This article is part of the IBD Index. Last updated on May 2, 2022.
In my (rather lengthy) article about the ketogenic diet, I discussed the background, risks, and potential benefits of a ketogenic diet in the context of IBD. Ketone supplements have become popular as both an adjunct to a ketogenic diet and as a way to get some of the benefits of ketone metabolism without the stringent dietary restrictions. But do they actually work? Are they safe? And are they worth trying if you have ulcerative colitis or Crohn’s disease?
Table of Contents
Ketone supplements vs. ketogenic diet: which is better?
Could ketone supplements be effective for IBD?
Inhibiting growth of Bifidobacterium and reducing Th17 activation
Overcoming energy starvation in enterocytes
Which type of ketone supplement is best?
D-BHB vs. L-BHB enantiomers
Available products and brands
Ketone supplement pharmacokinetics
Limitations of breath and urine for measuring ketosis
What about MCT oil?
The bottom line
Ketone Supplements vs. Ketogenic Diet: Which is Better?
We know that ketone supplements do, in fact, elevate circulating blood ketone levels (ie, they “work”).
A 2017 paper describes three studies testing the metabolism of ketone salts and ketone esters (both as drinks) in humans, reporting maximum beta-hydroxybutyrate (BHB) concentrations between 1.0 mM (for ketone salts) and 2.8 mM (for ketone esters). Levels returned to baseline within 3-4 hours.
However, an increased concentration of ketones in the blood is not the only feature of true metabolic ketosis.
For someone trying to lose weight, or resolve metabolic dysfunction, or treat neurodegenerative disorders or epilepsy, or improve outcomes for cancer treatment, it’s possible that the cascade of metabolic effects induced by a ketogenic diet is necessary for success; that’s beyond the scope of this article. But for IBD, that may not be the case.
As I discussed in my article about ketogenic diets, the most unique and intriguing potential mechanisms by which ketosis could benefit IBD patients (two of which I’ll mention below) appear to be dependent on the presence of ketone bodies themselves.
If that’s the case, it’s very possible that any benefits to be had from a ketogenic diet could be had through exogenous ketone supplementation, while avoiding many of the potential downsides of a ketogenic diet.
Just for fun, here’s a handy chart comparing and contrasting the effects of a ketogenic diet and exogenous ketones from the perspective of exercise performance:
Could Ketone Supplements Be Effective for IBD?
Of the several potential IBD-relevant mechanisms I discussed in my ketogenic diet article, the two that are most relevant to exogenous ketone supplementation are immune modulation via inhibition of Bifidobacterium growth and energy provision to enterocytes. We also have one relevant case report in a Crohn’s patient.
Inhibiting growth of Bifidobacterium and reducing Th17 activation
Notably, the inhibition of Bifidobacterium growth is a feature of ketone bodies themselves, rather than a consequence of dietary composition (like carbohydrate or fiber content). In the study cited, ketone ester supplements in mice elevated BHB in both the gut lumen and intestinal tissue and significantly decreased Bifidobacterium abundance.
While the various species of Bifidobacterium are generally considered to be commensal, we know that IBD is characterized by maladaptive response to commensal gut bacteria, and patients often have elevated Th17 activation compared to healthy controls, so it seems plausible that this mechanism could have therapeutic relevance.
Overcoming energy starvation in enterocytes
As discussed here, ketones may also provide an alternative fuel source for intestinal epithelial cells. Butyrate is generally considered the preferred fuel source for enterocytes, but IBD patients often have reduced luminal butyrate (from bacterial dysbiosis), impaired uptake and oxidation of butyrate, or both, leading to energy deficiency. (Source)
Since exogenous ketone supplementation elevates levels of ketone bodies in circulation, and ketone bodies are intermediates in the pathway for butyrate oxidation, they could provide an alternative source of readily-usable energy for enterocytes.
Unfortunately, we don’t yet have data to verify whether the above mechanisms could be clinically relevant for IBD patients. But as discussed in my aforementioned ketogenic diet article, there is one case report of a woman with Crohn’s disease who achieved remission using exogenous ketone salts and a relaxed low carbohydrate (but not ketogenic) diet: The effects of exogenous ketones on biomarkers of Crohn’s disease: A case report.
The authors report the case of a 51-year-old woman with fairly severe untreated Crohn’s disease (diagnosed for 25 years, unmedicated for 15) who felt “markedly better” after only one week of supplementation with BHB salts, and achieved full clinical remission after 3 months, along with significant improvements in body composition (fat loss with maintenance of lean mass).
She took 4g sodium BHB in water each morning for 2 weeks, then 4g of a mixture of sodium, calcium, and magnesium BHB twice per day thereafter. She experienced flatulence the first week, but reported no other side effects.
Her diet was described as a “flexible, non-ketogenic low-carb diet” with at least one higher-carb day per week. She apparently couldn’t eat large amounts of oils, and her diet overall was relatively low in calories.
The authors didn’t spend much time discussing the potential mechanisms that could be responsible for this patient’s dramatic results, but they speculate that the general anti-inflammatory effects of BHB could have played a role.
Which Type of Ketone Supplement Is Best?
In addition to ketone salts, which were used in the case described above, the other source of exogenous ketones is ketone esters.
L-BHB vs. D-BHB Enantiomers
One thing that’s helpful to understand when assessing ketone supplements is that BHB is chiral, which is an organic chemistry term meaning that it is not three‑dimensionally symmetrical. Thus, the two enantiomers, or “mirror image” versions, of BHB (denoted as D-BHB and L-BHB) have different properties.
There seems to be a bit of controversy (or at least incomplete understanding) regarding the role of L-BHB in the human body (possibly because most of the research characterizing these enantiomers has been done in rodents), but it’s generally accepted that only the D-BHB enantiomer is produced by the liver during normal human ketogenesis.
L-BHB may have helpful signaling and biosynthetic roles that we have not yet fully characterized (some discussion of this in the papers linked above, if you’re interested), but only D-BHB is efficiently used as an energy substrate.
Ketone salts consist of a ketone body, most often BHB, bound to a mineral ion such as sodium (Na+), potassium (K+), calcium (Ca+2), or magnesium (Mg+2). Most commercially available products use a blend of these salts to avoid overloading the body with any one electrolyte or mineral.
In published research, ketone salts generally elevate blood ketones to 0.5–1.5 mM for up to a few hours. (Source) Higher levels are generally prevented by the high mineral load and gastrointestinal intolerance associated with larger doses.
Ketone salts are more widely available and cheaper than ketone esters, and apparently taste far less unpleasant. (Although if you’re anything like me, taste is lowwww on your list of priorities when you’re in the throes of a chronic illness!)
Ketone esters consist of BHB esterified to a backbone molecule, most commonly 1,3‑butanediol. This molecule itself is converted to BHB in the liver, so this formulation of ketone ester is metabolized completely into BHB. (The company HVMN even sells a ketone supplement that is just 1,3‑butanediol, without any BHB attached to it.)
This ketone monoester can achieve much higher circulating BHB concentrations than salts in a relatively dose-dependent fashion, with fewer gastrointestinal side effects, which means there’s a risk of inducing ketoacidosis if overconsumed. (Source) Circulating BHB levels of ≥2.0 mM have generally been observed among studies using ketone monoester. (Source)
The longest study we have thus far had 24 volunteers consume 25mL of a ketone monoester drink three times per day for 28 days, and blood concentrations of BHB 30 minutes after the drink increased to between 1.8 and 6.3 mM, with an average maximum of 4.1 mM over the four weeks. (Source)
There’s also a new ketone diester in development, but not yet commercially available: 1,3‑butanediol (the “backbone” molecule in the common BHB ester discussed above) esterified to bis-hexanoyl (which is a precursor to the medium-chain triglyceride hexanoic acid). A randomized controlled trial found that one daily beverage (consumed with breakfast) achieved circulating BHB levels around 1 mM one hour after the drink. (Source)
Available Products and Brands
I did not do an exhaustive search of all extant ketone supplements, but there appear to be two major products containing the ketone monoester D-BHB-D-1,3-butanediol, along with a slew of various ketone salts.
Of note, unlike the liver, the factories that produce BHB do not have chiral specificity, so most ketone salts include a racemic (50/50) mixture of D-BHB and L-BHB. As I mentioned above, L-BHB may still provide some benefit, but for the purposes of energy metabolism, products with pure D-BHB will provide twice as many easily‑metabolizable ketones.
Also of note, most of the ketone supplement brands on the market seem to be marketed for athletic performance or weight loss, so many have additional additives such as caffeine or various amino acids.
Below is a table I put together summarizing some of the main products on the market, in alphabetical order:
|Audacious Nutrition (KETOSTART)||Salt||D/L-BHB as Ca and Na salts|
|deltaG||Ester||D-BHB/D-1,3-butanediol monoester||Funded by NIH and DARPA, and has been tested in more clinical studies than any other ketone supplement; first paper describing its chemical composition/synthesis.|
|Alcohol||D-1,3-butanediol||1,3-butanediol is the backbone molecule used in the available ketone monoester supplements, but is not itself a ketone ester (although it is converted to BHB by the liver).*|
|KetoForce||Salt||D/L-BHB as Na and K salts||This is the only supplement I’ve found that is unflavored and unsweetened. It was the salt used in these studies.|
|Salt||D-BHB as Na, Mg, Ca, and K salts||Also contains extra ingredients to increase weight loss and appetite suppression: L-leucine, L-taurine, acetyl-L-carnitine, and “Solathin”.|
|Salt||D/L-BHB as Na, Mg, and Ca salts|
|Ester||D-BHB/D-1,3-butanediol monoester||Used as a ketone monoester supplement in a few clinical trials.|
|Perfect Keto |
|Salt||L-BHB as Mg, Na, and Ca salts||Contains no D-BHB, which seems odd.|
|Salt||D-BHB as Na, Mg, and Ca||Amount of BHB not specified; “propriatary blend” includes L-arginine, L-taurine, and L-leucine.|
|TruBrain||Ester + Salt||BHB (unspecified) as ester (unspecified) and Na, Mg, and K salts||Doesn’t specify L/D proportions, and doesn’t specify the chemical identity of the “ester”.|
deltaG appears to be the most thoroughly documented and vetted ketone monoester supplement on the market; their website has a detailed timeline recording the formulation, production, testing, and patenting of the compound.
However, KetoneAid also has a ketone monoester product; this article on their website compares/contrasts the deltaG products and their own products. Assuming there isn’t blatant lying going on, it looks like you can get essentially the same compound from KetoneAid for less money, but deltaG appears to be a generally more reputable company. The two brands also have slightly different additional ingredients (and presumably taste), which is something to consider.
Ketone Supplement Pharmacokinetics
To give you an idea of the blood BHB levels you might achieve with ketone supplements, below is some of the pharmacokinetic data from the 2017 Stubbs et al study On the Metabolism of Exogenous Ketones in Humans.
For the first graph, the “low” and “high” doses were about 12g and 24g, respectively. You can see that ketone monoester raises blood BHB concentrations significantly more than the same amount of ketone salt.
Note that they used equimolar amounts of ester and salt, taking into consideration that each molecule of ketone monoester delivers two ketone “equivalents” (one from the BHB molecule, and one from the 1,3-butanediol).
The middle graph used the “high” dose of about 24g each.
The graph on the right compares BHB levels achieved with the “high” dose of ketone monoester when fed vs. fasting. The “fed” state comprised a breakfast of oatmeal, skim milk, and banana, providing 600 calories and a macronutrient ratio of 2:1:1 carbs to fat to protein.
As you can see, the circulating ketone levels achieved by the ketone monoester supplement are impressive, but once you start comparing the gram amounts used in this study to the gram amounts supplied per serving by the commercially available supplements (and the associated cost), you’ll probably be less enthused.
Limitations of Breath and Urine for Measuring Ketosis
I wanted to include one final excerpt from this study, regarding measuring ketosis. Stubbs et al, take it away…
“Breath acetone and urinary ketone measurements provide methods to approximate blood ketosis without repeated blood sampling. However, breath acetone did not change as rapidly as blood βHB following KE and KS drinks. Acetone is a fat-soluble molecule, so may have been sequestered into lipids before being slowly released, resulting in the differences observed here. Similarly, significant differences in blood D‑βHB between study conditions were not reflected in the urinary D-βHB elimination. As the amount of d-βHB excreted in the urine (≈0.1–0.5 g) represented ~1.5% of the total consumed (≈23.7 g), it appears that the major fate of exogenous d‑βHB was oxidation in peripheral tissues.
These results suggest that neither breath acetone nor urinary ketone measurements accurately reflect the rapid changes in blood ketone concentrations after ketone drinks, and that blood measurement should be the preferred method to quantitatively describe ketosis. That said, it should be noted that although commercial handheld monitors are the most practical and widely available tool for measuring blood ketones, they can overestimate blood D-βHB compared to laboratory measures and these monitors do not measure L-βHB and so may not provide accurate total blood ketone concentrations, especially if a racemic ketone salt has been consumed.” (Source)
What About MCT Oil?
One additional supplement that is popular for increasing circulating levels of ketones is medium-chain triglycerides, or MCT oil. MCTs contain fatty acids that are between 6‑12 carbons long: caproic acid (C6), caprylic acid (C8), capric acid (C10), and lauric acid (C12).
MCTs, particularly C8 and C10, are able to elevate blood ketone levels regardless of calorie or carbohydrate content of the diet, although the levels achieved are usually no higher than about 1 mM. (Source) And like ketone salts, high doses of MCT oil tend to produce gastrointestinal side effects.
(Fun fact: breast-feeding infants maintain a mild state of ketosis regardless of when they were last fed, in large part due to the relatively high proportion of MCTs in breast milk.)
The reason MCTs have this ketogenic property is because unlike longer-chain fatty acids, MCTs are absorbed into the portal vein and transported directly to the liver, rather than being first offered up to all the peripheral extrahepatic tissues of the body. MCTs can also enter beta-oxidation (and subsequent ketogenesis) without activation by carnitine. (Source)
Coconut oil is the best source of naturally occurring MCTs, but even then the amount is small. Most commercial MCT oils include purified C8 and C10, with some products such as Dave Asprey’s Brain Octane containing pure caprylic acid (C8).
Studies have shown that pure C8 is more ketogenic than other MCTs; see below. Note that the graph uses μM instead of mM (which has been used throughout this article so far), so you’ll need to move that decimal point three spaces to the left if you want a direct comparison.
As you can see, even pure C8 only achieved a peak blood ketone concentration of not even 1 mM, so while MCT oil is another tool in the toolbox, it isn’t in the same league as, say, a ketone monoester supplement.
If you’re curious, the breakfast given in the study (at the first arrow in the figure) consisted of 2 pieces of toast with raspberry jam, a piece of cheese, and 2 scrambled eggs.
The Bottom Line
- Ketone supplements allow for the elevation of circulating ketone bodies without needing to restrict dietary carbohydrate.
- Such an elevation of blood ketones could conceivably be therapeutic for IBD patients, possibly by providing an alternative fuel source to enterocytes with dysfunctional butyrate metabolism.
- One published case report describes a woman with Crohn’s disease who achieved remission using 4g of ketone salts twice per day in combination with a “relaxed” low-carb diet.
- Exogenous ketones are available as salts or esters; salts are more available, affordable, and taste less bad, but ketone monoesters can achieve much higher levels of circulating ketones with fewer gastrointestinal side effects.
- Most ketone salts contain a mix of D-BHB (which is the form naturally produced by the liver and is readily metabolized) and L-BHB (which is not). BioMAX and Pruvit both provide pure D-BHB.
- deltaG and KetoneAid provide the ketone monoester D-BHB-1,3-butanediol, which has been tested in numerous clinical trials and reliably achieves the highest blood BHB concentrations.
- MCT oil (especially pure C8, or caprylic acid) can also promote ketogenesis, with similar or slightly lower efficacy than ketone salts, and similar gastrointestinal side effects.
- All three supplements (ketone salts, ketone monoesters, and MCT oil) are generally safe, with the caveat that ketone monoesters could theoretically induce ketoacidosis if overconsumed (as if you ever would, with how much they cost…).
- Ketone salts and MCT oil are both apt to cause gastrointestinal side effects like diarrhea and bloating, which makes the dose self-limiting, but these effects are generally transient and can be reduced by introducing the supplement slowly.
- Ketone salts and MCT oil are both slower-acting than ketone esters, and taking into account considerations of cost and taste as well, some combination of the three products could be a good strategy for achieving sustained elevated blood ketones.