study (9) comparing KE to D+L-BHB showed that at the same dose of D-BHB equivalent, the increase blood ketone iAUC had the same magnitude, suggesting that exogenous D-BHB and KE produce similar ketosis.

Note that KE means Ketone Ester and the study (9) is this one: -

On the Metabolism of Exogenous Ketones in Humans

Ketone esters are available, but horribly expensive and taste really bad.

Conclusion

In previous posts the numerous possible beneficial modes of action of BHB were outlined. The summary post is here: -

Ketone Therapy in Autism (Summary of Parts 1-6)

In practise some people with autism seem to benefit a lot, some moderately and some not at all.

Monty, aged 16 with ASD, fits in the “moderately benefits” category.  The combination of about 20ml of caprylic acid (C8) plus a scoop of Potassium BHB powder does produce more speech.

It is not a cheap or very convenient therapy, compared the others I use.

I would agree with Nestlé that the limiting factor with BHB salts is the “salt”.  As they comment in their paper 

“compared to D+L-BHB, D-BHB significantly reduces the salt intake needed to achieve the same plasma ketone response”

Giving someone with heart disease "sodium anything" is not a good idea. A potassium salt would be safer, but even then, your heart is the limiting factor on potassium use.  Calcium salts are unwise in people with autism, because it appears to be able to upset calcium ion signalling, which would also be a potential risk in heart disease.

As I mentioned to one parent who is a big time user of BHB salts, if you switch to D-BHB you can either produce twice the ketones of regular potassium BHB, with the existing potassium load, or reduce your dosage by half and keep the same effect and save some money.

I think potassium D-BHB is good choice.  If you are taking bumetanide you may no longer need a potassium supplement (K-BHB becomes your potassium supplement).

I think people with autism and genuine mitochondrial disease are highly likely to benefit from D-BHB.  These are people who show symptoms in their entire body, i.e. lack of exercise endurance. For these people, eating (or producing via diet) large amounts of ketones will increase the production of ATP in their brains and so improve cognitive function.  D-BHB undergoes a different process to glucose, as it “converted” to ATP by the process called OXPHOS
(Oxidative phosphorylation). Some people with autism lack the enzyme complexes needed to complete OXPHOS, these people who should try D-BHB.

BHB has other beneficial effects, some relating to inflammation that seem to explain its benefit in other types of autism.  The effects were investigated here.

In the brains of people with Alzheimer’s there is decreased expression of glucose transporter 1 (GLUT 1) at the blood brain barrier. This starves the brain of glucose, which is fuel for the brain. D-BHB is an alternative fuel for mitochondria that is not dependent on GLUT 1.  People with early onset Alzheimer's would seem the best ones for this therapy, that would include many people with Down Syndrome. 

BHB + C8 in Autism, a Work-in-Progress

The potential benefit of the ketone BHB in autism was covered extensively in earlier posts.  It looks like different people may benefit for entirely different reasons and some may not benefit at all. 

Some MCT oils, taken as precursors to BHB, can actually make people worse.

Measuring ketones and glucose in blood

Click for a summary of the previous posts.

Ketone Therapy in Autism (Summary of Parts 1-6)

I know that some readers of this blog have found that BHB/C8 does indeed provide a benefit in their specific type of autism.  The benefit seems to vary, but given all the biological modes of action of the ketone BHB that is not surprising.  Increased speech is a frequently noted benefit.

My initial combination of Ketoforce plus C8 continues to be effective.

Substituting a cheaper MCT oil containing both C8 and C10 (Bulletproof XCT oil), was less effective and after a matter of weeks produced a negative effect. It appears that C10, after a while, can produce mild anxiety and agitation in some people. In our case this goes away when stopping the C8+C10 MCT oil and then reappears restarting it.

When it comes to C8, it appears that not all food grade 98% C8 products are actually what they claim to be. This is a recurring theme with all supplements, they lack the quality control you get with pharmaceuticals.

Our reader Yi did at one point raise the issue of BHB causing diuresis. We also experienced this and much more so with the “mixed” C8+C10 MCT oil, rather than the “pure” C8.

The combination of increased diuresis and all the sodium, magnesium, potassium in the BHB salts may very well create an issue with electrolyte levels. Potassium does seem to be the most critical one to monitor.

Different BHB products contain very different amounts of sodium, magnesium, potassium and so it is unwise to simply substitute one for another.

Our reader Agnieszka did experiment with different BHB products and found that, based on urine testing, Ketoforce was the most effective. I also think this is likely the best choice.  Ideally you would measure BHB in blood and devices are available (see above photo).

For people living in Europe, BHB products have fallen foul of EU legislation that requires new supplements to be approved before they can be sold in the European Union. As BHB is a recently introduced supplement, it cannot legally be sold in the EU until someone pays for it to be approved. This means that in EU countries that strictly apply the rules, like the UK, you cannot buy BHB, but in other EU countries you still can.

The same legal status regarding BHB in the EU also applies to Agmatine.

Another oddity is that Melatonin is banned as a supplement in the UK, but not other EU countries; it is a very popular supplement in North America.

Ketone Therapy in Autism (Summary of Parts 1-6)

Open the above file via Google Drive, so it is big enough to read. Click the link below. You can also take links from it to the relevant blog post.

https://drive.google.com/file/d/1Jl_JMUrX7suXz0n_yJPCLPinrvdddBhI/view?usp=sharing

In the mini series of posts on ketones and autism we have come across a long list of effects that will benefit certain groups of people.

1.     Change in gut Bacteria

2.     Ketones as a brain fuel    

3.     Niacin Receptor HCA2/ GPR109A

4.     NAD sparing

5.     CtBP Activation by reducing NADH/NAD+ ratio

6.     NLRP3 Inflammasome inhibition

7.     Class 1 HDAC inhibition

8.     Increase BDNF

9.     Ramification of Microglia

10.PKA activation

11.PPAR gamma activation

It was interesting that the beneficial effect of the Ketogenic Diet in epilepsy is driven by changes the high fat diet makes to the bacteria in your gut and seems to have nothing really to do with ketones. Well it took a hundred years to figure that one out.

In the case of Alzheimer’s, you can see that more than one effect is potentially beneficial. People with Alzheimer’s do have low glucose uptake to the brain, but they also have elevated inflammatory cytokine IL-1B.

In Huntington’s it is the HDAC inhibition effect that seems to be what helps.  This brings us back to HDAC inhibition as a potentially transformative therapy with long lasting effects. It appears that the small number of people who achieve long lasting benefit from short term use of sulforaphane or EGCG may have experienced HDAC inhibition changing the expression of up to 200 genes.  In the case of sulforaphane from broccoli, some people have gut bacteria that produces large amounts of the enzyme myrosinase, which means they convert very much more of the glucoraphanin in broccoli to sulforaphane (an HDAC inhibitor).

It does look like a low dose of a potent HDAC inhibiting cancer drug is what is needed by certain single gene autisms and perhaps some idiopathic autism. This was covered in a dedicated post where we saw the long-lasting benefit of short-term use of Romidepsin. Vorinostat, a very similar drug, but which is taken orally, should be trialled in Shank 3, Pitt Hopkins and Kabuki, to see if the same transformative long-lasting effect can be reproduced.

In Multiple Sclerosis (MS) the effect on Niacin receptor HCA2/GPR109A should help a lot, but so should PKA activation.

In mitochondrial disease it was suggested that increased ketosis will help conserve NAD, which may be deficient. Also, using ketones as an alternative brain fuel may bypass problems that occur when glucose is supposed to be the fuel and thereby boost brain function. The most important effect is likely to be activation of PPAR gamma by C10, which increases the number of mitochondria and boosts the enzyme complex 1.

Many of the people with autism and an overactive immune system stand to benefit from activating CtBP, inhibiting the NLRP3 inflammasome, or activating HCA2/GPR109A.

I think there should be clinical trials using a potent HCA2 activator in autism comorbid with immune over-activation. 

We can see that some people who respond to BHB, experience an immune rebound on cessation, so this helps narrow down the likely beneficial mode of action.  In this immune sub-group, the idea to using other activators of HCA2/GPR109A would seem worthwhile. 

PPAR gamma activation should help those with mitochondrial dysfunction, but this effect is produced only by C10, not BHB or C8. For C10 you eat a ketogenic diet or add it as a supplement (e.g. cheaper MCT oil, or coconut oil).

As recently highlighted by our reader Agnieszka, perhaps the fever effect in autism can be explained by short-term ketosis. Fever is known to sometimes raise the level of ketones, particularly in children (it is called non-diabetic ketosis).  So if your child's autism improves during, or just after fever, test the level of ketones in their urine.


Conclusion

We may have shown the benefits of a high fat ketogenic diet, but there are very many different fats and they do not all produce the same effects.

There are many saturated fatty acids, they are numbered based on how many Carbon atoms they have.

So, C8, known as Caprylic acid has the formula  C₈H₁₆O₂

Eating C8 looks to be a great way to increase the level of ketones in your blood.

Eating C10 should be good for people with mitochondrial dysfunction and people with diabetes.

Your food contains many other saturated fatty acids and your gut bacteria produce even more.

Common Name	Systematic Name	Structural Formula	Lipid Numbers
Propionic acid	Propanoic acid	CH3CH2COOH	C3:0
Butyric acid	Butanoic acid	CH3(CH2)2COOH	C4:0
Valeric acid	Pentanoic acid	CH3(CH2)3COOH	C5:0
Caproic acid	Hexanoic acid	CH3(CH2)4COOH	C6:0
Enanthic acid	Heptanoic acid	CH3(CH2)5COOH	C7:0
Caprylic acid	Octanoic acid	CH3(CH2)6COOH	C8:0
Pelargonic acid	Nonanoic acid	CH3(CH2)7COOH	C9:0
Capric acid	Decanoic acid	CH3(CH2)8COOH	C10:0
Undecylic acid	Undecanoic acid	CH3(CH2)9COOH	C11:0
Lauric acid	Dodecanoic acid	CH3(CH2)10COOH	C12:0
Tridecylic acid	Tridecanoic acid	CH3(CH2)11COOH	C13:0
Myristic acid	Tetradecanoic acid	CH3(CH2)12COOH	C14:0
Pentadecylic acid	Pentadecanoic acid	CH3(CH2)13COOH	C15:0
Palmitic acid	Hexadecanoic acid	CH3(CH2)14COOH	C16:0
Margaric acid	Heptadecanoic acid	CH3(CH2)15COOH	C17:0
Stearic acid	Octadecanoic acid	CH3(CH2)16COOH	C18:0
Nonadecylic acid	Nonadecanoic acid	CH3(CH2)17COOH	C19:0
Arachidic acid	Eicosanoic acid	CH3(CH2)18COOH	C20:0

C4, familiar as Butyric acid, helps maintain the integrity of the intestinal barrier and the blood brain barrier.  Butyric acid, or butyrate, is also an HDAC inhibitor and it seems that in animal models, and some humans, a small amount can be beneficial but large amounts can have a negative effect. A small amount in humans seems to be about 500 mg a day.  There are earlier posts is this blog on butyrate.

C3, familiar as Propionic acid, is bad for you and too much propionic acid will by itself cause autistic behaviours. NAC counters the effect of propionic acid in mouse models.

All those people eating coconut oil are consuming a 99% mixture of fatty acids with 1% phytosterols.

Phytosterols like β-Sitosterol, Stigmasterol, Avenasterol and Campesterol likely explain why coconut oil actually reduces "bad" cholesterol, rather than increasing it, as predicted by the American Heart Association and others. This counters the negative effect of the Palmitic acid (C16).

Lauric acid (C12) is thought to increase HDL ("good") cholesterol and may have a beneficial effect on acne.

Myristic acid (C14) is also thought to increase HDL ("good") cholesterol.

Palmitic acid (C16) raises LDL ("bad") cholesterol and large amounts have other negative effects.

Oleic acid is also found in olive oil and is seen as a fat with beneficial effects.

Fatty acid content of coconut oil
Type of fatty acid			pct
Caprylic saturated C8			7%
Decanoic saturated C10			8%
Lauric saturated C12			48%
Myristic saturated C14			16%
Palmitic saturated C16			9.5%
Oleic monounsaturated C18:1			6.5%
Other			5%
black: Saturated; grey: Monounsaturated; blue: Polyunsaturated

So the only "bad" part of coconut oil is the Palmitic acid (C16).

As for MCT oil, what is in that?

In pharmaceutical MCT oil, like the one sold by Nestle, the contents are:-

Shorter than C8      1%

C8 (Octanoic)      54%

C10 (Decanoic)   41%

Longer than C10    4%

What is the effect of those fatty acids with more than 10 carbon atoms?  Nobody likely knows.

Cooking with MCT Oil? 

This is what Nestle has in mind for dinner.


Mct Spaghetti With Meat Sauce

4 Tbsp. MCT Oil® (Medium Chain Triglycerides)
1 lb. very lean ground veal or beef
1 tsp. salt
1/2 tsp. pepper
1/4 cup chopped onion
3 Tbsp. chopped green pepper
1 cup MCT Tomato Sauce (see recipe on site)
2 cups cooked spaghetti

Heat MCT Oil; add veal, salt and pepper.
Cook until meat is brown.
Add onion, green pepper, and tomato sauce. Cook for 30 minutes over low heat.
Add cooked spaghetti, stir and serve.