high-fat ketogenic diet bad for the gut

Is a high-fat or ketogenic diet bad for your gut?

This article was originally published in October 2018 and updated in June 2020 to include the latest research. The major conclusions from the original article have not changed, with the exception that those with hydrogen sulfide overgrowth should probably steer clear of keto.

Low carb, high-fat ketogenic diets are becoming increasingly popular for everything from weight loss to autoimmunity. Many people have expressed concern about the impact that this dietary approach might have on the health of the gut and gut microbiome. But does a high-fat diet really spell disaster for the gut? Read on to learn why most animal studies are misleading, what the current research says, and why ketosis might even improve gut health in some cases.

If you’ve been reading my blog for a while, you know that I’m a proponent of a low-carb, high-fat or ketogenic diet for certain conditions. Keto is becoming increasingly popular for weight loss, blood sugar regulation, neurodegenerative diseases, and even as a component of integrative cancer treatment. Others choose periodic ketosis for the increased productivity, energy, and mental clarity.

In recent months, I’ve received a lot of questions as to the effects that this has on the health of the gut and gut microbiome. It seems there is this widespread notion that the only thing that feeds beneficial gut microbes is complex carbohydrates, and that if we don’t have dietary fiber, our gut barrier suffers, too.

But is this really true? In this article, I’ll dive into the research and provide a complete discussion of the evidence, including what we do and don’t know.

We don’t really know what constitutes a “healthy” microbiome

New technologies and an increasing interest in gut health in recent years have dramatically increased our understanding of gut microbes, and commercial microbiome tests now allow anyone to get a peek at the microbial world that resides in their gut. Unfortunately, the excitement has gotten ahead of the research, and the truth is, we know very little about what constitutes a “healthy” gut microbiota.

Pick any two people, and on average they will only share about a third of their gut microbiota. The other two thirds of their gut community will vary significantly depending on their genetics, geographical location, history of antibiotic and medication use, mode of birth, diet, and other factors that are yet to be discovered. We really don’t have enough information to say that one person’s “two-thirds” is any better than another person’s “two-thirds”, unless one of them has a major overgrowth or infection with a known pathogen.

You might say, well, couldn’t we look at microbial diversity? Or stability of the community? While it’s generally believed that diversity and community stability are key components of a healthy gut ecosystem, even these can sometimes be associated with diseased states.1,2 And some of the keystone “beneficial” microbes recognized by many to be crucial for microbiome health, such as Bifidobacterium, are completely absent from the guts of traditional cultures like the Hadza,3 yet these populations are virtually free of chronic disease.

The gut microbiome has evolved with us – often in the context of periodic ketosis

Our relationship with our gut microbes today is the product of thousands of generations of co-evolution. For millions of years, evolution hasn’t just been acting on our 23,000 human genes, it’s been acting on the nearly 4 million genes (both human and microbial) that are present in and on our bodies.4 We are who we are today because of how we evolved with our microbes.

The environment we evolved in required regular adaptation to changing conditions. Our ancestors did not always have steady access to food and would have undergone occasional bouts of fasting when food was scarce. As such, our bodies have the ability to burn and use carbohydrates when food is plentiful, and to turn dietary fat or stored body fat into ketones for energy when food or carbohydrates are scarce. This ability to shift our metabolism to changes in dietary intake is called metabolic flexibility.

So the real question here is: Why would our bodies have the metabolic flexibility to deal with the shifting availability of foods – and our gut microbiome not have the same metabolic flexibility? Would our ancestors really have developed a “diseased” microbiome every time starchy carbohydrates became scarce? I think not.

Let’s also consider traditional cultures like the Inuit. Did the Inuit, who ate very few plant foods, really have an unhealthy microbiome? Or did they have a microbiome that was uniquely adapted to their diet? Did they have rampant gut permeability and inflammation from their high-fat diet? Or did their gut also have a form of metabolic flexibility that allowed them to survive on primarily animal protein and fat?

We’ll discuss all of the underlying mechanisms in a moment, but my point here is this: A “healthy” microbiome is simply the microbiome that you have when you’re healthy. And what’s healthy for you may not be healthy for someone else.

(This is part of the reason why I always emphasize looking at the overall gut environment and current symptoms when helping clients with gut issues. If someone has low gut microbial diversity but feels fantastic, treating the gut may do more harm than good. )

But enough on that – let’s dive into the data.

Animal studies that use a “high-fat diet” are misleading

If you search any database of the scientific literature, you can find over a hundred studies that show feeding animals a “high-fat diet” leads to rampant gut dysbiosis, gut permeability, and systemic inflammation. People often cite these studies to suggest that a high-fat diet is also likely to be unhealthy for the human gut microbiome.

Look closer at the methods though, and you’ll see that the “high-fat diet” used in most animal studies is more accurately a diet high in refined soybean oil, lard, and refined sugar, and very low in fiber.5 Dr. Craig Warden, professor at UC Davis, has called this “the mouse equivalent of pork rinds, ribs, and coke.”6 In other words, the classic animal “high-fat diet” is much more reflective of the Standard American Diet than any carefully-crafted ketogenic diet.

Furthermore, human metabolism can easily adapt to a diet higher in fats or carbohydrate. The natural diet of a mouse on the other hand, is low in fat and high in carbohydrates, so it’s not all that surprising that mice develop issues when eating a diet that is so poorly matched with what they evolved to eat.

Moreover, the strain of mice most commonly used for such studies, the C57Bl/6 mouse, has been genetically selected for its ability to put on weight and raise glucose in response to a “high-fat diet”. While humans tend to show greater weight loss in response to low-carbohydrate diets, C57Bl/6 mice have greater weight gain and metabolic disruptions on low-carb diets. Dr. Richard Feinman and Dr. Saihan Borghjid write:

“The results suggest that rodent models of obesity may be most valuable in the understanding of how metabolic mechanisms can work in ways different from the effect in humans.” 7

The idea that we can translate any findings in these selectively bred mice fed a highly refined “high-fat diet” to health-conscious humans eating a carefully-crafted ketogenic diet is a gross misunderstanding of the underlying science.

So, let’s look at the human research instead.

(A ketogenic) diet rapidly and reproducibly alters the human gut microbiome

In 2014, David et al. published a study in the journal Nature where they put healthy human volunteers on a short-term plant-based diet or animal-based diet. They found that distinct gut microbial communities emerged within as little as three days.

This was a seminal study in microbiome research and one I’ve been aware of for some time (it’s been cited over 2,700 times since 2014). However, it wasn’t until I was doing the research for this article and looked at the supplementary data that I realized the animal-based diet was ketogenic!

While the plant-based diet included 300 grams of carbohydrate per day from cereal, vegetables, rice, lentils, and fruit, the animal-based diet included less than 3 grams of carbs per day, with 30% calories from protein and 70% calories from fat coming from eggs, meat, and cheese. This macronutrient ratio is consistent with a ketogenic diet. The researchers even confirmed that the subjects were in ketosis day two of the animal-based diet using urine ketone measurements.

So what did they find? Participants on the animal-based ketogenic diet saw no change in microbial alpha diversity (the diversity within individual samples). They saw an increase in the relative abundance of bile-tolerant microorganisms like Bilophila, Alistipes, and Bacteroides spp. and a decrease in the relative abundance of microbes known to metabolize complex dietary plant fibers, such as Roseburia, Eubacterium, and Ruminococcus spp.

In line with my evolutionary argument, the authors write:

“Our findings that the human gut microbiome can rapidly switch between herbivorous and carnivorous functional profiles may reflect past selective pressures during human evolution. Consumption of animal foods by our ancestors was likely volatile, depending on season and stochastic foraging success, with readily available plant foods offering a fallback source of calories and nutrients. Microbial communities that could quickly, and appropriately, shift their functional repertoire in response to diet change would have subsequently enhanced human dietary flexibility.”

In other words, our gut microbiota is simply adapting to the current availability of different food sources – it’s not necessarily becoming any more or less pathogenic by the amount of carbohydrate or fat in the diet. (Note: some overgrowths may be exacerbated on a ketogenic diet – but more on that later.)

Ketogenic diet-induced changes in the gut microbiome may be protective in multiple sclerosis

What about longer-term studies? One study published in the journal Frontiers in Microbiology in 2017 examined the long-term effects of a ketogenic diet on the fecal microbiota in 25 patients with multiple sclerosis.8

Multiple sclerosis (MS) is an autoimmune disease that affects the nervous system. Like many autoimmune diseases, MS is associated with gut pathologies. In fact, some researchers suspect that gut dysbiosis and intestinal permeability may precede development of autoimmunity in the first place.9 Thus, it follows that if a ketogenic diet can significantly improve symptoms of MS,10 it’s probably not harming the gut, and may even be improving gut health.

So what did the study find? Patients with MS tended to have reduced Roseburia, Bacteroides, and Faecalibacterium prasunitzii at baseline compared to healthy individuals. They then went on a ketogenic diet for 6 months. The authors write:

“The effects of a ketogenic diet were biphasic. In the short term, bacterial concentrations and diversity were further reduced. They started to recover at week 12 and exceeded significantly the baseline values after 23–24 weeks on the ketogenic diet.” 8

This suggests that, while short-term dietary changes can rapidly shift the composition of the gut microbiota, we may need to look at long-term dietary changes and collect samples at multiple time points to determine the true effect of a dietary intervention like keto.

Ketogenic diets increase gut ketone levels, reduce Bifidobacterium abundance, and decrease intestinal pro-inflammatory Th17 cells (NEW!)

A study recently published by Dr. Peter Turnbaugh’s laboratory (and presented by Dr. Turnbaugh at the 2020 Virtual Microbiome Summit) confirmed that a ketogenic diet can alter the structure and function of the gut microbiota. 11

The group enrolled 17 overweight and obese men for the first part of the study. They had them consume a baseline control diet for four weeks, followed by four weeks on a defined ketogenic diet. Among the most significant changes on the ketogenic diet was a dramatic reduction in the abundance of several Bifidobacterium species.

The researchers next performed controlled feeding studies in mice. They found that ketogenic mouse diets had a unique impact on the gut microbiome relative to conventional high-fat diets, with the abundance of Bifidobacterium decreasing with increasing carbohydrate restriction. Further experiments found that both a ketogenic diet or ketone ester supplementation led to an increase in beta-hydroxybutyrate in the lumen of the gut, and in colon tissue.

Ketone bodies directly inhibited the growth of Bifidobacterium. Interestingly, this was associated with a reduction in small intestinal Th17 cells. Th17 cells are a subset of T helper cells that produce the pro-inflammatory cytokine IL-17 as part of the adaptive immune response. These cells play an important role at maintaining the gut mucosal barrier and contribute to pathogen clearance at mucosal surfaces. However, Th17 cells have also been implicated in autoimmune and inflammatory disorders, including rheumatoid arthritis, multiple sclerosis, and psoriasis.12

To round out their findings, they transplanted fecal material from human donors collected during the baseline diet or ketogenic diet into germ-free mice, to determine if the change in Th17 cells was dependent on the keto-induced changes in the microbiota. Lo and behold, mice that received the keto-fed microbiota had significantly lower intestinal Th17 cells.

Interestingly, there were no changes in the overall bile acid pool on the baseline diet compared to the ketogenic diet.

Perhaps the most interesting figure of the whole paper though is Supplementary Figure 4. Previous work had shown that mice fed fiber-free diets had a significant breakdown of the colonic mucus layer. However, this was not seen on a ketogenic diet. The authors write:

“A ketogenic diet maintains a robust mucus layer despite the lack of fermentable carbohydrates.”

This is a key finding. Low-carbers can rest easy knowing that if they’re in ketosis, they are likely not degrading their gut mucus layer. The ketogenic diet not only maintained mucus width, but also the expression of Muc2, the primary constituent of gut mucus.

I would have loved to see how the ketogenic diet alters intestinal permeability, gut hypoxia, or other measures of gut pathology. Dr. Turnbaugh mentioned that we may see future experiments from their lab in this regard.

Alright, so we’ve now seen quite a bit of evidence in humans for keto-induced changes in the gut microbiome, and seen how a keto diet impacts the gut microbiota and mucus layer of mice. Let’s look at a few other well-designed animal studies.

The gut microbiome mediates the anti-seizure effects of the ketogenic diet

Ketogenic diets are frequently used to treat epilepsy that is unresponsive to drug treatments. While incredibly effective, exactly how the ketogenic diet confers benefits on brain activity remained elusive for decades.

However, a study published in the journal Cell in May 2018 by Dr. Elaine Hsiao’s group suggests that the beneficial effects of the ketogenic diet on epilepsy are mediated through the gut microbiome.13 In other words, if a ketogenic diet didn’t change the microbiome, it wouldn’t be effective at preventing seizures.

The study was performed in a mouse model of epilepsy (using different strains than the one I mentioned earlier). Like previous studies, they were able to show that feeding the mice a ketogenic diet protected them against seizures. They further demonstrated, however, that treating the mice with broad-spectrum antibiotics abolished the protection against seizures. Similarly, germ-free mice, which are raised in sterile incubators and have no gut microbiome, were not protected against seizures, even when consuming a ketogenic diet.

Interestingly, the ketogenic diet in this study reduced microbial diversity, but increased the abundance of Akkermansia muciniphila and Parabacteroides spp. The researchers wondered if these two microbes were responsible for the seizure protection and tried treating mice fed a normal high-carbohydrate chow diet with Akkermansia and Parabacteroides. Amazingly, this conferred protection against the seizures.

Further mechanistic experiments identified a bacterial pathway that elevated the ratio of the inhibitory neurotransmitter GABA relative to the excitatory neurotransmitter glutamate in the brain. GABA calms activity in the brain, so this explains the seizure reduction, and may also explain why many people find the ketogenic diet beneficial for reducing anxiety.

Now that we’ve covered all of the relevant human and animal experimental data that we have to date, I want to dive into a few mechanistic explanations for changes in gut physiology that occur with ketogenic diets.

Won’t keto reduce your production of butyrate?

By this point you might be asking, how is the gut surviving without any fermentable carbohydrates?

It’s a fair question. We know that gut bacteria metabolize complex carbohydrates to produce short-chain fatty acids (SCFAs) like acetate, propionate, and butyrate. The SCFA butyrate has important signaling functions in the gut and is well known as the preferred fuel source for gut epithelial cells. Published estimates suggest that butyrate provides about 70 percent of the energy requirements for colon epithelial cells. And we need a regular supply of butyrate to maintain gut barrier function…right?

Nope. Turns out that there are several other molecules than can perform many of the signaling functions of butyrate and serve as a source of fuel for the gut epithelial cells! In fact, this idea of a “preferred” fuel source may be skewed from studying people (and rodents) who are eating large amounts of carbohydrates. In other words, butyrate production may be reduced on a ketogenic diet, but other molecules can take its place to help maintain gut barrier function.

Ketone bodies and isobutyrate can replace butyrate

There are three molecules that can replace butyrate: isobutyrate, acetoacetate and beta-hydroxybutyrate.

Isobutyrate is a metabolite of protein fermentation that is typically produced at lower levels than butyrate. When butyrate is less abundant, isobutyrate can be taken up by from the gut lumen by gut epithelial cells and metabolized for energy. Fecal isobutyrate was found to be elevated in the 2014 study I mentioned above in humans consuming the animal-based ketogenic diet.14

Moreover, isobutyrate can stimulate the same receptors as butyrate in the gut (GPR41, GPR43, and GPR109a) to stimulate mucus secretion, antimicrobial peptide release, and immune regulation.15 And while isobutyrate may be produced at lower levels on a moderate-high-protein diet than butyrate would be produced on a high-carbohydrate diet,14 isobutyrate has been shown to be a more potent stimulator of GPR41 (FFAR3), one of the primary receptors for butyrate, than butyrate itself.16 In other words, what isobutyrate lacks in concentration, it may make up for in potency!

The other two molecules, acetoacetate and beta-hydroxybutyrate (βHB), are the two major ketone bodies produced by the liver. Like butyrate, βHB can also stimulate GPR109a, reducing intestinal inflammation. Most notably, however, both βHB and acetoacetate are intermediates in the pathway for butyrate metabolism. In other words, when butyrate is taken up by gut epithelial cells, it is actually converted into βHB first, and then acetoacetate, before being broken down further for energy.17 See the figure I put together below:

Gut epithelial cells are known to express the monocarboxylate transporter MCT1 on the basolateral surface (the side of the cell closest to the bloodstream).18 MCT1 is well-known to transport ketones and is particularly expressed in cells that use ketone bodies for energy. Several older papers suggest that indeed, gut epithelial cells are capable of utilizing ketone bodies from the vascular bed.19,20

Ketones may help overcome impaired butyrate uptake

The ability to use ketones instead of butyrate may not seem advantageous, until you consider that many people with inflamed guts have mucosal damage where butyrate uptake is impaired.

So what does this mean? If you have a healthy microbiome and gut mucosa, butyrate is probably well equipped to deal with all your gut’s needs, no ketones needed.

However, if you:

  • have ulcerative colitis or other mucosal damage, where butyrate uptake is impaired,
  • have gut dysbiosis characterized by a lack of butyrate-producers, or
  • are on restrictive diet such as low-FODMAP or SCD, resulting in reduced butyrate production,

it may be wise to try therapeutic nutritional ketosis to support gut epithelial cell metabolism, at least until treating the underlying gut pathologies and healing the gut mucosa.

Unfortunately, few studies have been performed on ketogenic diets for Crohn’s disease, ulcerative colitis, or irritable bowel syndrome. One case report found that a paleolithic, ketogenic diet induced complete remission in a young boy with severe Crohn’s disease.21 A second case report found that a low carbohydrate diet with ketone ester supplementation significantly reduced inflammation and improved quality of life in a patient with Crohn’s disease.22

Another study of 13 patients with diarrhea-predominant irritable bowel syndrome (IBS-D) found that 10 reported relief of symptoms during a 4-week ketogenic diet.23 Anecdotally, many people with ulcerative colitis have found relief from ketogenic diets, including popular health blogger and biochemist Robb Wolf.

To my knowledge, no studies to date have assessed the effects of ketones or a ketogenic diet on gut barrier function. This is a fairly simple experiment that I would love to see someone perform.

Exogenous ketones may boost gut butyrate (NEW)

Given that a ketogenic diet is fairly restrictive, many people have taken to using ketone esters or salts to achieve ketosis. Other people may use ketone esters or salts on top of a ketogenic diet to achieve a deeper state of ketosis.

Intriguingly, some in vitro data suggests that, at least in some individuals, ketone esters or salts may increase gut butyrate levels. A 2020 study published in Scientific Reports investigated the dynamics of beta-hydroxybutyrate salts 12 human fecal microbiota samples in an in vitro fermentation chamber.24 In seven of the samples (βHB utilizers), more than 54 percent of the βHB was metabolized after 30 hours of fermentation. This was associated with an increased abundance of the genus Coprococcus, a known butyrate-producer, which was correlated with increased butyrate production. In the other five fecal samples (βHB non-utilizers), less than 19 percent of BHB was metabolized, and no change in fecal butyrate was observed.

The authors surmised that the microbes were converting βHB to butyrate. This idea is supported by a 2018 study published in Cell Metabolism, which found that intermittent fasting in rodents resulted in enriched microbial pathways related to the synthesis and degradation of ketone bodies.25  Another possible mechanism is via activation of PPAR-gamma and maintenance of gut hypoxia, which will in turn support populations of butyrate-producers in the gut.

Can fat itself be a source of butyrate? (NEW)

I’ve received a few questions since I first published this article back in 2018 as to whether butter or ghee could act as a significant source of butyrate on a low carb, high-fat diet. Butter is the most concentrated food source of butyrate, with about 3-4 percent butyrate by weight. Ghee, or clarified butter, is likely about 5-6 percent butyrate due to the higher fat content, though I have not seen any published analyses.

Channeling my intro chem conversions here (someone please check my math 😊), let’s say you have a quarter cup of butter: 1/4 cup butter is 14 grams, so .04 percent butyrate x 14 grams = 0.56 grams of butyrate. Divide that by the molecular weight of butyrate (88.11 g/mol) to get 0.006 mol = 6 mmol of butyrate for every 1/4 cup of butter.

The concentration of butyrate in a healthy gut is 70-140 mmol/L in the proximal colon and 20-70 mmol/L in the distal colon. Daily production of SCFAs in the colon is estimated between 300-400 mmol total, and theoretically could be as high as 800 mmol per day.

So, 6 mmol is definitely not an insignificant amount, and could certainly have therapeutic benefits. It’s still relatively small compared to what you would get from fiber fermentation or the amount of cellular energy I suspect you could get from ketone bodies, but comparable to the amount you might get from two ProButyrate capsules.

In other words, butter or ghee can definitely be a component of a healthy ketogenic diet, but I wouldn’t be pounding the butter just for the sake of butyrate.

Ketones mediate small intestinal stem cell homeostasis (NEW!)

A study published in the journal Cell in late 2019 by a group of researchers at MIT found that ketone body signaling regulates the normal function of intestinal stem cells and their ability to respond to injury.

The gut epithelium is extensively folded, with peaks (villi) and valleys (crypts) in the epithelial surface. Intestinal stem cells (ISCs) reside at the bottom of each crypt, and are responsible for renewing the entire gut epithelium every few days or repairing any damage that occurs.

ISCs are tightly controlled by a number of different growth factors that influence their development. Previous studies had shown that dietary nutrients play an important role in determining ISC function, but nobody had yet looked at ketone bodies and their potential role.

The research group first found that the ketone-generating enzyme HMG-CoA synthase 2 (HMGCS2) was enriched in small intestinal stem cells. HMGCS2 is found in many different tissues and is known to limit the rate of ketone formation.

Ablating the Hmgcs2 gene in the intestine diminished beta-hydroxybutyrate levels in the crypts and compromised stem cell function and regeneration of the gut epithelium after injury. Giving exogenous (supplemental) βHB rescued stem cell function and partially restored intestinal regeneration.

They next investigated the effects of a ketogenic diet, and found that it increased HMGCS2 expression, ISC number, function, and post-injury regeneration. In contrast, a glucose-supplemented diet suppressed intestinal stem cell ketogenesis and skew differentiation of stem cells towards goblet and Paneth cells.

Notably, once stem cells had differentiated into mature epithelial cells and migrated up out of the crypt, they expressed very little HMGCS2. This suggests that mature epithelial cells do NOT possess the ability to generate large amounts of ketones through the classical ketogenic pathway (via condensation of two molecules of acetyl coA), though we know that they do have the ability to utilize ketones.

Thus, it follow that if (1) we are seeing high levels of ketones in mature intestinal epithelial cells on a ketogenic diet (as we did in the Turnbaugh paper), and (2) these are not being generated IN mature epithelial cells (as is suggested by the lack of HMGCS2 in this paper), then the ketones are almost certainly coming from circulation.

Along these lines, the authors write:

“Because exogenous ketones rectify Hmgcs2 loss in vitro and in vivo, liver or other non-intestinal sources of ketones may substitute or supplement ISC-generated ketones in KTD-mediated regeneration, where circulating ketone levels are highly elevated.”

But don’t high-fat diets increase LPS absorption?

Another common argument for avoiding high-fat diets is that they increase intestinal absorption of lipopolysaccharide (LPS). LPS is a molecule found in the cell walls of gram-negative bacteria. If it gets into circulation, it can cause low-grade, systemic inflammation.

To really understand this mechanism, we need to review how fats are digested and absorbed. When we eat fat, specialized cells in the small intestine release a hormone called cholecystokinin (CCK). CCK stimulates the gallbladder to secrete bile into the small intestine. Here, the bile acids surround fat molecules, helping to make them water soluble (much like dish detergent helps to emulsify oil).

It turns out that LPS has a high affinity for these water-soluble packages, called micelles. Micelles eventually diffuse toward the gut epithelium, where their contents (including LPS) are picked up by gut epithelial cells. The epithelial cells repackage the lipids and LPS into chylomicrons, which can then be exported to the liver via the lymphatics (the vessels that carry the lymph of the immune system).

When we consume more long chain fatty acids, our body makes more of these chylomicrons, so more LPS can hitch a ride in this fashion.26 Indeed, fat-enriched meals have been shown to moderately increase serum levels of LPS in both mice and humans.27,28 While this is absolutely a real phenomenon and worth considering, I believe this is generally a non-issue for several reasons.

First, several studies suggest that the transport of LPS by chylomicrons may confer an advantage because it favors clearance of LPS by the liver, reducing the toxicity of LPS.29,30 Moreover, chylomicrons also have an innate ability to inactivate LPS.31 Altogether, the increased absorption of LPS appears to reduce inflammation in the gut mucosa.32

This is especially important since the primary mode of systemic exposure to LPS is not through fat absorption, but through a leaky gut! When the gut is permeable, large amounts of LPS can leak into the submucosa and bloodstream, causing localized gut immune responses and systemic inflammation.

In other words, compared to full-blown intestinal permeability, chylomicron-induced LPS absorption is likely a drop in the bucket. (In fact, for those who are dealing with severe intestinal permeability, chylomicron-induced detoxification of LPS may even reduce inflammation enough to facilitate healing of the gut epithelium.)

Furthermore, if fat-induced LPS absorption was an issue, we would expect to see increased systemic inflammation in those fed a high-fat ketogenic diet. On the contrary, subjects fed ketogenic diets almost universally experience a reduction in systemic inflammation.33

Alright so, hopefully by this point, I’ve convinced you that high-fat diets are not to be feared for their lack of butyrate or increased absorption of LPS. In the next section, we’ll see how bile acids might also contribute to a healthier gut.

Bile acids are critical for gut health

Some people have also suggested that a high-fat diet might be detrimental to the gut microbiota and gut barrier because it stimulates increased secretion of bile acids. Generally speaking, the more fat you eat, the more bile is released into the small intestine.

Indeed, some studies have shown that sustained exposure of the gut barrier to high concentrations of bile acids results in intestinal permeability. However, physiologic doses of bile acids have been shown to support barrier function, inducing the secretion of mucus from goblet cells, promoting epithelial cell migration, and boosting gut innate immune defenses.34

Bile acids also have antimicrobial properties, helping to regulate the gut microbiota, and may particularly protect against small intestinal dysbiosis.35 Several studies also suggest that bile acids activate enteroendocrine cells to release serotonin, which helps promote gut motility.36

Exploring the ins and outs of every type of conjugated and deconjugated bile acid is beyond the scope of this article, and something I’ll hope to cover in a future post. Overall, I do not believe there is sufficient evidence to suggest that the physiologic increase of bile acids seen with a ketogenic diet is harmful to the gut microbiota or gut barrier function.

What about the carnivore diet?

The carnivore diet has recently been touted as a cure-all for a wide variety of diseases. While an all-meat diet might be beneficial as a short-term therapeutic diet and, anecdotally, many people experience improvement in their symptoms, there is limited data on the long-term safety of this dietary approach.

It is theoretically possible to get all of your nutrients from an animal-based diet, assuming that you eat nose-to-tail and consume all parts of the animal. Interestingly, the short-term animal-based diet featured in the study I mentioned above was associated with increased expression of bacterial genes for vitamin biosynthesis.14 As a low residue diet, a reduction in gut inflammation may also improve nutrient status in the short-term. However, we know very little about how the carnivore diet might impact nutrient status, hormones, fertility, and thyroid function in the long-term.

Moreover, there is no evidence that any ancestral population lived on only meat or only plants. Even the Inuit and other populations that lived in far northern latitudes went to great lengths to forage plants when they could or boost their fertility in other ways. In his book “Nutrition and Physical Degeneration, A Comparison of Primitive and Modern Diets and Their Effects”, Weston A. Price wrote:

 “Among the Indians in the moose country near the Arctic Circle a larger percentage of the children were born in June than in any other month. This was accomplished, I was told, by both parents eating liberally of the thyroid glands of the male moose as they came down from the high mountain areas for the mating season, at which time the large protuberances carrying the thyroids under the throat were greatly enlarged.”

In other words, these cultures had the traditional wisdom to self-medicate with thyroid glands of other animals to make up for the reduced fertility conferred by their lack of plant foods. Most modern “carnivores” are not doing this, and many are consuming muscle meat alone.

I certainly empathize with those who have found the carnivore diet to provide relief of symptoms. That being said, I believe in most cases, a therapeutic ketogenic diet could be just as effective and that the need to go complete carnivore to relieve symptoms is a sign of an underlying gut infection. Once this is addressed, the ideal diet likely includes some form of plant foods.

When a ketogenic diet is not a good idea: hydrogen sulfide (NEW)

Alright, so hopefully I have convinced you that there is nothing to fear in general about ketogenic diets in regard to gut health. However, I do want to talk about one potential caveat, and that is individuals with hydrogen sulfide overgrowth.

Hydrogen sulfide (H2S) is a colorless gas that is normally produced in the body and acts as an important signaling molecule at low concentrations. However, certain gut bacteria can also produce hydrogen sulfide, and an overgrowth of these bacteria can lead to excess hydrogen sulfide. H2S has been associated with diarrhea, gut hypersensitivity, IBS, IBD, and colorectal cancer.37

The most common H2S producers in the human gut are Desulfovibrio, Bilophila wadsworthia, and Fusobacterium nucleatum. These bacteria tend to thrive on a diet that is high in animal protein and fat. Thus, if you have H2S overgrowth, it’s probably best to avoid consuming a ketogenic diet until you’ve been able to address the issue and rebalance the gut. In fact, a higher fiber, largely plant-based, Mediterranean-style diet might actually be best for H2S.

For more on hydrogen sulfide overgrowth and strategies to address it, stay tuned for my upcoming course release.

Summary & practical tips for gut health on a ketogenic diet

To summarize, there is no clear evidence that a well-designed high-fat or ketogenic diet is detrimental to the gut microbiota or gut barrier function. In fact, keto-induced changes in the gut microbiota and gut barrier may even be the reason we see so many benefits from ketosis.

Moreover, we don’t really know what constitutes a healthy gut microbiota, and ketones and isobutyrate can replace the short-chain fatty acid butyrate that we typically think of as crucial for gut barrier function. Several case reports indicate that a ketogenic diet may reduce inflammation and improve quality of life in IBS and IBD.

I want to stress that I do not believe that a ketogenic diet is right for everyone. My intention with this article was not to suggest that everyone with a gut issue should try a ketogenic diet. I simply wanted to clear up a lot of the confusion and provide a more complete discussion of the evidence for ketogenic diets in relation to gut health.

There are also right and wrong ways to do a ketogenic diet when it comes to gut health. A ketogenic diet high in refined seed oils and processed meats is not going to provide the same therapeutic benefit to the gut as one that includes healthy fats, pastured meats, and lots of non-starchy vegetables.

On that note, here are my top seven tips to doing right by your gut when consuming a high-fat or ketogenic diet:

1) Focus on high-quality fats, like avocados, avocado oil, olive oil, fatty fish, coconut oil, pastured ghee, butter, tallow, etc. Try to get a mixture of monounsaturated, polyunsaturated, and saturated fat.* Avoid highly processed and refined oils like canola, corn, and soybean oil.

**If you plan to remain on a ketogenic diet long-term, I recommend getting a full cardiovascular profile after you have been on the diet for 1-2 months. A small subset of individuals  (“hyper-responders”) will have an increase in LDL particle number and may need to tweak their fat intake or consider a modified ketogenic diet to ensure they are not increasing cardiovascular risk.

2) Eat your (non-starchy) veggies! Just because you don’t necessarily need the butyrate doesn’t mean you should skimp on vegetables. Try to get a variety of both raw and cooked veggies of all types and colors.

3) Indulge with berries. Berries are a great low-carbohydrate source of prebiotic fiber to selectively promote the growth of beneficial bacteria.

4) Drink coffee and eat cocoa. Polyphenols promote the growth of beneficial bacteria, so consume coffee and cocoa as tolerated. Those with severe gut permeability or autoimmunity may want to avoid these foods initially.

5) Consider nutrient density and eat nose-to-tail. Consume organ meats, shellfish, seafood, and be sure to balance methionine-rich muscle meats with glycine-rich animal foods like collagen and bone broth.

6) Experiment! The best way to know if keto works for you is to try it for a few weeks and see how you feel. Pay particular attention to your energy, skin, mood, productivity, digestion, and bowel movements.

7) Try “the keto zone”.Unless you have a good reason to be in nutritional ketosis, there is no need to be in keto indefinitely. By maintaining a carb intake of 20-120 grams (depending on your activity level), you can easily slip in and out of ketosis. In fact, this may help your gut and your microbiome maintain peak metabolic flexibility.

That’s all for now! Be sure to let me know what you thought in the comments below and subscribe to my newsletter so you never miss a post.

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  6. Majority of studies of high-fat diets in mice inaccurately portrayed. http://secure.ucdmc.ucdavis.edu/welcome/features/20080702_diet_warden/index.html.
  7. Borghjid, S. & Feinman, R. D. Response of C57Bl/6 mice to a carbohydrate-free diet. Nutr Metab (Lond) 9, 69 (2012).
  8. Swidsinski, A. et al. Reduced Mass and Diversity of the Colonic Microbiome in Patients with Multiple Sclerosis and Their Improvement with Ketogenic Diet. Front Microbiol 8, 1141 (2017).
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  10. Storoni, M. & Plant, G. T. The Therapeutic Potential of the Ketogenic Diet in Treating Progressive Multiple Sclerosis. Multiple Sclerosis International https://www.hindawi.com/journals/msi/2015/681289/abs/ (2015) doi:10.1155/2015/681289.
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  12. Zambrano-Zaragoza, J. F., Romo-Martínez, E. J., Durán-Avelar, Ma. de J., García-Magallanes, N. & Vibanco-Pérez, N. Th17 Cells in Autoimmune and Infectious Diseases. Int J Inflam 2014, (2014).
  13. Olson, C. A. et al. The Gut Microbiota Mediates the Anti-Seizure Effects of the Ketogenic Diet. Cell 173, 1728-1741.e13 (2018).
  14. David, L. A. et al. Diet rapidly and reproducibly alters the human gut microbiome. Nature 505, 559–563 (2014).
  15. Rahim, A. & Bin, M. B. H. Gut microbial metabolome: regulation of host metabolism by SCFAs. (2016).
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  17. Henning, S. J. & Hird, F. J. Ketogenesis from butyrate and acetate by the caecum and the colon of rabbits. Biochem. J. 130, 785–790 (1972).
  18. Iwanaga, T. & Kishimoto, A. Cellular distributions of monocarboxylate transporters: a review. Biomed. Res. 36, 279–301 (2015).
  19. Roediger, W. E. W. Utilization of Nutrients by Isolated Epithelial Cells of the Rat Colon. Gastroenterology 83, 424–429 (1982).
  20. Hanson, P. J. & Parsons, D. S. Factors affecting the utilization of ketone bodies and other substrates by rat jejunum: effects of fasting and of diabetes. The Journal of Physiology 278, 55–67 (1978).
  21. Tóth, C., Dabóczi, A., Howard, M., Miller, N. J. & Clemens, Z. Crohn’s disease successfully treated with the paleolithic ketogenic diet. International Journal of Case Reports and Images (IJCRI) 7, 570–578 (2016).
  22. Lowery, R. P., Wilson, J. M., Sharp, M. H., Wilson, G. J. & Wagner, R. The effects of exogenous ketones on biomarkers of Crohn’s disease: A case report. Journal of Gastroenterology and Digestive Diseases 2, (2017).
  23. Austin, G. L. et al. A Very Low-Carbohydrate Diet Improves Symptoms and Quality of Life in Diarrhea-Predominant Irritable Bowel Syndrome. Clinical Gastroenterology and Hepatology 7, 706-708.e1 (2009).
  24. Sasaki, K., Sasaki, D., Hannya, A., Tsubota, J. & Kondo, A. In vitro human colonic microbiota utilises D-β-hydroxybutyrate to increase butyrogenesis. Scientific Reports 10, 8516 (2020).
  25. Cignarella, F. et al. Intermittent Fasting Confers Protection in CNS Autoimmunity by Altering the Gut Microbiota. Cell Metabolism 27, 1222-1235.e6 (2018).
  26. Ghoshal, S., Witta, J., Zhong, J., de Villiers, W. & Eckhardt, E. Chylomicrons promote intestinal absorption of lipopolysaccharides. Journal of Lipid Research 50, 90–97 (2009).
  27. Erridge, C., Attina, T., Spickett, C. M. & Webb, D. J. A high-fat meal induces low-grade endotoxemia: evidence of a novel mechanism of postprandial inflammation. Am. J. Clin. Nutr. 86, 1286–1292 (2007).
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  33. Pinto, A., Bonucci, A., Maggi, E., Corsi, M. & Businaro, R. Anti-Oxidant and Anti-Inflammatory Activity of Ketogenic Diet: New Perspectives for Neuroprotection in Alzheimer’s Disease. Antioxidants (Basel) 7, (2018).
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high-fat ketogenic diet bad for the gut

Is a high-fat or ketogenic diet bad for your gut?

This article was originally published in October 2018 and updated in June 2020 to include the latest research. The major conclusions from the original article have not changed, with the exception that those with hydrogen sulfide overgrowth should probably steer clear of keto.

Low carb, high-fat ketogenic diets are becoming increasingly popular for everything from weight loss to autoimmunity. Many people have expressed concern about the impact that this dietary approach might have on the health of the gut and gut microbiome. But does a high-fat diet really spell disaster for the gut? Read on to learn why most animal studies are misleading, what the current research says, and why ketosis might even improve gut health in some cases.

If you’ve been reading my blog for a while, you know that I’m a proponent of a low-carb, high-fat or ketogenic diet for certain conditions. Keto is becoming increasingly popular for weight loss, blood sugar regulation, neurodegenerative diseases, and even as a component of integrative cancer treatment. Others choose periodic ketosis for the increased productivity, energy, and mental clarity.

In recent months, I’ve received a lot of questions as to the effects that this has on the health of the gut and gut microbiome. It seems there is this widespread notion that the only thing that feeds beneficial gut microbes is complex carbohydrates, and that if we don’t have dietary fiber, our gut barrier suffers, too.

But is this really true? In this article, I’ll dive into the research and provide a complete discussion of the evidence, including what we do and don’t know.

We don’t really know what constitutes a “healthy” microbiome

New technologies and an increasing interest in gut health in recent years have dramatically increased our understanding of gut microbes, and commercial microbiome tests now allow anyone to get a peek at the microbial world that resides in their gut. Unfortunately, the excitement has gotten ahead of the research, and the truth is, we know very little about what constitutes a “healthy” gut microbiota.

Pick any two people, and on average they will only share about a third of their gut microbiota. The other two thirds of their gut community will vary significantly depending on their genetics, geographical location, history of antibiotic and medication use, mode of birth, diet, and other factors that are yet to be discovered. We really don’t have enough information to say that one person’s “two-thirds” is any better than another person’s “two-thirds”, unless one of them has a major overgrowth or infection with a known pathogen.

You might say, well, couldn’t we look at microbial diversity? Or stability of the community? While it’s generally believed that diversity and community stability are key components of a healthy gut ecosystem, even these can sometimes be associated with diseased states.1,2 And some of the keystone “beneficial” microbes recognized by many to be crucial for microbiome health, such as Bifidobacterium, are completely absent from the guts of traditional cultures like the Hadza,3 yet these populations are virtually free of chronic disease.

The gut microbiome has evolved with us – often in the context of periodic ketosis

Our relationship with our gut microbes today is the product of thousands of generations of co-evolution. For millions of years, evolution hasn’t just been acting on our 23,000 human genes, it’s been acting on the nearly 4 million genes (both human and microbial) that are present in and on our bodies.4 We are who we are today because of how we evolved with our microbes.

The environment we evolved in required regular adaptation to changing conditions. Our ancestors did not always have steady access to food and would have undergone occasional bouts of fasting when food was scarce. As such, our bodies have the ability to burn and use carbohydrates when food is plentiful, and to turn dietary fat or stored body fat into ketones for energy when food or carbohydrates are scarce. This ability to shift our metabolism to changes in dietary intake is called metabolic flexibility.

So the real question here is: Why would our bodies have the metabolic flexibility to deal with the shifting availability of foods – and our gut microbiome not have the same metabolic flexibility? Would our ancestors really have developed a “diseased” microbiome every time starchy carbohydrates became scarce? I think not.

Let’s also consider traditional cultures like the Inuit. Did the Inuit, who ate very few plant foods, really have an unhealthy microbiome? Or did they have a microbiome that was uniquely adapted to their diet? Did they have rampant gut permeability and inflammation from their high-fat diet? Or did their gut also have a form of metabolic flexibility that allowed them to survive on primarily animal protein and fat?

We’ll discuss all of the underlying mechanisms in a moment, but my point here is this: A “healthy” microbiome is simply the microbiome that you have when you’re healthy. And what’s healthy for you may not be healthy for someone else.

(This is part of the reason why I always emphasize looking at the overall gut environment and current symptoms when helping clients with gut issues. If someone has low gut microbial diversity but feels fantastic, treating the gut may do more harm than good. )

But enough on that – let’s dive into the data.

Animal studies that use a “high-fat diet” are misleading

If you search any database of the scientific literature, you can find over a hundred studies that show feeding animals a “high-fat diet” leads to rampant gut dysbiosis, gut permeability, and systemic inflammation. People often cite these studies to suggest that a high-fat diet is also likely to be unhealthy for the human gut microbiome.

Look closer at the methods though, and you’ll see that the “high-fat diet” used in most animal studies is more accurately a diet high in refined soybean oil, lard, and refined sugar, and very low in fiber.5 Dr. Craig Warden, professor at UC Davis, has called this “the mouse equivalent of pork rinds, ribs, and coke.”6 In other words, the classic animal “high-fat diet” is much more reflective of the Standard American Diet than any carefully-crafted ketogenic diet.

Furthermore, human metabolism can easily adapt to a diet higher in fats or carbohydrate. The natural diet of a mouse on the other hand, is low in fat and high in carbohydrates, so it’s not all that surprising that mice develop issues when eating a diet that is so poorly matched with what they evolved to eat.

Moreover, the strain of mice most commonly used for such studies, the C57Bl/6 mouse, has been genetically selected for its ability to put on weight and raise glucose in response to a “high-fat diet”. While humans tend to show greater weight loss in response to low-carbohydrate diets, C57Bl/6 mice have greater weight gain and metabolic disruptions on low-carb diets. Dr. Richard Feinman and Dr. Saihan Borghjid write:

“The results suggest that rodent models of obesity may be most valuable in the understanding of how metabolic mechanisms can work in ways different from the effect in humans.” 7

The idea that we can translate any findings in these selectively bred mice fed a highly refined “high-fat diet” to health-conscious humans eating a carefully-crafted ketogenic diet is a gross misunderstanding of the underlying science.

So, let’s look at the human research instead.

(A ketogenic) diet rapidly and reproducibly alters the human gut microbiome

In 2014, David et al. published a study in the journal Nature where they put healthy human volunteers on a short-term plant-based diet or animal-based diet. They found that distinct gut microbial communities emerged within as little as three days.

This was a seminal study in microbiome research and one I’ve been aware of for some time (it’s been cited over 2,700 times since 2014). However, it wasn’t until I was doing the research for this article and looked at the supplementary data that I realized the animal-based diet was ketogenic!

While the plant-based diet included 300 grams of carbohydrate per day from cereal, vegetables, rice, lentils, and fruit, the animal-based diet included less than 3 grams of carbs per day, with 30% calories from protein and 70% calories from fat coming from eggs, meat, and cheese. This macronutrient ratio is consistent with a ketogenic diet. The researchers even confirmed that the subjects were in ketosis day two of the animal-based diet using urine ketone measurements.

So what did they find? Participants on the animal-based ketogenic diet saw no change in microbial alpha diversity (the diversity within individual samples). They saw an increase in the relative abundance of bile-tolerant microorganisms like Bilophila, Alistipes, and Bacteroides spp. and a decrease in the relative abundance of microbes known to metabolize complex dietary plant fibers, such as Roseburia, Eubacterium, and Ruminococcus spp.

In line with my evolutionary argument, the authors write:

“Our findings that the human gut microbiome can rapidly switch between herbivorous and carnivorous functional profiles may reflect past selective pressures during human evolution. Consumption of animal foods by our ancestors was likely volatile, depending on season and stochastic foraging success, with readily available plant foods offering a fallback source of calories and nutrients. Microbial communities that could quickly, and appropriately, shift their functional repertoire in response to diet change would have subsequently enhanced human dietary flexibility.”

In other words, our gut microbiota is simply adapting to the current availability of different food sources – it’s not necessarily becoming any more or less pathogenic by the amount of carbohydrate or fat in the diet. (Note: some overgrowths may be exacerbated on a ketogenic diet – but more on that later.)

Ketogenic diet-induced changes in the gut microbiome may be protective in multiple sclerosis

What about longer-term studies? One study published in the journal Frontiers in Microbiology in 2017 examined the long-term effects of a ketogenic diet on the fecal microbiota in 25 patients with multiple sclerosis.8

Multiple sclerosis (MS) is an autoimmune disease that affects the nervous system. Like many autoimmune diseases, MS is associated with gut pathologies. In fact, some researchers suspect that gut dysbiosis and intestinal permeability may precede development of autoimmunity in the first place.9 Thus, it follows that if a ketogenic diet can significantly improve symptoms of MS,10 it’s probably not harming the gut, and may even be improving gut health.

So what did the study find? Patients with MS tended to have reduced Roseburia, Bacteroides, and Faecalibacterium prasunitzii at baseline compared to healthy individuals. They then went on a ketogenic diet for 6 months. The authors write:

“The effects of a ketogenic diet were biphasic. In the short term, bacterial concentrations and diversity were further reduced. They started to recover at week 12 and exceeded significantly the baseline values after 23–24 weeks on the ketogenic diet.” 8

This suggests that, while short-term dietary changes can rapidly shift the composition of the gut microbiota, we may need to look at long-term dietary changes and collect samples at multiple time points to determine the true effect of a dietary intervention like keto.

Ketogenic diets increase gut ketone levels, reduce Bifidobacterium abundance, and decrease intestinal pro-inflammatory Th17 cells (NEW!)

A study recently published by Dr. Peter Turnbaugh’s laboratory (and presented by Dr. Turnbaugh at the 2020 Virtual Microbiome Summit) confirmed that a ketogenic diet can alter the structure and function of the gut microbiota. 11

The group enrolled 17 overweight and obese men for the first part of the study. They had them consume a baseline control diet for four weeks, followed by four weeks on a defined ketogenic diet. Among the most significant changes on the ketogenic diet was a dramatic reduction in the abundance of several Bifidobacterium species.

The researchers next performed controlled feeding studies in mice. They found that ketogenic mouse diets had a unique impact on the gut microbiome relative to conventional high-fat diets, with the abundance of Bifidobacterium decreasing with increasing carbohydrate restriction. Further experiments found that both a ketogenic diet or ketone ester supplementation led to an increase in beta-hydroxybutyrate in the lumen of the gut, and in colon tissue.

Ketone bodies directly inhibited the growth of Bifidobacterium. Interestingly, this was associated with a reduction in small intestinal Th17 cells. Th17 cells are a subset of T helper cells that produce the pro-inflammatory cytokine IL-17 as part of the adaptive immune response. These cells play an important role at maintaining the gut mucosal barrier and contribute to pathogen clearance at mucosal surfaces. However, Th17 cells have also been implicated in autoimmune and inflammatory disorders, including rheumatoid arthritis, multiple sclerosis, and psoriasis.12

To round out their findings, they transplanted fecal material from human donors collected during the baseline diet or ketogenic diet into germ-free mice, to determine if the change in Th17 cells was dependent on the keto-induced changes in the microbiota. Lo and behold, mice that received the keto-fed microbiota had significantly lower intestinal Th17 cells.

Interestingly, there were no changes in the overall bile acid pool on the baseline diet compared to the ketogenic diet.

Perhaps the most interesting figure of the whole paper though is Supplementary Figure 4. Previous work had shown that mice fed fiber-free diets had a significant breakdown of the colonic mucus layer. However, this was not seen on a ketogenic diet. The authors write:

“A ketogenic diet maintains a robust mucus layer despite the lack of fermentable carbohydrates.”

This is a key finding. Low-carbers can rest easy knowing that if they’re in ketosis, they are likely not degrading their gut mucus layer. The ketogenic diet not only maintained mucus width, but also the expression of Muc2, the primary constituent of gut mucus.

I would have loved to see how the ketogenic diet alters intestinal permeability, gut hypoxia, or other measures of gut pathology. Dr. Turnbaugh mentioned that we may see future experiments from their lab in this regard.

Alright, so we’ve now seen quite a bit of evidence in humans for keto-induced changes in the gut microbiome, and seen how a keto diet impacts the gut microbiota and mucus layer of mice. Let’s look at a few other well-designed animal studies.

The gut microbiome mediates the anti-seizure effects of the ketogenic diet

Ketogenic diets are frequently used to treat epilepsy that is unresponsive to drug treatments. While incredibly effective, exactly how the ketogenic diet confers benefits on brain activity remained elusive for decades.

However, a study published in the journal Cell in May 2018 by Dr. Elaine Hsiao’s group suggests that the beneficial effects of the ketogenic diet on epilepsy are mediated through the gut microbiome.13 In other words, if a ketogenic diet didn’t change the microbiome, it wouldn’t be effective at preventing seizures.

The study was performed in a mouse model of epilepsy (using different strains than the one I mentioned earlier). Like previous studies, they were able to show that feeding the mice a ketogenic diet protected them against seizures. They further demonstrated, however, that treating the mice with broad-spectrum antibiotics abolished the protection against seizures. Similarly, germ-free mice, which are raised in sterile incubators and have no gut microbiome, were not protected against seizures, even when consuming a ketogenic diet.

Interestingly, the ketogenic diet in this study reduced microbial diversity, but increased the abundance of Akkermansia muciniphila and Parabacteroides spp. The researchers wondered if these two microbes were responsible for the seizure protection and tried treating mice fed a normal high-carbohydrate chow diet with Akkermansia and Parabacteroides. Amazingly, this conferred protection against the seizures.

Further mechanistic experiments identified a bacterial pathway that elevated the ratio of the inhibitory neurotransmitter GABA relative to the excitatory neurotransmitter glutamate in the brain. GABA calms activity in the brain, so this explains the seizure reduction, and may also explain why many people find the ketogenic diet beneficial for reducing anxiety.

Now that we’ve covered all of the relevant human and animal experimental data that we have to date, I want to dive into a few mechanistic explanations for changes in gut physiology that occur with ketogenic diets.

Won’t keto reduce your production of butyrate?

By this point you might be asking, how is the gut surviving without any fermentable carbohydrates?

It’s a fair question. We know that gut bacteria metabolize complex carbohydrates to produce short-chain fatty acids (SCFAs) like acetate, propionate, and butyrate. The SCFA butyrate has important signaling functions in the gut and is well known as the preferred fuel source for gut epithelial cells. Published estimates suggest that butyrate provides about 70 percent of the energy requirements for colon epithelial cells. And we need a regular supply of butyrate to maintain gut barrier function…right?

Nope. Turns out that there are several other molecules than can perform many of the signaling functions of butyrate and serve as a source of fuel for the gut epithelial cells! In fact, this idea of a “preferred” fuel source may be skewed from studying people (and rodents) who are eating large amounts of carbohydrates. In other words, butyrate production may be reduced on a ketogenic diet, but other molecules can take its place to help maintain gut barrier function.

Ketone bodies and isobutyrate can replace butyrate

There are three molecules that can replace butyrate: isobutyrate, acetoacetate and beta-hydroxybutyrate.

Isobutyrate is a metabolite of protein fermentation that is typically produced at lower levels than butyrate. When butyrate is less abundant, isobutyrate can be taken up by from the gut lumen by gut epithelial cells and metabolized for energy. Fecal isobutyrate was found to be elevated in the 2014 study I mentioned above in humans consuming the animal-based ketogenic diet.14

Moreover, isobutyrate can stimulate the same receptors as butyrate in the gut (GPR41, GPR43, and GPR109a) to stimulate mucus secretion, antimicrobial peptide release, and immune regulation.15 And while isobutyrate may be produced at lower levels on a moderate-high-protein diet than butyrate would be produced on a high-carbohydrate diet,14 isobutyrate has been shown to be a more potent stimulator of GPR41 (FFAR3), one of the primary receptors for butyrate, than butyrate itself.16 In other words, what isobutyrate lacks in concentration, it may make up for in potency!

The other two molecules, acetoacetate and beta-hydroxybutyrate (βHB), are the two major ketone bodies produced by the liver. Like butyrate, βHB can also stimulate GPR109a, reducing intestinal inflammation. Most notably, however, both βHB and acetoacetate are intermediates in the pathway for butyrate metabolism. In other words, when butyrate is taken up by gut epithelial cells, it is actually converted into βHB first, and then acetoacetate, before being broken down further for energy.17 See the figure I put together below:

Gut epithelial cells are known to express the monocarboxylate transporter MCT1 on the basolateral surface (the side of the cell closest to the bloodstream).18 MCT1 is well-known to transport ketones and is particularly expressed in cells that use ketone bodies for energy. Several older papers suggest that indeed, gut epithelial cells are capable of utilizing ketone bodies from the vascular bed.19,20

Ketones may help overcome impaired butyrate uptake

The ability to use ketones instead of butyrate may not seem advantageous, until you consider that many people with inflamed guts have mucosal damage where butyrate uptake is impaired.

So what does this mean? If you have a healthy microbiome and gut mucosa, butyrate is probably well equipped to deal with all your gut’s needs, no ketones needed.

However, if you:

  • have ulcerative colitis or other mucosal damage, where butyrate uptake is impaired,
  • have gut dysbiosis characterized by a lack of butyrate-producers, or
  • are on restrictive diet such as low-FODMAP or SCD, resulting in reduced butyrate production,

it may be wise to try therapeutic nutritional ketosis to support gut epithelial cell metabolism, at least until treating the underlying gut pathologies and healing the gut mucosa.

Unfortunately, few studies have been performed on ketogenic diets for Crohn’s disease, ulcerative colitis, or irritable bowel syndrome. One case report found that a paleolithic, ketogenic diet induced complete remission in a young boy with severe Crohn’s disease.21 A second case report found that a low carbohydrate diet with ketone ester supplementation significantly reduced inflammation and improved quality of life in a patient with Crohn’s disease.22

Another study of 13 patients with diarrhea-predominant irritable bowel syndrome (IBS-D) found that 10 reported relief of symptoms during a 4-week ketogenic diet.23 Anecdotally, many people with ulcerative colitis have found relief from ketogenic diets, including popular health blogger and biochemist Robb Wolf.

To my knowledge, no studies to date have assessed the effects of ketones or a ketogenic diet on gut barrier function. This is a fairly simple experiment that I would love to see someone perform.

Exogenous ketones may boost gut butyrate (NEW)

Given that a ketogenic diet is fairly restrictive, many people have taken to using ketone esters or salts to achieve ketosis. Other people may use ketone esters or salts on top of a ketogenic diet to achieve a deeper state of ketosis.

Intriguingly, some in vitro data suggests that, at least in some individuals, ketone esters or salts may increase gut butyrate levels. A 2020 study published in Scientific Reports investigated the dynamics of beta-hydroxybutyrate salts 12 human fecal microbiota samples in an in vitro fermentation chamber.24 In seven of the samples (βHB utilizers), more than 54 percent of the βHB was metabolized after 30 hours of fermentation. This was associated with an increased abundance of the genus Coprococcus, a known butyrate-producer, which was correlated with increased butyrate production. In the other five fecal samples (βHB non-utilizers), less than 19 percent of BHB was metabolized, and no change in fecal butyrate was observed.

The authors surmised that the microbes were converting βHB to butyrate. This idea is supported by a 2018 study published in Cell Metabolism, which found that intermittent fasting in rodents resulted in enriched microbial pathways related to the synthesis and degradation of ketone bodies.25  Another possible mechanism is via activation of PPAR-gamma and maintenance of gut hypoxia, which will in turn support populations of butyrate-producers in the gut.

Can fat itself be a source of butyrate? (NEW)

I’ve received a few questions since I first published this article back in 2018 as to whether butter or ghee could act as a significant source of butyrate on a low carb, high-fat diet. Butter is the most concentrated food source of butyrate, with about 3-4 percent butyrate by weight. Ghee, or clarified butter, is likely about 5-6 percent butyrate due to the higher fat content, though I have not seen any published analyses.

Channeling my intro chem conversions here (someone please check my math 😊), let’s say you have a quarter cup of butter: 1/4 cup butter is 14 grams, so .04 percent butyrate x 14 grams = 0.56 grams of butyrate. Divide that by the molecular weight of butyrate (88.11 g/mol) to get 0.006 mol = 6 mmol of butyrate for every 1/4 cup of butter.

The concentration of butyrate in a healthy gut is 70-140 mmol/L in the proximal colon and 20-70 mmol/L in the distal colon. Daily production of SCFAs in the colon is estimated between 300-400 mmol total, and theoretically could be as high as 800 mmol per day.

So, 6 mmol is definitely not an insignificant amount, and could certainly have therapeutic benefits. It’s still relatively small compared to what you would get from fiber fermentation or the amount of cellular energy I suspect you could get from ketone bodies, but comparable to the amount you might get from two ProButyrate capsules.

In other words, butter or ghee can definitely be a component of a healthy ketogenic diet, but I wouldn’t be pounding the butter just for the sake of butyrate.

Ketones mediate small intestinal stem cell homeostasis (NEW!)

A study published in the journal Cell in late 2019 by a group of researchers at MIT found that ketone body signaling regulates the normal function of intestinal stem cells and their ability to respond to injury.

The gut epithelium is extensively folded, with peaks (villi) and valleys (crypts) in the epithelial surface. Intestinal stem cells (ISCs) reside at the bottom of each crypt, and are responsible for renewing the entire gut epithelium every few days or repairing any damage that occurs.

ISCs are tightly controlled by a number of different growth factors that influence their development. Previous studies had shown that dietary nutrients play an important role in determining ISC function, but nobody had yet looked at ketone bodies and their potential role.

The research group first found that the ketone-generating enzyme HMG-CoA synthase 2 (HMGCS2) was enriched in small intestinal stem cells. HMGCS2 is found in many different tissues and is known to limit the rate of ketone formation.

Ablating the Hmgcs2 gene in the intestine diminished beta-hydroxybutyrate levels in the crypts and compromised stem cell function and regeneration of the gut epithelium after injury. Giving exogenous (supplemental) βHB rescued stem cell function and partially restored intestinal regeneration.

They next investigated the effects of a ketogenic diet, and found that it increased HMGCS2 expression, ISC number, function, and post-injury regeneration. In contrast, a glucose-supplemented diet suppressed intestinal stem cell ketogenesis and skew differentiation of stem cells towards goblet and Paneth cells.

Notably, once stem cells had differentiated into mature epithelial cells and migrated up out of the crypt, they expressed very little HMGCS2. This suggests that mature epithelial cells do NOT possess the ability to generate large amounts of ketones through the classical ketogenic pathway (via condensation of two molecules of acetyl coA), though we know that they do have the ability to utilize ketones.

Thus, it follow that if (1) we are seeing high levels of ketones in mature intestinal epithelial cells on a ketogenic diet (as we did in the Turnbaugh paper), and (2) these are not being generated IN mature epithelial cells (as is suggested by the lack of HMGCS2 in this paper), then the ketones are almost certainly coming from circulation.

Along these lines, the authors write:

“Because exogenous ketones rectify Hmgcs2 loss in vitro and in vivo, liver or other non-intestinal sources of ketones may substitute or supplement ISC-generated ketones in KTD-mediated regeneration, where circulating ketone levels are highly elevated.”

But don’t high-fat diets increase LPS absorption?

Another common argument for avoiding high-fat diets is that they increase intestinal absorption of lipopolysaccharide (LPS). LPS is a molecule found in the cell walls of gram-negative bacteria. If it gets into circulation, it can cause low-grade, systemic inflammation.

To really understand this mechanism, we need to review how fats are digested and absorbed. When we eat fat, specialized cells in the small intestine release a hormone called cholecystokinin (CCK). CCK stimulates the gallbladder to secrete bile into the small intestine. Here, the bile acids surround fat molecules, helping to make them water soluble (much like dish detergent helps to emulsify oil).

It turns out that LPS has a high affinity for these water-soluble packages, called micelles. Micelles eventually diffuse toward the gut epithelium, where their contents (including LPS) are picked up by gut epithelial cells. The epithelial cells repackage the lipids and LPS into chylomicrons, which can then be exported to the liver via the lymphatics (the vessels that carry the lymph of the immune system).

When we consume more long chain fatty acids, our body makes more of these chylomicrons, so more LPS can hitch a ride in this fashion.26 Indeed, fat-enriched meals have been shown to moderately increase serum levels of LPS in both mice and humans.27,28 While this is absolutely a real phenomenon and worth considering, I believe this is generally a non-issue for several reasons.

First, several studies suggest that the transport of LPS by chylomicrons may confer an advantage because it favors clearance of LPS by the liver, reducing the toxicity of LPS.29,30 Moreover, chylomicrons also have an innate ability to inactivate LPS.31 Altogether, the increased absorption of LPS appears to reduce inflammation in the gut mucosa.32

This is especially important since the primary mode of systemic exposure to LPS is not through fat absorption, but through a leaky gut! When the gut is permeable, large amounts of LPS can leak into the submucosa and bloodstream, causing localized gut immune responses and systemic inflammation.

In other words, compared to full-blown intestinal permeability, chylomicron-induced LPS absorption is likely a drop in the bucket. (In fact, for those who are dealing with severe intestinal permeability, chylomicron-induced detoxification of LPS may even reduce inflammation enough to facilitate healing of the gut epithelium.)

Furthermore, if fat-induced LPS absorption was an issue, we would expect to see increased systemic inflammation in those fed a high-fat ketogenic diet. On the contrary, subjects fed ketogenic diets almost universally experience a reduction in systemic inflammation.33

Alright so, hopefully by this point, I’ve convinced you that high-fat diets are not to be feared for their lack of butyrate or increased absorption of LPS. In the next section, we’ll see how bile acids might also contribute to a healthier gut.

Bile acids are critical for gut health

Some people have also suggested that a high-fat diet might be detrimental to the gut microbiota and gut barrier because it stimulates increased secretion of bile acids. Generally speaking, the more fat you eat, the more bile is released into the small intestine.

Indeed, some studies have shown that sustained exposure of the gut barrier to high concentrations of bile acids results in intestinal permeability. However, physiologic doses of bile acids have been shown to support barrier function, inducing the secretion of mucus from goblet cells, promoting epithelial cell migration, and boosting gut innate immune defenses.34

Bile acids also have antimicrobial properties, helping to regulate the gut microbiota, and may particularly protect against small intestinal dysbiosis.35 Several studies also suggest that bile acids activate enteroendocrine cells to release serotonin, which helps promote gut motility.36

Exploring the ins and outs of every type of conjugated and deconjugated bile acid is beyond the scope of this article, and something I’ll hope to cover in a future post. Overall, I do not believe there is sufficient evidence to suggest that the physiologic increase of bile acids seen with a ketogenic diet is harmful to the gut microbiota or gut barrier function.

What about the carnivore diet?

The carnivore diet has recently been touted as a cure-all for a wide variety of diseases. While an all-meat diet might be beneficial as a short-term therapeutic diet and, anecdotally, many people experience improvement in their symptoms, there is limited data on the long-term safety of this dietary approach.

It is theoretically possible to get all of your nutrients from an animal-based diet, assuming that you eat nose-to-tail and consume all parts of the animal. Interestingly, the short-term animal-based diet featured in the study I mentioned above was associated with increased expression of bacterial genes for vitamin biosynthesis.14 As a low residue diet, a reduction in gut inflammation may also improve nutrient status in the short-term. However, we know very little about how the carnivore diet might impact nutrient status, hormones, fertility, and thyroid function in the long-term.

Moreover, there is no evidence that any ancestral population lived on only meat or only plants. Even the Inuit and other populations that lived in far northern latitudes went to great lengths to forage plants when they could or boost their fertility in other ways. In his book “Nutrition and Physical Degeneration, A Comparison of Primitive and Modern Diets and Their Effects”, Weston A. Price wrote:

 “Among the Indians in the moose country near the Arctic Circle a larger percentage of the children were born in June than in any other month. This was accomplished, I was told, by both parents eating liberally of the thyroid glands of the male moose as they came down from the high mountain areas for the mating season, at which time the large protuberances carrying the thyroids under the throat were greatly enlarged.”

In other words, these cultures had the traditional wisdom to self-medicate with thyroid glands of other animals to make up for the reduced fertility conferred by their lack of plant foods. Most modern “carnivores” are not doing this, and many are consuming muscle meat alone.

I certainly empathize with those who have found the carnivore diet to provide relief of symptoms. That being said, I believe in most cases, a therapeutic ketogenic diet could be just as effective and that the need to go complete carnivore to relieve symptoms is a sign of an underlying gut infection. Once this is addressed, the ideal diet likely includes some form of plant foods.

When a ketogenic diet is not a good idea: hydrogen sulfide (NEW)

Alright, so hopefully I have convinced you that there is nothing to fear in general about ketogenic diets in regard to gut health. However, I do want to talk about one potential caveat, and that is individuals with hydrogen sulfide overgrowth.

Hydrogen sulfide (H2S) is a colorless gas that is normally produced in the body and acts as an important signaling molecule at low concentrations. However, certain gut bacteria can also produce hydrogen sulfide, and an overgrowth of these bacteria can lead to excess hydrogen sulfide. H2S has been associated with diarrhea, gut hypersensitivity, IBS, IBD, and colorectal cancer.37

The most common H2S producers in the human gut are Desulfovibrio, Bilophila wadsworthia, and Fusobacterium nucleatum. These bacteria tend to thrive on a diet that is high in animal protein and fat. Thus, if you have H2S overgrowth, it’s probably best to avoid consuming a ketogenic diet until you’ve been able to address the issue and rebalance the gut. In fact, a higher fiber, largely plant-based, Mediterranean-style diet might actually be best for H2S.

For more on hydrogen sulfide overgrowth and strategies to address it, stay tuned for my upcoming course release.

Summary & practical tips for gut health on a ketogenic diet

To summarize, there is no clear evidence that a well-designed high-fat or ketogenic diet is detrimental to the gut microbiota or gut barrier function. In fact, keto-induced changes in the gut microbiota and gut barrier may even be the reason we see so many benefits from ketosis.

Moreover, we don’t really know what constitutes a healthy gut microbiota, and ketones and isobutyrate can replace the short-chain fatty acid butyrate that we typically think of as crucial for gut barrier function. Several case reports indicate that a ketogenic diet may reduce inflammation and improve quality of life in IBS and IBD.

I want to stress that I do not believe that a ketogenic diet is right for everyone. My intention with this article was not to suggest that everyone with a gut issue should try a ketogenic diet. I simply wanted to clear up a lot of the confusion and provide a more complete discussion of the evidence for ketogenic diets in relation to gut health.

There are also right and wrong ways to do a ketogenic diet when it comes to gut health. A ketogenic diet high in refined seed oils and processed meats is not going to provide the same therapeutic benefit to the gut as one that includes healthy fats, pastured meats, and lots of non-starchy vegetables.

On that note, here are my top seven tips to doing right by your gut when consuming a high-fat or ketogenic diet:

1) Focus on high-quality fats, like avocados, avocado oil, olive oil, fatty fish, coconut oil, pastured ghee, butter, tallow, etc. Try to get a mixture of monounsaturated, polyunsaturated, and saturated fat.* Avoid highly processed and refined oils like canola, corn, and soybean oil.

**If you plan to remain on a ketogenic diet long-term, I recommend getting a full cardiovascular profile after you have been on the diet for 1-2 months. A small subset of individuals  (“hyper-responders”) will have an increase in LDL particle number and may need to tweak their fat intake or consider a modified ketogenic diet to ensure they are not increasing cardiovascular risk.

2) Eat your (non-starchy) veggies! Just because you don’t necessarily need the butyrate doesn’t mean you should skimp on vegetables. Try to get a variety of both raw and cooked veggies of all types and colors.

3) Indulge with berries. Berries are a great low-carbohydrate source of prebiotic fiber to selectively promote the growth of beneficial bacteria.

4) Drink coffee and eat cocoa. Polyphenols promote the growth of beneficial bacteria, so consume coffee and cocoa as tolerated. Those with severe gut permeability or autoimmunity may want to avoid these foods initially.

5) Consider nutrient density and eat nose-to-tail. Consume organ meats, shellfish, seafood, and be sure to balance methionine-rich muscle meats with glycine-rich animal foods like collagen and bone broth.

6) Experiment! The best way to know if keto works for you is to try it for a few weeks and see how you feel. Pay particular attention to your energy, skin, mood, productivity, digestion, and bowel movements.

7) Try “the keto zone”.Unless you have a good reason to be in nutritional ketosis, there is no need to be in keto indefinitely. By maintaining a carb intake of 20-120 grams (depending on your activity level), you can easily slip in and out of ketosis. In fact, this may help your gut and your microbiome maintain peak metabolic flexibility.

That’s all for now! Be sure to let me know what you thought in the comments below and subscribe to my newsletter so you never miss a post.

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