In this video, Nick Norwitz presents recent pre‑clinical and translational research showing that ketogenic diets and exogenous ketone esters protect against multiple sclerosis (MS)–like pathology by generating “hidden” ketone bodies in intestinal epithelial cells. These gut‑derived ketones (beta‑hydroxybutyrate) reshape the microbiome, enriching bacteria that produce the metabolite indole lactate, which suppresses inflammatory Th17 cells and confers neuroprotection. Key experiments include (1) feeding mice a ketogenic diet versus a high‑carb control, demonstrating reduced disease scores and inflammation; (2) supplementing control‑diet mice with ketone esters, reproducing the protective effect; (3) intestinal‑specific knockout of HMGCS2, abolishing protection without altering circulating ketones, establishing the importance of hidden intestinal ketones; (4) fecal transplant and in‑vitro microbiome assays showing ketone‑driven enrichment of indole‑lactate‑producing bacteria; and (5) analysis of human MS patient microbiomes revealing lower indole lactate levels that correlate inversely with disease severity, and that ketone treatment raises indole lactate ex vivo. Norwitz extrapolates these findings to suggest broader therapeutic potential of ketogenic interventions for other neurological and psychiatric disorders (schizophrenia, depression, Alzheimer’s, Parkinson’s). He concludes by offering free MCAT‑style question banks linked to the discussed paper, encouraging curiosity and metabolic health mainstreaming.
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Really exciting new data were just published on how a ketogenic diet can help treat neurological disease, in particular multiple sclerosis. But if you think this video is just for those with MS or those who know someone with MS, you'd be wrong. I have broader points to make about the powers of ketogenic diets, including the powers of what I'm going to call hidden ketones. And I'll explain what I mean by that in a little bit. But first, I should describe multiple sclerosis so you know what we're talking about. Multiple sclerosis is a neurological disease where the body attacks the myelin sheaths that are wrapped around nerve cells that help nerve cells communicate with one another. And this leads to dysfunction in the nervous system and symptoms like vision loss, extreme pain, fatigue, and impaired coordination. It's a pretty debilitating condition, and there's no definitive treatment for multiple sclerosis, although acute attacks can be treated with high-dose corticosteroids, and many patients are on disease-modifying immunotherapy. However, there are data from animal models and human clinical trials to suggest ketogenic diets, which place the body into a state of ketosis, —that itself is anti-inflammatory and naturally immune-modulating—can help with multiple sclerosis. For example, in one 6-month phase 2 trial, human patients with multiple sclerosis put on a ketogenic diet exhibited a 50% decrease improvement in fatigue and depression scores, and improvements in physical health and mental health quality of life scores, and improvements in neurological disability. So there's real clinical promise here, but a question remains: how? What is the mechanism? And what broader truths can we gather from understanding those mechanisms? Well, a new study was just published in Cell Reports in a mouse model of multiple sclerosis showing that a ketogenic diet and exogenous ketones can improve multiple sclerosis type disease through changes in the microbiome. And it works at a high level like this: ketogenic diets cause cells in the intestine, intestinal epithelial cells, to make ketone bodies, including the ketone body beta-hydroxybutyrate. And this beta-hydroxybutyrate in the gut changes the microbiome to select for specific bacteria that make another metabolite called indole lactate, which shuts down inflammatory cells like Th17 cells, leading to improvements in multiple sclerosis type pathology and providing neuroprotection. Now that's the high level, but I want to show you more of what they really did. For this paper, in the first experiment, they gave multiple sclerosis mice either a ketogenic diet or a control diet that was high enough in carbs to prevent ketosis, and they measured disease progression. And then the control mice Disease score increased, but this was protected against by the ketogenic diet. What's more, levels of inflammatory cells around the body, including in the spleen and in the brain, were lower in the mice fed the ketogenic diet. Interestingly, they also found a similar effect in mice fed the control diet, higher in carbs, but also given a ketone diet. Ester supplement, which demonstrates that the ketones were the active neuroprotective component. But here's where things get really cool. Now, you may know your liver can make ketone bodies, but your intestinal cells, your intestinal epithelial cells, can as well. And I call these hidden ketone bodies because they may never end up in your bloodstream and thus can't be detected by routine measures. They're specific to the gut. So if you do a finger stick, which is how I measure my ketones, you might not see these ketones. Nevertheless, these hidden gut intestinal ketones are important, as the researchers then prove. What they did next was knock out a key enzyme that makes ketones, HMGCS2, specifically in intestinal epithelial cells. These are the HMGCS2 delta IEC mice, delta as in they knocked them out. But they knocked them out in the intestines, not in the liver. And this led to a drop in intestinal ketones specifically, without impacting blood ketone levels, which is pretty cool. And as you can see here, knocking out the ability to make intestinal hidden ketones abolished the protective effects of a very low carbohydrate ketogenic diet, but without impacting circulating ketones. And this demonstrates the importance of the hidden intestinal ketones in modulating this neurological disease. And again, the next question is, but how does it work? Well, through a series of further experiments, including fecal transplants, the researchers found that ketones, either made by the body or introduced through a ketone ester supplement, shifted the microbiome to enrich for specific bacteria that make an immune-modulatory metabolite indole lactate. And the indole lactate then helps to shut down inflammatory immune cells, leading to the broad neuroprotective effects. Hopefully that makes sense. If not, ask your questions in the comments. And what's more, to dot their i's and cross their t's, the researchers looked at microbiome samples from human patients with multiple sclerosis, and they found that one indole lactate, this immune modulatory ketone-associated biomolecule, indole lactate levels were lower in patients with multiple sclerosis as compared to healthy controls. And two, indole lactate levels in human patients were also inversely associated with disease severity. This means lower levels of the hidden ketone-associated biomolecule indole lactate were associated with worse disease. Lower indole lactate, worse disease. And then 3, treating human microbiome samples with ketones likewise increased levels of this immune-modulating indole lactate. And this all provides strong data that hidden intestinal ketones shape the human microbiome with probable disease-modifying effects in humans with neurological disease, multiple sclerosis. Because remember, it's already been shown that ketogenic diets can help in human MS cases. So, to summarize, my big takeaways are these: ketogenic diets can be immensely beneficial for a range of mental health and neurological conditions. We talked in this video about multiple sclerosis, but schizophrenia, depression, Alzheimer's, Parkinson's all can be affected by ketogenic diets as shown in the literature. Also, the mechanisms behind how ketogenic diets work are fascinating, and thus far we've only scratched the surface of these mechanisms. Mechanisms, which gets me really excited. And finally, by gaining deeper understanding about mechanisms, we can innovate targeted approaches to help people with greater efficiency and effectiveness. Which is why, in part, I love to say stay curious, because it's not only fun, but it can help people. And talking about fun and medicine and actually medical school, If you want to test your medical and biological knowledge, or if you know a young person who wants to become a doctor and apply to medical school, I'm now providing free MCAT-style medical school prep questions associated with select videos like this one based on the paper I just described. It's in collaboration with the company Exam Crackers. These question banks are totally free and part of our shared mission to help put the metabolism back into medicine. And you can get more information about this and their courses below. And thanks for watching, learning, and staying curious. Together, I know we can make metabolic health mainstream.
