Recent research from the MIT explored how a ketogenic diet, intermittent fasting, and exogenous ketones play important roles in maintaining intestinal stem cell function. We already know that beta-hydroxybutyrate (BHB), the ketone body used in H.V.M.N. Ketone Ester, has beneficial effects on appetite, metabolism, and neurotransmitter function.

Now, this study provides new evidence that BHB itself may play a key mediating role in gut health & stem cell function...even without intermittent fasting or eating a low-carb, high-fat diet. What did the researchers discover and what can you take away from these exciting findings?

Let's find out.

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Welcome to the H.V.M.N. Research Roundup — where we explore some of the newest, most interesting, and sometimes most controversial studies in the field of nutrition, metabolism, and human performance.

In this episode, we are going to analyze a research paper that studied the role of ketones (BHB) in intestinal health and stem cell function.

What You Need to Know First

The gut is responsible for digesting food and absorbing nutrients, as well as serving as a barrier to prevent harmful bacteria from entering the body through our food. It's highly dynamic and active organ and our intestinal lining is actually replaced every few days by shedding old cells for new ones. This means that the lining needs to be continuously regenerated through stem cells. Stem cells are a trendy topic as people speculate and experiment with them for healing injury and promoting anti-aging. Because there is such high turnover in intestine, availability of stem cells is critical to intestinal health and function. The ability of our stem cells to regenerate declines with aging, and conditions like irritable bowel disease — or IBD — are characterized by compromised gut function and intestinal damage. In laymen's terms, all the typical gut symptoms: stomach pain, bloating, gas, diarrhea, constipation. Persistent leaky gut issues can lead to broader systematic inflammation and other related diseases.

We've touched on the "leaky gut" problem various times on our channel, and a good discussion was with former Ironman world champ Pete Jacobs in Episode 119 of the H.V.M.N. Podcast, who's implementing a carnivore diet to manage his gut issues.

But, how can we naturally boost stem cell regenerative capacity? What we eat, basically, what we give the gut to process is an obvious place to start. The presence of certain nutrients in the intestines and the gut microbiome may be responsible for actually allowing stem cells to maintain “stemness” and preserve their regenerative capacity to maintain intestinal homeostasis. Many studies have shown how the intestinal environment can be changed or damaged by diet. Interestingly, some previous studies have shown that fasting can enhance stem cell regenerative capacity in young and old mice.

Fasting depletes glycolysis and drives metabolism towards fat oxidation and ketosis, which is a metabolic switch that stimulates regeneration and increased their function. This is exciting because it implies that lifestyle modifications can cause profound shifts within our cells.

Let's move onto the study we'll be exploring today.

The study, titled “Ketone Body Signaling Mediates Intestinal Stem Cell Homeostasis and Adaptation to Diet” was recently published in the journal “Cell.”

Led by Omer Yilmaz at the MIT Koch Institute for Integrative Cancer Research, this study explored how a high-fat ketogenic diet and exogenous ketone bodies govern signaling programs in the body that maintain intestinal stem cell function. Given that his team's previous research has shown that a shift of intestinal stem cells to fatty acid metabolism causes a profound boost in regenerative capacity, they hypothesized that the same shift may occur due to a ketogenic diet. We know ketone bodies like beta-hydroxybutyrate have signaling roles in the body and can help regulate things like appetite, metabolism, and neurotransmitter function. This study provides evidence that BHB itself may play a key mediating role in maintaining intestinal health too. That is: ketones themselves (and not necessarily through fasting or a ketogenic diet) alone can drive some of the metabolic and functional benefit.

Study Structure

Let’s take a look at the study design. The researchers put groups of mice onto three different nutritional interventions.

1. Ketogenic diet
2. Exogenous ketones on standard diet
3. Exogenous glucose on standard diet

To understand the gene pathways, the scientists focused on one gene in particular that was more highly expressed in stem cells compared to regular progenitor cells. This was a gene known as HMGCS2. This gene encodes the enzyme HMG CoA synthase — which is a rate limiting enzyme for the production of ketone bodies. HMG CoA synthase is necessary to produce ketone bodies from fatty acids in the liver. Without it, endogenous ketosis can’t occur. Keep this gene HMGCS2 in mind throughout this analysis.

Essentially, with the three interventions, the protocol was set up to control for endogenous ketone production through HMGCS2. This helps confirm the mechanism of action as well as the role of the ketone body themselves. Great experiment setup.

There were three key experiments in this study that are particularly relevant to our discussion on ketone bodies and their role in intestinal signaling. The first involved giving exogenous ketones to mice who were lacking the enzyme HMG CoA synthase. These mice were created by using a “knockout” technique — the mice were actually engineered not to have the particular gene and thus lacked its function. In these mice, the researchers provided two different forms of exogenous BHB. Interestingly functionally very similar to the food grade H.V.M.N. Ketone Ester we commercialize . The same mice were also subjected to intestinal damage through radiation in order to test how BHB or a lack of BHB would influence the stem cell regenerative response to injury.

The authors also wanted to know whether or not endogenously produced ketones achieved through a ketogenic diet could enhance ISC number or function. ISC's are a type of cell that remodels the intensitine. To test ketones effect on ISC function, they fed mice a ketogenic diet for 4 - 6 weeks.

In addition to putting mice on a ketogenic diet, they also investigated how a diet in stark contrast to keto would influence intestinal stem cell function — so they fed ice a glucose-supplemented, a.k.a. high sugar diet for 4 weeks. In all groups, they measured the number and function of intestinal stem cells, the protein expression of the enzyme HMG Coa synthase in the intestine, serum levels of the body BHB, and the activity of different signaling pathways that are known to be responsible for stem cell differentiation and function.

With the experiments laid out, it’s now time to look at some of the study’s findings.

Study Results

Even in the absence of a ketogenic diet, it was observed that intestinal stem cells have naturally high levels of the enzyme HMGCS2 — they were already proficient at producing ketone bodies to regulate stem cell signaling, and did so even in non-ketogenic mice. It appears that intestinal stem cells produce and use ketone bodies even when a regular diet is followed, and this allows the maintenance of intestinal tissue. This suggests that ketones themselves (and not other effects of ketogenic diet) have a baseline role in maintaining intestinal health.

Importantly, when you knock out this enzyme in ISCs, stem cell function declines, indicating a necessary role of ketone bodies in stem cell communication. Next, let’s cover what happened when the exogenous ketone BHB was provided to each strain of mice — those with and those without the HMGCS2 gene. When mice lacking the ketogenic enzyme were given oral BHB, they experienced a partially restored regenerative capacity of their intestines after the radiation damage. In the mice not given BHB and still lacking HMGCS2, significant intestinal damage was noted. The authors suggest that ketone bodies themwelves drive much of the benefit of a ketogenic diet. The loss of endogenous ketosis via the enzyme HMGCS2 did not eliminate the BHB benefit. Exciting result!

What about the keto diet mice? After 4 - 6 weeks of a ketogenic diet, these mice had significantly elevated levels of the enzyme HMGCS2 throughout their intestine and had enhanced activity of the Notch pathway — a pathway involved in stem cell function and regeneration capacity. The increase in HMGCS2 was associated with the nearly 6.8 fold elevation in intestinal BHB concentrations. Ketogenic diet mice also had significantly greater numbers of intestinal stem cells and greater stem cell proliferation compared to mice fed a standard chow diet. The keto diet not only improved the number of stem cells, but also improved their overall function. For one, the cells of keto diet-fed mice were more capable of forming into organoids — which are artificially grown masses of cells that resemble an organ.

Additionally, the ketogenic diet enhanced intestinal stem cell regenerative output in response to the radiation damage to their intestine. And what happened on the glucose-supplemented diet? Unsurprisingly, this diet led to a reduced amount of HMGCS2 in the intestine of mice and reduced levels of BHB. These results make sense, because dietary glucose increases insulin, and rapidly shuts off ketone body production. Long story short, these mice weren’t in ketosis. As a result, this high-sugar diet decreased the ability of intestinal stem cells to regenerate by around 2-fold after radiation-induced injury. Interestingly, this loss of function could be rescued by a single oral dose of BHB. These results show that suppression of ketone production by glucose has similar effects to knocking out the HMGCS2 gene in the mice.

Some major conclusions from these findings are that intestinal stem cells are rich in the enzyme HMGCS2, and that the richness of this enzyme in intestinal stem cells produces ketone bodies which normally regulate intestinal stemness — a function which is enhanced in the presence of a ketogenic diet or exogenous ketones. What are the implications of these findings?

Our Analysis

This study provides additional data that while ketone bodies serve as an energy source under periods of low energy availability, they are also signaling metabolites. One hypothesis that I continue to see strengthened is that ketones themselves are a key factor of why ketogenic diet works. This implies that exogenous ketones may drive much of the benefit of a ketogenic diet without the need to consumer a ketogenic diet or fast. This would be a game changer.

This study again provides evidence that BHB — whether in the intestine or throughout the circulation — may provide a diverse signal that coordinates diet and metabolism, resulting in the adaptation of our intestinal system. This may perhaps result in an improved ability of the intestines to regenerate after injury, and perhaps heal. This might imply that a long-term ketogenic diet might reshape the intestinal environment in profound ways. Whether this is beneficial has yet to be determined.

Even in the absence of a high-fat diet, this study showed that intestinal stem cells produced unusually high levels of ketone bodies. In an interview with MIT News, the study lead explained how “ketone bodies are one of the first examples of how a metabolite instructs stem cell fat in the intestine.”

Our body may thus use changes in the levels of ketones bodies in response to different dietary or energetic patterns to coordinate and adapt stem cells to different physiological states such as starvation or high energy availability. The ketogenic diet in mice enhanced their stem cell capacity to regenerate. Perhaps even more interesting, feeding a glucose diet prevented ketone body production and impaired stem cell regeneration. This brings into question whether a large reason for intestinal issues and poor gut health might be our OWN suppression of stem cell ketone body production through diet. Could consuming too much glucose or too many dietary carbohydrates, cause a shift in our stem cell microenvironment and lead to impaired function or intestinal diseases?

These findings also make sense from an evolutionary perspective. In times of energy or caloric deprivation such as fasting, where ketone body production would be high, the intestine would need to preserve and possibly even enhance stem cell function. This study supports that theory. Then, when food becomes replete and energy is available, we have a very large pool of stem cells to draw upon to repopulate the cells in the intestine. This theory is also supported by the previous findings of this group that fasting leads to increased intestinal stem cell regeneration.

A question is raised by the authors about the potential implications that these findings have for cancer. For instance, some tumors are known to begin with the over-proliferation of certain types of stem cells. Heightened stem cell activity is linked to cancer development in the intestines. Could driving this pathway too much through diet or pharmacological intervention impact cancer formation? This is a valid question that is still open to science in order to unpack the important nuances.

Key Takeaway

This study really gives us some insight into a potential large role that ketones have in human health. By eating a ketogenic diet or elevating ketones through exogenous ketone supplementation, we might be enhancing our body’s adaptive and regenerative abilities — at least that of the intestine. This could have profound implications for healing diseases related to compromised gut health and function.

Could the ketogenic diet or consuming exogenous ketones like H.V.M.N. Ketone Ester prove to be effective in regenerating intestinal damage due to a lifetime of a poor diet, chemotherapy, or gastrointestinal diseases? There is some data here to suggest why this could work, but we will have to wait for more studies to definitively find out.