How can a ketogenic diet help heal a leaky brain and make the blood-brain barrier stronger and more resilient?
That’s a really good question. So I am going to answer it. In this blog post, we are going to discuss what the blood-brain barrier is, what symptoms we can expect to take place if it becomes damaged and leaky, and even lab tests that can be used to try to evaluate if it’s leaky.
Your blood-brain barrier (BBB) is super important
First, just a little bit of anatomy and function. Just enough so you understand what’s involved.
The BBB separates the blood from the extracellular cerebrospinal fluid and protects the brain from bloodborne pathogens and toxins while allowing the diffusion of oxygen, carbon dioxide, and small lipophilic molecules/ethanol. Maintenance of the BBB is essential for a tight control of the chemical composition of the brain’s interstitial fluid (ISF) essential for synaptic function as well as offering a form of protection against bloodborne pathogens
Kakaroubas, N., Brennan, S., Keon, M., & Saksena, N. K. (2019). Pathomechanisms of blood-brain barrier disruption in ALS. Neuroscience journal, 2019. https://doi.org/10.1155/2019/2537698
The BBB is a collection of blood vessels and astrocytes that together keep things out of the brain from systemic circulation. It has different transporters that allow some things to pass through.
But just like a leaky gut as the BBB declines in health it cannot maintain its integrity and things get into the brain that should not. These might include:
- Chemicals and Environmental Toxins
- Pathogens (bacteria and viruses)
- Food proteins (e.g., gluten)
- Various inflammatory mediators in the bloodstream (e.g., lipopolysaccharide)
- Circulating anti-bodies
- Hormone imbalances (true hypothyroidism)
When these things get through a leaky blood-brain barrier they activate the brain’s immune system to try to protect the brain. Specifically, microglial cells become activated. If you have a leaky BBB, it means things are getting up there all the time that do not belong. And this means the microglial activation is happening constantly. That’s not good. That sets the stage for chronic neuroinflammation. And if your brain cannot repair itself fast enough to keep up with the damage going on from chronic neuroinflammation, it’s going to set you up for a neurodegenerative process.
Brains need micronutrients to repair the damage, make neurotransmitters and important enzymes, and to generate energy. Do you know how your brain gets the majority of the vitamins it needs for those processes? Your BBB. Yep, that’s right! Most of the essential water-soluble vitamins (e.g., B vitamins) and other important metabolites are transported into the brain using specific transporters in the BBB.
Some of these transporters are used to pass glucose into the brain. As we have discussed in previous articles, this does not have to be glucose you eat. Your body is more than happy to make the glucose substrate you need for certain parts of your brain to work. But if your BBB is damaged and the transporters used for that purpose are damaged or not working (BBB can become insulin resistant) then you are not going to get to use that glucose for energy. And in this way, BBB deterioration can happen and its deterioration can perpetuate energy crises in the brain.
If your BBB is damaged, that can cause a problem for all of those transporters, whose job is to get nutrients and fuel into your brain.
This means your brain ages MUCH faster than it is supposed to. And it doesn’t matter if you are 15 or 27 or 34 or in your 40s or 50s or 60s. Neurodegenerative processes happen at any age. A leaky BBB is not an old person’s problem. It is an “every person of any age sort of problem.” And it needs to be considered and addressed.
Don’t get me wrong. I am glad to see leaky GUT get a lot of airtime and concern. I am relieved it is finally on people’s radars in a real way. Healing a leaky gut is important because you need to keep the body’s immune system quiet to keep the brain’s immune system from becoming overactive. You need healthy digestive tracts to be able to break down and absorb your nutrients through your gut and you need a healthy microbiome for probably a billion reasons.
You can learn more about healthy microbiomes here.
But there is a whole other barrier that needs to be promoted and understood by the general public and people who are struggling with brains that do not work as well as they would like. And that’s why this post is being written. A leaky brain is a thing.
When the BBB is broken down the major thing that happens is that you get neuroinflammation. When there is a neuroinflammatory process, people begin to complain about having symptoms of brain fog.
When you have brain fog, it means something is interfering with normal synapse function.
Synapses constitute a highly specialized and vital part of neuronal cells. They are the primary sites of communication between neuronal cells, and therefore, they are involved in all aspects of neuronal physiology. Proper synaptic function is a prerequisite for normal brain function, and even minor disturbances may lead to neurological disorders.
Xylaki, M., Atzler, B., & Outeiro, T. F. (2019). Epigenetics of the Synapse in Neurodegeneration. Current neurology and neuroscience reports, 19(10), 1-10. https://doi.org/10.1007/s11910-019-0995-y
Neuroinflammation interferes with nerve conduction speed and you may notice that thinking and motor tasks become less efficient or come less easily. Neuroinflammation also “uncouples” mitochondria. Mitochondria are your cell powerhouses. They provide the energy your cell needs to function. From firing those synapses to keeping the cell healthy with the energy to do basic cell housekeeping. What do uncoupled mitochondria feel like? It feels like brain fatigue. Your brain gets tired faster. Maybe you cannot drive in heavy traffic anymore, withstand long social interactions or read as much as you used to. Your ability to do tasks and pay attention is diminished.
Neuroinflammation can wax and wane. Some weeks there are mood and cognitive disturbances, and other weeks you will experience less of those symptoms. This simply means that the brain is having some success, some of the time, managing the inflammatory process and repairing neurodegeneration as it is happening.
But as you can imagine, the root causes that create a leaky BBB should not be ignored, and at some point the brain fog may become chronic, as the immune system becomes chronically overactive and the rate at which damage is done outstrips the body’s antioxidant systems, creating oxidative stress and setting off significant neurodegenerative processes.
Growing evidence shows that oxidative stress (OS) plays a critical role in the induction of BBB changes.
Kadry, H., Noorani, B., Bickel, U., Abbruscato, T. J., & Cucullo, L. (2021). Comparative assessment of in vitro BBB tight junction integrity following exposure to cigarette smoke and e-cigarette vapor: A quantitative evaluation of the protective effects of metformin using small-molecular-weight paracellular markers. Fluids and Barriers of the CNS, 18(1), 1-15. https://doi.org/10.1186/s12987-021-00261-4
I keep mentioning these neurodegenerative “processes” because while occasional neurodegeneration happens, once it escalates into something chronic (aka a process) the neurodegeneration feeds itself, creating a loop of constant damage, nutrient depletion, additional neuroinflammation, and other factors that can make it much more difficult to turn it around after a certain point of damage. If allowed to go unchecked it can in fact cause a level of damage that cannot be remediated. And that is why this blog sounds the alarm that brain fog needs to be taken seriously and treated with powerful nutritional and functional psychiatry treatments that halt the root causes of neurodegenerative processes. Regardless of reason or diagnosis.
How do I know if I have a leaky brain?
There are different antibody markers associated with BBB permeability. These include S100B, aquaporin 4, glial fibrillary acidic protein, and zonulin antibodies. Your functional medicine practitioner can order tests like these through Cyrus Laboratory.
You can get tested, but here is the thing. If you know you have a leaky gut, or you have been diagnosed with a leaky gut, then there is a very good chance that you have a leaky BBB. Because a leaky gut allows things to enter the bloodstream that should not. And some of those things are direct assaults on the BBB. The correlation between leaky gut and leaky BBB is super high. They go together.
For example, the antibodies produced against gluten, that are not stopped by the BBB can bind to astrocytes and neurofilament proteins in the cerebellum and cause a condition called Gluten Ataxia. The neurodegenerative process leading up to this diagnosis can look like brain fog symptoms that include trouble speaking, odd tingling sensations in the extremities, poor coordination and balance, and maybe problems using your arms and legs or your fingers and hands (e.g., you begin to notice more problems getting your fingers to work while you crochet).
Maybe you have toxins in your body, whether through exposure to a chemical from a typical household product or something you inhaled from your environment walking down the street (this happens constantly). If your BBB is healthy, these are not going to cross into the brain. But if it isn’t healthy, whatever the substance it will cross into the brain, activating microglia that release inflammatory cytokines.
These unwelcome substances that made it through your BBB, and should not be anywhere near the brain, will bind and attach to different proteins and break things. What do I mean by “break things” exactly? I mean they will bind to places other things were supposed to bind to, and not allow something to function properly. They will get in the way and inhibit important mechanisms your brain needs to function and keep your brain healthy.
How your BBB got leaky
Your BBB is basically endothelial cells and astrocytes (astroglia). Both of these are easily damaged in environments of chronic inflammation. Chronic diseases that increase inflammation in the body (which is probably all of them) can play a role in breaking down the BBB. Some of the medications that mainstream medicine uses to treat the chronic disease can cause a breakdown of the BBB (e.g., corticosteroids). It can also happen as a result of a traumatic brain injury (TBI) (e.g., car accidents, falls) because the BBB may not sufficiently heal after such an assault. Chronic inflammatory gut problems can create a state of systemic inflammation because of leaky gut (permeability) releasing more zonulin or lipopolysaccharides (LPS) into the bloodstream, which then impairs the health of the BBB directly.
What else causes problems for my BBB?
If you have high levels of homocysteine on your blood tests, you have a higher likelihood that your BBB is leaky. If you have genetic SNIPS such as MTHFR, you are at higher risk of problems keeping your BBB intact and healthy. You can improve the odds by taking a methylated B-complex.
Other factors that create BBB permeability include the following:
- Sedentary lifestyle
- Alcohol consumption
- Chronic sleep deprivation
You would probably like to know what can be done to fix it.
How ketogenic diets might help heal a leaky brain
Most of our information about how ketones affect the BBB comes from animal studies. Personally, I am relieved by that. I don’t want anyone cutting into anyone’s head trying to figure out what’s going on in there. So don’t get hung up on the idea that because these come from animal studies somehow the findings are not legit for your BBB. There is a lot of the same machinery going on.
Improved brain and BBB metabolism
When your body is making ketones on a ketogenic diet, it can provide an alternative energy source for the damaged BBB. They just happen to be THE preferred fuel source for the brain. They get into the brain without the fuss or muss of needing a happy or working transporter (e.g., simple diffusion or facilitated diffusion). Monocarboxylate transporters mediate ketone body entry into the brain, and they are in abundance all through the BBB, including the plasma membrane of the choroid plexus, the endothelial and epithelial cells, glia, and neurons. Literally, oodles of ways to get those ketones on up in there to fuel your brain. Those ketones get used in the mitochondrial matrix (a membrane in your cell batteries) that makes energy.
And here is what I need you to get also. The BBB uses energy from ketones also. Those little cells that make up the BBB try to make their own ketone-based energy all the time. And if you are on a ketogenic diet those cells are going to be replete with the energy they need to tighten up the junctions needed to keep the BBB strong and intact.
Did I mention brains need a lot of energy? Pretty cool that there is a way to get it the energy it needs that doesn’t require more effort. Right? It’s kind of like a passive income stream instead of buying into hustle culture. I mean, we can get those GLUT receptors working again eventually as our healing progresses. But we are never going to progress in our healing if we starve the brain in the meantime. It’s just going to perpetuate the neurodegenerative processes going on. As a bonus, ketone bodies also directly enhance GLUT1 activity, and GLUT1 is a transporter that helps that glucose get where it belongs.
Ketones are anti-inflammatory
We just don’t have a medication that provides the same level of anti-inflammatory effects as safely or effectively as the ketogenic diet.
The therapeutic efficacy of large-spectrum anti-neuroinflammatory drugs is limited by their side effects after even transient immunosuppression.
JANIGRO, D. (2022). Effects of the Ketogenic Diet on the Blood–Brain Barrier. Ketogenic Diet and Metabolic Therapies: Expanded Roles in Health and Disease, 346. P.355
When there is chronic immune activation there is damage that is done in the brain and to the BBB. This causes inflammation and additional stress for the body in trying to maintain the tight junctions in the BBB. This inflammation can damage those important vascular structures that are a part of the BBB. It can damage the glial and astrocytes. Ketogenic diets turn down inflammation. The ketones produced on a ketogenic diet behave as signaling molecules, literally telling genes involved in chronic inflammation to turn themselves off. Pretty useful for helping that little BBB catch up on repairs, maintain its integrity and function, and perpetuate its own healing if you ask me.
Now back to those vascular structures. There are a lot of dementias that have vascular disease components. Ketones increase cerebral blood flow uptake and this increased blood flow and use of oxygen is thought to contribute to the well-documented neuroprotective effects of ketone bodies. A leaky BBB is an etiological factor in some dementias (e.g., Alzheimer’s) and it is thought that benefits seen in with ketogenic diets in these populations may in part be due to improved BBB function. The hypothesis that ketones improve neurovascular function in dementias is a current area of research study.
As if all this were not reasoning enough for using a ketogenic diet to help heal the leaky brain, ketones help create more of the very proteins the BBB uses to heal those gap junctions that got leaky, to begin with.
Supplement Options
Because I believe you have the right to know all the ways you can feel better, I am going to list some of the supplements that are used that have varying levels of evidence of improving the BBB. But let me be perfectly clear in that I don’t think this is anywhere near as cool or as effective for healing the BBB as a well-formulated ketogenic diet. None of these heal insulin resistance. None of these are alternative fuel sources for the brain. Some of these can improve the function and blood flow to the epithelial and endothelial cells, and some can provide some improved antioxidant action so you can try to play catch up with oxidative stress.
Will you get some BBB healing from these supplements? Yes, you might. As long as the neurodegenerative cascade you have going on doesn’t have too much momentum. But if your BBB permeability is from a stroke or TBI, or early dementia processes, these do not provide the correct fuel source your brain needs to combat brain hypometabolism. These supplements do not provide improved micronutrients or even macronutrients for maintenance and repair towards optimized brain and BBB function.
If you are serious about healing your brain, don’t be afraid to do the thing you are imagining is really hard. I promise you, that learning how to implement and sustain a ketogenic diet is not nearly as hard as having a brain that doesn’t work. A brain that keeps you from enjoying life fully.
A brain that is in constant distress with mood issues and memory problems?
THAT IS HARD. Every. Single. Day.
A ketogenic diet is a learning curve and you deserve support in implementing it. But I promise you, as someone who has recovered my own brain, it is not nearly as hard as you are imagining. You are already going through one of the hardest things. Ketogenic diets are easy in comparison.
Supplements that can assist with BBB repair include fish oils, Ginko Bilboa, vinpocetine, alpha-lipoic acid, and glutathione (get liposomal, learn why here LINK), and resveratrol.
I will sometimes use some of these in addition to a ketogenic diet as adjunctive therapy, but I do not use them by themselves to heal BBBs or other parts of the brain. And so I do not know the exact dosages that people use if they are using these as primary therapy for this purpose. But again, you will be able to research those variables for your own healing.
Conclusion
In the Brain Fog Recovery Program I teach, we use ketogenic diets, personally optimized nutritional supplementation, and coaching towards functional medicine interventions that help treat a leaky BBB and help people live their very best life. Because let’s be honest. How do you experience life? Through your brain. You don’t have to live with brain fog symptoms, regardless of reason or diagnosis. Just because your doctor ignored your complaints about your inability to focus, remember things, or maintain your mood doesn’t mean there are no effective treatments.
I am happy to help you learn all the ways you can feel better!
References
Achanta, L. B., & Rae, C. D. (2017). β-Hydroxybutyrate in the Brain: One Molecule, Multiple Mechanisms. Neurochemical Research, 42(1), 35–49. https://doi.org/10.1007/s11064-016-2099-2
Carnevale, R., Pastori, D., Nocella, C., Cammisotto, V., Baratta, F., Del Ben, M., Angelico, F., Sciarretta, S., Bartimoccia, S., Novo, M., Targher, G., & Violi, F. (2017). Low-grade endotoxemia, gut permeability and platelet activation in patients with impaired fasting glucose. Nutrition, Metabolism and Cardiovascular Diseases, 27(10), 890–895. https://doi.org/10.1016/j.numecd.2017.06.007
Cheng, S., Chen, G.-Q., Leski, M., Zou, B., Wang, Y., & Wu, Q. (2006). The effect of d,l-β-hydroxybutyric acid on cell death and proliferation in L929 cells. Biomaterials, 27(20), 3758–3765. https://doi.org/10.1016/j.biomaterials.2006.02.046
Chiry, O., Fishbein, W. N., Merezhinskaya, N., Clarke, S., Galuske, R., Magistretti, P. J., & Pellerin, L. (2008). Distribution of the monocarboxylate transporter MCT2 in human cerebral cortex: An immunohistochemical study. Brain Research, 1226, 61–69. https://doi.org/10.1016/j.brainres.2008.06.025
Chiry, O., Pellerin, L., Monnet-Tschudi, F., Fishbein, W. N., Merezhinskaya, N., Magistretti, P. J., & Clarke, S. (2006). Expression of the monocarboxylate transporter MCT1 in the adult human brain cortex. Brain Research, 1070(1), 65–70. https://doi.org/10.1016/j.brainres.2005.11.064
Choquet, D., & Triller, A. (2013). The Dynamic Synapse. Neuron, 80(3), 691–703. https://doi.org/10.1016/j.neuron.2013.10.013
Cucullo, L., Hossain, M., Puvenna, V., Marchi, N., & Janigro, D. (2011). The role of shear stress in Blood-Brain Barrier endothelial physiology. BMC Neuroscience, 12(1), 40. https://doi.org/10.1186/1471-2202-12-40
Cummins, P. M. (2011). Occludin: one Protein. Many Forms. Mol. Cell. Biol. 32, 242–250. doi: 10.1128/mcb.06029-11
Damir Janigro. (n.d.). IJMS | Free Full-Text | Ketone Bodies Promote Amyloid-β1–40 Clearance in a Human in Vitro Blood–Brain Barrier Model. Retrieved June 5, 2022, from https://www.mdpi.com/1422-0067/21/3/934
Damir Janigro. (2022). Effects of the Ketogenic Diet on the Blood-Brain Barrier. In Ketogenic Diet and Metabolic Therapies: Expanded Roles in Health and Disease (2nd ed., pp. 346–363). Oxford University Press.
Datis Kharrazian. (2020, July 23). Leaky Brain: Brain fog, memory loss, depression. https://www.youtube.com/watch?v=ulj5wuGajFw
Fasano, A. (2020). All disease begins in the (leaky) gut: Role of zonulin-mediated gut permeability in the pathogenesis of some chronic inflammatory diseases. F1000Research, 9, F1000 Faculty Rev-69. https://doi.org/10.12688/f1000research.20510.1
FoundMyFitness. (2022, May 31). Intestinal Permeability: The Bacterial link to Aging, Brain Barrier Dysfunction & Metabolic Disorder. https://www.youtube.com/watch?v=evQAzGaW1JU
Frontiers | Neurological Symptoms of COVID-19: The Zonulin Hypothesis | Immunology. (n.d.). Retrieved May 22, 2022, from https://www.frontiersin.org/articles/10.3389/fimmu.2021.665300/full
Gibson, C. L., Murphy, A. N., & Murphy, S. P. (2012). Stroke outcome in the ketogenic state – a systematic review of the animal data. Journal of Neurochemistry, 123(s2), 52–57. https://doi.org/10.1111/j.1471-4159.2012.07943.x
Glial Fibrillary Acidic Protein—An overview | ScienceDirect Topics. (n.d.). Retrieved May 22, 2022, from https://www.sciencedirect.com/topics/neuroscience/glial-fibrillary-acidic-protein
Jensen, N. J., Wodschow, H. Z., Nilsson, M., & Rungby, J. (2020). Effects of Ketone Bodies on Brain Metabolism and Function in Neurodegenerative Diseases. International Journal of Molecular Sciences, 21(22), 8767. https://doi.org/10.3390/ijms21228767
Kadry, H., Noorani, B., Bickel, U., Abbruscato, T. J., & Cucullo, L. (2021). Comparative assessment of in vitro BBB tight junction integrity following exposure to cigarette smoke and e-cigarette vapor: A quantitative evaluation of the protective effects of metformin using small-molecular-weight paracellular markers. Fluids and Barriers of the CNS, 18(1), 28. https://doi.org/10.1186/s12987-021-00261-4
Kakaroubas, N., Brennan, S., Keon, M., & Saksena, N. K. (2019). Pathomechanisms of Blood-Brain Barrier Disruption in ALS. Neuroscience Journal, 2019, e2537698. https://doi.org/10.1155/2019/2537698
Llorens, S., Nava, E., Muñoz-López, M., Sánchez-Larsen, Á., & Segura, T. (2021). Neurological Symptoms of COVID-19: The Zonulin Hypothesis. Frontiers in Immunology, 12. https://www.frontiersin.org/article/10.3389/fimmu.2021.665300
Masino, S. A. (2022). Ketogenic Diet and Metabolic Therapies: Expanded Roles in Health and Disease. Oxford University Press.
Masino, S. A., & Rho, J. M. (2012). Mechanisms of Ketogenic Diet Action. In J. L. Noebels, M. Avoli, M. A. Rogawski, R. W. Olsen, & A. V. Delgado-Escueta (Eds.), Jasper’s Basic Mechanisms of the Epilepsies (4th ed.). National Center for Biotechnology Information (US). http://www.ncbi.nlm.nih.gov/books/NBK98219/
Morris, G., Fernandes, B. S., Puri, B. K., Walker, A. J., Carvalho, A. F., & Berk, M. (2018). Leaky brain in neurological and psychiatric disorders: Drivers and consequences. Australian & New Zealand Journal of Psychiatry, 52(10), 924–948. https://doi.org/10.1177/0004867418796955
Olung, N. F., Aluko, O. M., Jeje, S. O., Adeagbo, A. S., & Ijomone, O. M. (2021). Vascular Dysfunction in the Brain; Implications for Heavy Metal Exposures. Current Hypertension Reviews, 17(1), 5–13. https://doi.org/10.2174/1573402117666210225085528
Rahman, M. T., Ghosh, C., Hossain, M., Linfield, D., Rezaee, F., Janigro, D., Marchi, N., & van Boxel-Dezaire, A. H. H. (2018). IFN-γ, IL-17A, or zonulin rapidly increase the permeability of the blood-brain and small intestinal epithelial barriers: Relevance for neuro-inflammatory diseases. Biochemical and Biophysical Research Communications, 507(1), 274–279. https://doi.org/10.1016/j.bbrc.2018.11.021
Reports | Free Full-Text | Gluten Ataxia Associated with Dietary Protein Cross-Reactivity with GAD-65. (n.d.). Retrieved May 22, 2022, from https://www.mdpi.com/2571-841X/3/3/24
Rhea, E. M., & Banks, W. A. (2019). Role of the Blood-Brain Barrier in Central Nervous System Insulin Resistance. Frontiers in Neuroscience, 13. https://www.frontiersin.org/article/10.3389/fnins.2019.00521
Rose, J., Brian, C., Pappa, A., Panayiotidis, M. I., & Franco, R. (2020). Mitochondrial Metabolism in Astrocytes Regulates Brain Bioenergetics, Neurotransmission and Redox Balance. Frontiers in Neuroscience, 14. https://www.frontiersin.org/article/10.3389/fnins.2020.536682
Takahashi, S. (2020). Metabolic compartmentalization between astroglia and neurons in physiological and pathophysiological conditions of the neurovascular unit. Neuropathology, 40(2), 121–137. https://doi.org/10.1111/neup.12639
Vojdani, A., Vojdani, E., & Kharrazian, D. (2017). Fluctuation of zonulin levels in blood vs stability of antibodies. World Journal of Gastroenterology, 23(31), 5669–5679. https://doi.org/10.3748/wjg.v23.i31.5669
Xiao M, Xiao ZJ, Yang B, Lan Z and Fang F (2020) Blood-Brain Barrier: More Contributor to Disruption of Central Nervous System Homeostasis Than Victim in Neurological Disorders. Front. Neurosci. 14:764. doi: 10.3389/fnins.2020.00764
Xylaki, M., Atzler, B., & Outeiro, T. F. (2019). Epigenetics of the Synapse in Neurodegeneration. Current Neurology and Neuroscience Reports, 19(10), 72. https://doi.org/10.1007/s11910-019-0995-y
Yang, Z., & Wang, K. K. W. (2015). Glial Fibrillary acidic protein: From intermediate filament assembly and gliosis to neurobiomarker. Trends in Neurosciences, 38(6), 364–374. https://doi.org/10.1016/j.tins.2015.04.003
Zekeridou, A., & Lennon, V. A. (2015). Aquaporin-4 autoimmunity. Neurology – Neuroimmunology Neuroinflammation, 2(4). https://doi.org/10.1212/NXI.0000000000000110
Zheng, W., & Ghersi-Egea, J.-F. (2020). ToxPoint: Brain Barrier Systems Play No Small Roles in Toxicant-induced Brain Disorders. Toxicological Sciences, 175(2), 147–148. https://doi.org/10.1093/toxsci/kfaa053
1 Comment