How ketogenesis and ketones Treat Inflammation

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Intro

Inflammation is a biological mechanism our bodies use to deal with internal and external events, such as combatting infections, repairing tissues or mitigating the immediate consequences of a fractured bone.

However, it often carries a negative connotation since many diseases provoke symptoms through the process of inflammation. So although it is absolutely necessary for keeping the human body functioning properly, like so many things in biology, too much or too little is the problem. Inflammation can be managed with and without drugs.

Here we will focus on ketogenesis and ketones with regards to treating inflammation since both drug and drug-free approaches can be discussed.

What is ketogenesis?

Ketogenesis is the process whereby your body produces molecules called ketone bodies, also called ketones (see What’s a Ketone?). For my fellow nerds, gaze upon the ketogenesis pathway below (1). For the non-initiated, simply keep in mind that the liver is ground-zero for ketogenesis, where fat is used as the raw material to produce 3 kinds of ketone bodies.

Humans are remarkably good at ketogenesis. For comparison, dogs too can make ketones but the degree to which they require protein, carbohydrate or caloric restriction to do so is greater (2,3). Produce enough ketones by upregulating ketogenesis and you will move into a metabolic state state called ketosis.

Humans require this metabolic state to handle long fasts and carbohydrate restriction. Ketosis or ketones also happen to affect inflammatory processes such as the NLRP3 inflammasome.

What’s the NLRP3 inflammasome?

The NLRP3 inflammasome is part of the innate immune system, the defence system we have to react quickly and non-specifically to biological threats, such as a sudden infection from a wound. Specifically, the NLRP3 inflammasome is a large protein that is made from recruitment of a bunch of smaller ones [4]. Imagine it assembling like Power Rangers or Transformers do.


Interestingly, when an NLRP3 inflammasome forms, there is only 1 per cell. It is the largest within its class of molecules measuring 2 µM (an massive molecular complex!). Once assembled, it mediates the release of what you can think of as ‘inflammation bullets’ called cytokines, specifically the interleukins called IL-1β and IL-18. This inflammasome can also give the go-ahead for cells to activate caspase-1, a major switch used to decide whether or not to commit suicide.

The NLRP3 inflammasome senses threats which may, for instance, be toxins, too much glucose or too much ATP amongst other things. So it’s a great alarm system to have! Problem is, it’s not made to be chronically activated above a certain level, something that can happen if we’re exposed to too much air pollution or we consume inflammatory foods on a daily basis.

These situations may be mitigated somewhat by spurring ketogenesis or exogenous ketones to help dampen the activity of this inflammasome. Ketogenesis can be engaged by eating a high-fat diet low in carbohydrates and by fasting (intermittently or for longer periods of time.

How does ketogenesis or ketones modulate the NLRP3 inflammasome?

The ketone body β-hydroxybutyrate, BhB for short, has a particularly interesting effect on the NLRP3 inflammasome. It sticks to the big protein complex and stops it from firing the IL-β and IL-18 bullets causing inflammation. It also stops the inflammasome from activating the caspase-1 switch [5]. .

What diseases or conditions could benefit from dampening NLRP3-mediated inflammation?

Research into inflammasomes is relatively new. The first NLRP inflammasome was discovered in 2002 [6]. Some of what we know comes from experimenting on cells in a flask and some more from experiments on rodents or humans.

Many diseases have an important inflammatory component which may be either cause or consequence.

Metabolic therapies, especially those requiring the activity of ketone bodies, appear to be promising candidates. However their efficacy depends on the particular disease and not all have been adequately tested in humans yet. Nevertheless, there are 3 diseases or conditions worth discussing in this regard.

Late-stage severe obesity

The fat tissue of people with late-stage severe obesity is highly inflamed due to, in large part, the activity of the NLRP3 inflammasome [7]. Consequently, the latter has been designated as a therapeutic target by some researchers [8]. The figure below depicts imbalances in the elements listed on the left-hand side leading to insulin resistance via NLRP3 inflammasome activation, and resulting in the diseases and symptoms listed on the right-hand side [9].

Rheumatoid arthritis

Rheumatoid arthritis is a condition where joints like the knees and wrists are swollen, stiff and painful. It has a major inflammatory component to it. IL-β, the cytokine bullet fired by the NLRP3 inflammasome, destroys cartilage in rheumatoid arthritis.

In rodents and humans, blocking IL-β stops the destruction of cartilage [10]. This makes therapies that can target IL-β, either directly or indirectly, very interesting.

Epilepsy (or other CNS disorders)

Epilepsy can present in many ways but generally it can be described as a strong sensory disturbance leading to convulsions and loss of consciousness. It is thought to be due to electrical disturbances in the brain since this feature very strongly correlates with seizure activity.

There is evidence suggesting that brain cells with dysregulated production of reactive oxygen species (ROS) or inappropriate K+ efflux activate the NLRP3 inflammasome and trigger epilepsy [11]. The human brain is particularly well suited to using ketone bodies as a major source of energy which makes its therapeutic use for epilepsy all the more intriguing.

fasting or a combination of these interventions could be useful to control NLRP3-mediated inflammation.

If appropriate, what kind of ketogenic therapy should I use?

This is a difficult question to answer. For instance, it’s not always clear which aspect of, say, a ketogenic diet used to reverse obesity is actually doing the work. Is it the appetite appetite suppressing effects? Is the lowered inflammation in fat tissue normalizing local insulin signaling? Or a combination of both and more? And in epilepsy, is a ketone-based metabolism improving seizure control through normalized ROS signaling? Or is it due to dampened inflammation deriving from NLRP3 inflammasome activity? Whatever the case may be, there are different ketone-based approaches that are available and worth considering.

For a drug-centric approach, exogenous ketones are available, such as ketone esters and ketone salts. These can now be bought [12]. Although not cheap, they are relatively safe and do not currently require a prescription in most countries. One advantage with exogenous ketones is it is easier and quicker to get a desired level of ketones circulating in the bloodstream than it is through dietary manipulation.
For drug-free approaches, ketogenic diets or some form of fasting can generate levels of ketones that have therapeutic effects on inflammation. On the plus side, fasting or intermittent-fasting is a time-tested intervention in obesity as well as epilepsy. It is free and human physiology is well-adapted to it. Unfortunately, it is hard to implement in an era where the food industry and medical establishment generally discourage this intervention.

Ketogenic diets have similar advantages since they are cheaper than many expensive medications for epilepsy or immune therapies for rheumatoid arthritis. However, few dietitians or doctors can help their patients implement well-formulated ketogenic diets which reduces the odds of long-term success.

Conclusion

Inflammation is a life-maintaining biological process. However, it needs to be kept in check and not activated chronically above a certain level. Otherwise, it can lead to symptoms or outright disease. It can be controlled with certain drug and lifestyle interventions, such as exogenous ketones and ketogenesis.

These interventions are relatively safe and have data suggesting they they can be used to control inflammation. Preferably, this should be discussed with medical professionals before using them, especially when suffering from a medical condition and on medication.

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