Why the Ketogenic Diet Is More Anti-Inflammatory When the Gut Microbiome Is Supported First

The ketogenic diet is often described as an anti-inflammatory diet, but ketosis alone does not guarantee that inflammation will come down. Ketones can produce important anti-inflammatory effects, particularly beta hydroxybutyrate (BHB),  which acts as both an energy source and a signalling molecule. Youm et al. (2015) demonstrated that BHB can inhibit the NLRP3 inflammasome, an inflammatory pathway involved in insulin resistance, metabolic disease and several neurological and autoimmune conditions. Reducing glucose fluctuations, lowering insulin and producing ketones can therefore create an important shift in inflammatory signalling. However, the quality of the ketogenic diet and the condition of the gut microbiome will influence how much of this potential benefit we receive.

The gut microbiome is one of the body’s most important regulators of inflammation. When the intestinal barrier is strong, beneficial microbes help maintain the mucus layer, support immune regulation and produce short chain fatty acids such as butyrate. Butyrate provides energy for the cells lining the colon and helps maintain the integrity of the intestinal barrier. When the microbiome is imbalanced and the intestinal barrier becomes more permeable, bacterial components such as lipopolysaccharide can enter the circulation and stimulate systemic inflammation. In this environment, a person may be producing ketones while still receiving inflammatory signals from the gut. This is why I believe that the microbiome should be assessed and supported before, or at least alongside, the introduction of a therapeutic ketogenic metabolic therapy. 

One of the mistakes people make when starting a ketogenic diet is removing carbohydrates without considering what those carbohydrates were feeding. Refined carbohydrates and sugar may need to be reduced, but onions, garlic, leeks, asparagus, artichokes, cruciferous vegetables, nuts, seeds, herbs and spices perform a very different role. They provide fermentable fibers and polyphenols that nourish the bacteria involved in maintaining the intestinal barrier and producing beneficial metabolites. If all these foods disappear, the diet may become high in fat but very low in microbial nourishment. Ferraris et al. (2021) found that one month of a classical therapeutic ketogenic diet reduced fecal short chain fatty acids in a small group of people with epilepsy. The study only included seven participants and used a strict 4:1 ketogenic ratio, so it cannot be applied to every ketogenic diet. However, it demonstrates why the microbial effects of a ketogenic diet should not be ignored.

The current human research does not show one consistent ketogenic microbiome. Rew et al. (2022) reviewed the available human studies and found considerable variation in microbial responses. Some studies reported potentially beneficial changes, while others found reductions in bacteria such as Bifidobacterium and in microbes associated with fiber fermentation. These differences may be explained by the degree of carbohydrate restriction, the health of the individual, the length of the intervention and, most importantly, the foods used to construct the diet. A ketogenic diet based on extra virgin olive oil, avocado, oily fish, nuts, seeds and a diverse selection of vegetables will interact with the microbiome differently from a diet dominated by butter, cream, processed meats and very little plant food.

The type of dietary fat becomes particularly important when dysbiosis is already present. Certain high fat dietary patterns can alter bile acid metabolism and create an environment that favors bile tolerant and hydrogen sulfide producing organisms such as Bilophila wadsworthia. Natividad et al. (2018) found that Bilophila wadsworthia interacted with a high fat diet to increase intestinal inflammation, impair barrier function and worsen metabolic dysfunction. This was an animal study, so it does not prove that saturated fat will automatically cause these effects in every person. It does, however, show how the microbiome can influence the way a high fat diet is processed. If someone already has high levels of hydrogen sulfide producing bacteria, intestinal inflammation or poor microbial diversity, simply increasing fat without addressing the intestinal environment may not produce the outcome we want.

Optimising the microbiome does not mean that someone must eat a high carbohydrate diet before entering ketosis. I often encourage people to work towards 40 or more different plant foods across the week using low carbohydrate vegetables, herbs, spices, nuts, seeds, olives, cacao, small portions of berries and fermented foods where tolerated. Fiber can be increased gradually through foods such as chia seeds, flaxseeds, avocado, leafy vegetables, mushrooms, garlic, onions and leeks. For some people, targeted prebiotic fibers may also be useful, but these need to be introduced carefully when there is significant dysbiosis. The objective is not simply to achieve the highest possible ketone reading. It is to produce ketones while continuing to support the microbial pathways involved in butyrate production, intestinal barrier integrity and immune regulation.

This is why I do not believe that a ketogenic diet should become a low diversity diet. Ketosis and microbial diversity are not opposing goals. A well formulated ketogenic diet can include an extraordinary variety of vegetables, herbs, spices, seeds, nuts, fermented foods and polyphenols while keeping carbohydrate intake low. It can also be personalized using symptoms, metabolic markers, food tolerance and stool testing where appropriate. Someone with low butyrate producers, poor microbial diversity or an abundance of hydrogen sulfide producing organisms may require a different ketogenic strategy from someone whose microbiome is already resilient. The goal is to create an internal environment in which ketosis can do its best work.

References

Youm, Y. H., Nguyen, K. Y., Grant, R. W., et al. (2015). The ketone metabolite β-hydroxybutyrate blocks NLRP3 inflammasome mediated inflammatory disease. Nature Medicine, 21, 263–269. https://doi.org/10.1038/nm.3804

Rew, L., Harris, M. D., & Goldie, J. (2022). The ketogenic diet: Its impact on human gut microbiota and potential consequent health outcomes: A systematic literature review. Gastroenterology and Hepatology From Bed to Bench, 15(4), 326–342. https://doi.org/10.22037/ghfbb.v15i4.2600

Ferraris, C., Meroni, E., Casiraghi, M. C., Tagliabue, A., De Giorgis, V., & Erba, D. (2021). One month of classic therapeutic ketogenic diet decreases short chain fatty acids production in epileptic patients. Frontiers in Nutrition, 8, 613100. https://doi.org/10.3389/fnut.2021.613100

Natividad, J. M., Lamas, B., Pham, H. P., et al. (2018). Bilophila wadsworthia aggravates high fat diet induced metabolic dysfunctions in mice. Nature Communications, 9, 2802. https://doi.org/10.1038/s41467-018-05249-7