The immune system and inflammation are inseparable – the immune system invokes inflammation as part of its armoury, while inflammation provokes an immune response. So, understanding inflammation is helped by an appreciation of the immune systems that constantly (and usually imperceptibly) protect us.
Our immune Systems
We have two immune ‘systems’ that have different roles but that are cooperative. The first one knows what to do most of the time and responds quickly. This is our innate immune system that we are born with and that responds to known threats but that cannot adapt to new threats. The other, the adaptive immune system, is called upon when the innate system fails or is overwhelmed. It tackles new and unexpected attacks. It takes a while to find a solution (a number of days), but it is more targeted and powerful when it does and it remembers the solution for next time around (conferring immunity).
Mostly this goes on silently. Only when we are confronted by a serious battle (with a potent influenza virus, for example), and the early defences have failed do we experience symptoms of the fight. Then, we suffer and complain while complex responses unfold, ignoring our complaints and adding to them as needed – the weapons that the immune system uses to attack an influenza virus are what mostly give us our symptoms, not the virus itself.
For example, it is immune-mediated inflammation that causes a ‘sore throat’ or joint aches. As our immune cells engulf a virus or the cells it has infected, they need to be expelled to clear the way for fresh rallys – the sneezing and nose-blowing is a primary means of elimination, Likewise a ‘productive’ cough. The fever or cold-hot cycling that we experience is to stress the virus (at our expense). The immune system even triggers a ‘sickness behaviour’ in the brain that leads to feelings of depression, fatigue and anxiety. This is thought to be an evolved response to conserve energy (but maintain awareness) while re-directing energy to fuel the heightened immune response, particularly fever.
Turning off the immune response is as important as turning it on. Persisting symptoms can be due to a continuation of the immune response even after the virus has been eliminated (how annoying is that). For a similar reason, some experience a mild flu after receiving a flu shot. It is not biologically possible to get the flu from a flu-inoculation, however, some people might get the symptoms of a mild flu because the injection wakes up the immune system to prepare a defence. A weakened immune system (in infants and the elderly) can contribute to flu-related deaths. However, it has been suggested that too strong an immune system (in the young and healthy) could also be fatal – an aggressive virus might trigger an immune over-reaction and the body destroys both itself and the virus in a pyrrhic victory.
But, back to inflammation. What is it exactly? The classic symptoms of acute inflammation include redness, heat, swelling and pain, and usually come from an increase in the dilation and permeability of blood vessels and increased blood flow. The purpose is to deliver, at speed and without impediment, the body’s defences to the tissues under attack.
However, it is chronic inflammation that is the long-term health issue, and it has been associated with virtually all chronic and degenerative diseases. Some examples are auto-immune or auto-inflammatory diseases (rheumatoid arthritis, multiple sclerosis, gout, allergies and hypersensitivities), heart disease, cancer, type 2 diabetes, obesity, non-alcoholic fatty liver disease, Parkinson’s disease, Alzheimer’s disease and many psychiatric conditions such as major depression (and its often tragic outcome – suicide). This last point may be surprising, however, it is linked to the immune system’s ’sickness behaviour’, in this case chronically elevated. Bipolar disorder, schizophrenia and obsessive-compulsive disorder have also been linked to chronic inflammation.
Even apparently healthy individuals can live with chronic, low-level inflammation (usually attributed to factors such as stress, diet, environment and lifestyle) without overt clinical symptoms other than perhaps a general malaise. In this situation, inflammation becomes a risk-factor for more serious chronic disease. We can detect sub-clinical inflammation by looking for the molecular, cellular and protein messengers in the blood that normally coordinate an inflammatory response. Our innate immune system has a number of pre-prepared inflammatory responses (known as inflammasomes) that it can draw on to deal with a perceived threat, and the biomarkers associated with these systems can be measured.
There are a large number of biomarkers (at least 15-20), all with different but complementary roles. Each of these has a ’normal range’, however the aim is to get them all as low as possible. This is similar to insulin resistance – some individuals may not have clinical insulin resistance, but be at the upper limit of the normal range and so be more susceptible to weight gain or progression to diabetes.
Diet and inflammation
Which brings me to the ketogenic diet. A low-carbohydrate high-fat ketogenic diet (KD) has the potential to reduce chronic inflammation in a number of interrelated ways.
One is replacing glucose with ketones to fuel metabolism, because glucose (from starchy carbohydrates and sugars) is pro-inflammatory. This can be seen by measuring inflammatory biomarkers after ingestion (or injection) of glucose – they rise and fall in keeping with the level of blood glucose.
Ketosis is effective for reducing body fat and weight, because the body adapts to converting fat to ketones to fuel metabolism. Our fat cells are more than just passive receptacles for fat accumulation, they are metabolically active and they release inflammatory messengers. It has been suggested that adipose tissue may have been an ancient immune system, However, now chronic obesity means chronic inflammation.
The KD minimises starchy carbohydrates so as to reduce glucose, however, since a significant source of starchy carbohydrates are the grain flours, the KD will secondarily reduce dietary gluten. Taking wheat as an example, gluten is formed from the two main wheat proteins, gliadin and glutenin (the purpose of kneading bread is to form gluten from these proteins). However, there is a downside for many people – ‘leaky gut’, and in about 1% of the population, debilitating celiac disease. It is the gliadin protein (not gluten itself) that is the culprit.
Normally, molecules cross from the gut to the circulation (blood or lymph) in a very controlled way – the cells in the gut wall determine what to allow in. A ‘leaky gut’ is what it implies, the cells in the gut wall pull apart from each other, allowing whatever happens to be in the gut to travel through the gaps directly into the circulation. Molecules that the gut wall would normally block trigger an immune response leading to chronic inflammation. There is also a ‘leaky brain’ in which the blood-brain barrier becomes more permeable and which is also inflammatory. Thus reducing gliadin-containing grains (wheat, rye, oats, semolina etc) can have a two-fold effect on inflammation – reducing ‘leaky gut’ and reducing blood glucose. There is serious suggestion, including plausible mechanisms, that the ‘leaky gut’ underlies all the chronic diseases of modern western civilisation.
A mystery might be why gluten intolerance has become so widespread only in modern times. This may be due to a greater awareness and improved diagnosis, however, industrialised agriculture and processed food are likely to have played a bigger role. The modern hybridisation of wheat to increase yield per acre (by ten-fold in some cases) and disease resistance, that began around the 1960’s, has modified the gliadin protein molecule’s amino acid profile and therefore how it behaves during digestion. Wheat strains higher in gluten were developed because this was favoured by processed food manufacturers. Then there’s our unprecedented consumption, urged on by dietary guidelines. Lastly, with traditional agriculture, there were substantial delays between harvesting and milling the grain – it could be days, but can now be as short as a few hours. The delay enabled a fermentation process to get started in the grain, which improved the digestibility of the gliadin. For a similar reason, fermented breads, such as sourdough, are also better tolerated. Likewise, fermented milk products (cheese, yoghurt), that convert lactose to lactic acid, can be consumed by lactose intolerant individuals.
Finally, it is often claimed that saturated fats, which are part of a KD, are pro-inflammatory. This depends on context. A high-fat high-sugar diet, which perhaps defines modern eating, can be expected to be inflammatory. However we have evidence that a KD (with much reduced sugars) is anti-inflammatory (see later). I suspect that this claim is a part of the general demonisation of saturated fats that started in the 60’s but that is beginning to unravel. More important, polyunsaturated fats, promoted as healthy by authorities, are pro-inflammatory because of their high levels of omega-6. This fatty acid is essential in small amounts, but in larger quantities it is inflammatory and, furthermore, inhibits the anti-inflammatory omega-3s. For this, and a significant number of other reasons, polyunsaturated vegetable oils should have no part in our diets (as I explain in more detail here). The fats in a KD are rendered animal fats or cold-pressed (not refined) saturated or monounsaturated fats from olives, avocados, coconut etc.
To recap, replacing glucose with ketones, reducing weight and reducing most grain-based carbohydrates can have a beneficial effect on chronic inflammation. These are indirect consequences of a KD. However, we also have evidence that ketones can directly modulate inflammation.
Ketones and inflammation
Ketones can block one of the major inflammasomes (identified as NLRP3 – I apologise for introducing an arcane acronym). As an indication of the importance of NLRP3, laboratory models of disease indicate it is activated in type 2 diabetes, atherosclerosis, multiple sclerosis, Alzheimer’s disease, cancer, bone loss and gout (the list is sure to be longer than that). For these reasons, it is the most studied of the inflammasomes. NLRP3 may or may not be the cause of a disease, but it is activated by the products of the disease process and thus can exacerbate disease progression. A mechanism whereby ketones can block this inflammasome has been identified – it acts on a major regulator of the inflammasome (NF kappa-B, which is also fundamental to DNA transcription and cell survival). It is yet to be determined whether ketones can be harnessed to block NLRP3 in a clinically-meaningful way in the human, however at least there is the potential to do that.
There have been few properly controlled human studies of the effect of a KD on inflammatory biomarkers. However, one detailed study has been undertaken showing that a range of these biomarkers can be reduced with a KD. The biomarkers involved are consistent with reducing the activation of NLRP3.
In a previous post, I drew attention to three ways that ketones could reduce oxidative stress caused by free-radicals and other reactive species. Here, I have outlined ways in which a KD could be beneficial for lowering chronic inflammation, either indirectly (by reducing glucose, weight and gluten) or more directly by inhibiting an inflammasome that has been implicated in a host of important diseases. Oxidative stress, inflammation and immunity are highly inter-related. Taken together, a role for ketones in health is looking increasingly important.
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My ketogenic diet page – KD
Lu et al (2014) BHBA suppresses LPS-induced inflammation in BV-2 cells by inhibition NF kappa-B activation.