Gut Bacteria

#164: Jong Rho, MD- How Ketones Affect Whole Body Metabolism and Inflammation

by Mike Mutzel



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Mike Mutzel Podcast High Intensity Health


About Jong M Rho, MD

Dr. Rho attended Cumming School of Medicine at University of Calgary. He is Professor of the Departments of Paediatrics, Clinical Neurosciences, Physiology and Pharmacology and Section Chief, Paediatric Neurology, Alberta Children's Hospital.


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Show Notes

01:30 Interest in the Ketogenic Diet: Interest in the diet stems from its efficacy against seizures in those who don’t respond to anti-seizure drugs. Thirty to forty percent of people with epilepsy have seizures that do not respond to drugs.

02:48 Attributes of Beta Hydroxybutyrate:  Beta hydroxybutyrate is a simple metabolite that is the result of fatty acid oxidation, used as an energy molecule. During brain development it is used as a carbon skeleton for creating membranes around cells. It has anti-inflammatory properties, disrupting the formation of multimeric protein complexes that produce inflammation systemically. Basic metabolism is linked tightly to immune system regulation. Beta hydroxy is poised within the metabolism and immune system. Beta hydroxy is also an epigenetic modulator. It is a histone deacetylase inhibitor, which can alter the way genes are ultimately expressed in our bodies.

04:01 Cancer Research: Cancer researchers have pioneered the H-stack inhibitors for cancer. The results of this research may be applicable to other neurological diseases, such as epilepsy. H-stack inhibitors are expensive and fraught with significant side effects.

04:51 Ketogenic Diet and the Disease State: The ketogenic diet renders a homeostatic effect. It normalizes the types of things that happen under disease states. If you have a neurologic condition that alters gene expression, like tumors, and you apply the diet as an adjunctive therapy with a view to the gene expression profile, the diet normalizes it to pre-tumor conditions.

05:36 Impacts upon Metabolism: The diet has been shown to return metabolism to normal, rather than revved or sluggish. The diet increases energy reserve, mostly through ketones. Too much glucose is not good for cellular function and the ketogenic diet tends to reduce the overall glucose burden and keep it on a more even keel, positively impacting brain function.

07:02 Impacts of Fatty Acids: A medium chained triglyceride, decanoic acid, blocks glutamate receptors. Glutamate is overly expressed in disease states. Blocking glutamate can have a protective effective and may protect brain cells from dying. Alzheimer’s drugs typically affect the cholinergic axis. Some ALS drugs block glutamate release. What a cell is doing at any particular point in time can have dramatic effects upon the expression and activity of receptors and channels at the cell membrane surface, as well as synaptic transmission.

08:57 Brain Development and Ketones: Ketones pass through the placenta and help the infant brain to develop, providing the carbon atoms to produce the molecules necessary to create the membranes around the brain cells. Women who are insulin resistant, overweight or obese, tend to have children with neurologic disorders. Breast milk is high in fat, meaning that it is a sort of ketogenic diet. In animal studies, if you change the diet of the suckling rodent, it changes its susceptibility to injury of the brain. The fat taken in by the pup is protective against excitotoxic injury. The metabolic state of the brain will determine how much resilience a person may have to future injury or the development of disease.

10:46 Reducing Inflammation: The NLRP3 inflammasome is the best example of reducing inflammation. Fatty acids can regulate ppar receptors (peroxisome proliferator-activated receptors), and they regulate inflammation via different pathways. The ketone body, beta hydroxybutyrate, disrupts the assembly of the large complex within the cell that has to be created before inflammatory processes are activated, where cytokine like interleukins are released. Beta hydroxybutyrate has also been shown to modulate a membrane receptor called hydroxycarboxylic acid receptors (HCA2 receptor) and that too can regulate inflammation.

12:32 Ketones and the Mitochondria: Not long ago we only thought that the simple beta hydroxybutyrate was necessary for producing ATP. It has potent effects throughout the body. It alters the critical death switch in the mitochondria, preventing it from happening and saving the cell from death.

15:46 Carbohydrate Restriction: A several decade study looked at the effects of carbohydrate restriction in primates. Longevity was substantially increased in the carbohydrate restricted animals. They even looked much younger than same age primates.

17:20 Diabetic Ketoacidosis: More ketones are not always better. Many of us who are doing the ketogenic diet measure ketones somewhere between 3 and 5 mmol. Ketones in diabetic ketoacidosis are 10 to 100 fold higher.  The ketone bodies are not balanced by glucose usage, leading to accumulation of ketones. At high levels, they can cause an acidotic state, brain dysfunction and ultimately coma, if not corrected.

18:39 Mitochondria Cell Death: Mitochondria are responsible for more than producing ATP. They regulate the survivability of the cell and regulates calcium. There is one protein complex within the inner membrane and within the mitochondria that tends to regulate its survivability. It is called the MTP pore (mitochondrial permeability transition pore). Anything that keeps that from activating or alters the threshold can be protective for the cell. Beta hydroxybutyrate inhibits the MTP transition in brain mitochondria in normal and epileptic brains. This is an anti-seizure effect. This all happens at the low mml level. On a ketogenic diet, our brains are more like a Tesla than a diesel engine.

21:56 Superoxide Dismutase Upregulation: The ketogenic diet reduces free radical modulation within the mitochondria and oxidative stress. Superoxide dismutase is necessary to rid us of bad free radical players. If you don’t have enough, you experience more damage.

23:01 “Fat is Bad for You”: We have been told for decades that fat is bad for us, so we made up for calories lost with increased carbohydrate intake. We made a profound impact upon how the body works. Reduce your carb intake. Increase your fat intake. Maintain a reasonable amount of protein. Through just this, you can make a profound effect upon disease risk and perhaps longevity.

25:10 Ketogenic Diet and Your Microbiome: The human gut microbiome is being investigated for its effects upon gut function and other organ systems, most notably the brain. If you alter your diet, you alter the microbiome. In a mouse autism model, it was found that the microbiome is radically different in autism, with a higher level of bugs that cause inflammatory changes. Feeding both the autistic mice and the normal control group mice ketogenic diets, levels of the inflammation causing bugs were substantially reduced. It may be a generic effect. Autism could be a peripheral effect from the microbiome, a direct effect of certain substrates impacted by the diet or a combination.

27:47 Homeostasis: Diseases produce shifts. Returning to normal can be done with diet. There are measurable significant clinical benefits by just changing the diet.

28:25 The Big Picture: There are many complicated processes that take compounds and modify them. We are only scratching the surface. It requires a systems biology approach and needs to be seen in a big data way. In epilepsy, despite decades and billions of dollars invested in drug development, the efficacy rates of anti-seizure control have not changed.

32:18 Diet Response: Some people do not respond to the diet and others are super-responders. Few people have addressed this ATP-sensitive potassium channel. It is a relevant player in ketone body action and may be responsible for dampening excitation of the brain in epileptic patients. Do polymorphisms in the KATP channel gene relate to efficacy and response to the diet? So far in research, it does not appear to do so. It would be good to know ahead of time who will respond to the diet, so we can skip the drug therapies.

33:53 Making the Ketogenic Shift: Once you switch your lifestyle and buying patterns at the store, the diet is simple to follow. At first it is a compliance challenge to restrict carbohydrates that you grew up consuming. You don’t need to go on a strict classic ketogenic diet in order to render a beneficial effect.  It can be customized. You need to figure it out yourself and be willing to fail.

35:56 Brain Cancer Survivors: There are many case studies of people with brain cancer going on ketogenic diets and becoming survivors.

36:12 Autism and Ketogenic Diet: We have an epidemic of autism. We don’t have any therapies that address core symptoms that produce the disabling condition. The animal literature suggests that ketogenic therapy will improve all of the behavior domains that we see in autism.

37:40 Dr. Rho’s Elevator Pitch: The primary lesson from the ketogenic diet is that a simple alteration in the type of foods we eat is the basis for preventing disease, treating disease and is something that can be done pragmatically without billions of dollars and the decades needed for drug development. Fats are not bad. Through the unfounded philosophy that fats are bad, we have created a health problem throughout the world.

40:00 Dr. Rho’s Conferences: Every two years the Global Symposium on Ketogenic Therapies is held for professionals. Patients and families are directed to the Charlie Foundation or Matthew’s Friends websites. These are two of the main organizations responsible for education and advocacy for ketogenic therapies. On these websites you can find ketogenic diet centers worldwide. The majority of countries around the world are offering ketogenic programs for patients. Diets around the world can be altered to produce the same ketogenic effects.




Join the conversation

  1. You mentioned about the old drug Koisyt Kinon. I am not pronouncing it correctly. Can you please write the correct spelling. Thanks.

      • i think it was Cholecystokinin (CCK) …
        thanks for this podcast, Mike. Absolutely one of my favourites.
        I’ve not been able to do keto diet with my autistic son because he’s histamine intolerant and has issues with ammonia toxicity.. (which we’ve mostly resolved through shifting his gut microbiota to reduce enterobacter sp. through a higher fibre / lower protein diet… ie replacing some meat meals with bean meals)
        histamine and ammonia issues are very common in the autistic population and often crop up with a vengeance on a SCD or GAPS style diet… appears to be a combination of metabolic and/or dysbiotic issues???
        but somewhat of a double bind when it comes to implementing a keto diet, which purportedly has benefit for ASD. I just can’t find a way to a low histamine keto lunch box!
        I wonder if you’ve come across any useful that could help???

  2. This was wonderful information, my daughter, now 24 (diagnosed with epilepsy as a young child) slowly removed herself from the pharmaceutical drugs ( too many side effects) and introduced herself to the ketogenic diet around age 18. Being a young adult she found it challenging at times but has come to realize when she’s in ketosis she never has a seizure. She knows there is much more to learn. I will be passing on this info, the Charlie foundation etc to her and anyone else interested. Thanks again!
    We will be following!

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