Tied To the Mast

When most people think of mast cells, they mostly think about histamine intolerance (HI). HI symptoms include, in no particular order, asthma, congestion, diarrhea, facial flushing, headache, hypotension, urticaria, vertigo and vomiting. Then they think about avoiding mast cell triggers. Alcohol, aspirin, hot food insect stings, these are a few of their un-fav’rite things.

But there is so much more to mast cells than histamine. They are a pharmacological treasure chest. Under the right conditions (and sometimes the wrong ones) they also secrete the anticoagulant heparin, together with a horde of proteases, leukotrienes and cytokines such as tumour necrosis factor, which cause inflammation and can also cause tissue damage.

They secrete prostaglandin D2 which recruits immune cells, makes you sleepy and, by inducing bronchoconstriction, makes asthma worse. They produce pro-angiogenic factors such as VEGF and TGF-beta, which enhance healing after trauma but also enable increased tumorigenesis. In total, they generate around 400 different mediator substances (1).

Mast cells are deeply involved in the symptomology of asthma, allergy in general, and anaphylaxis. They play a pivotal role in driving the tissue destruction that is a hallmark of autoimmune disease, and almost all other chronic degenerative disorders (2). They may also exacerbate cancer (3), which would go some way to explaining why anti-histamines reduce the risk of some cancers – though they appear to raise the risk of others (4).

And they seem to be becoming a bit of a problem.

Allergy, autoimmune disease and cancer have increased hugely within the last three generations (5-7). Since the start of this century, histamine intolerance has gone from unknown to a condition that, according to some researchers, occurs in up to 3% of the world’s population (8-10).

Could all these things be connected? Should we be taking more care of our mast cells? If so, what would that entail? And why do we even need them?

Mast cells are responsible for a range of immune functions. They are among the first responders to tissue damage (11) and to many pathogens, and there is evidence that the ablation of mast cells increases the risk of infection, at least in some tissues (12). They are also sensors of and responders to hypoxemia, air pressure, vibration, light (1) and insect and snake venoms, which they can to some extent neutralise (13).

The many messenger substances they release modulate the innate and adaptive immune systems, the cardiovascular system, the respiratory system and the central nervous system (14).

Mast cells thus act as sensors of a wide range of environmental and psychological stressors (15-17). Within this broad range of functionality they are also essential for metabolic regulation, and specifically for dealing with the metabolic stress of fasting.

During fasting, mast cells in the gut release histamine, which increases the synthesis of oleoylethanolamide (OEA) in the liver (18). This triggers hepatic ketogenesis, a metabolic program which converts the fatty acids released from your fat depots (when fasting) to ketone bodies which fuel the brain and the muscles during prolonged fasting and exercise (19).

This process may not be as relevant today as it was in earlier times of food insecurity, but if (when) hard times return you’ll be glad you held onto your mast cells. And there’s the rub; mast cells never used to be a problem. They served an ecologically and metabolically vital purpose, allowing higher organisms like us to micro-adapt to a challenging and changing world, and did so in a cost-effective manner: until dietary shift happened.

Eco-warriors, some in my immediate circle, prefer to focus on climate shift. The increase in many allergies is due to increased pollen exposure, they say, thanks to longer and hotter summers (20). That’s true, but prior to the 19^th century we lived predominantly rural lives and were exposed to far larger quantities of plant allergens, yet allergy was relatively uncommon (21).

Something else must have changed.

In modern times the 1-3, 1-6 beta glucans and other ‘old friends’ have been removed (22, 23), leaving our TH1 / TH2 ratio unbalanced and hence more prone to allergy (24-26). Our intakes of anti-inflammatory omega 3 PUFA’s and polyphenols have also fallen, exacerbating the inflammatory aspects of allergy and increasing its severity.

Our natural defenses have thus been degraded, leaving us exposed to allergens in ways our arboreal and more recent ancestors never experienced. Try sharing that idea with a chimpanzee, however (which I have not attempted), or an eco-warrior (which I have). Climate shift is apparently the root of all evil, from kidney stones (27, 28) to violent crime (29) and madness (30).

There is some truth in these arguments too. Kidney stones do relate to hydration, but they are also linked to poor diet and the over-use of antibiotics (ie 31). As for violent crime, it is affected by the temperature but also by a host of socioeconomic and nutritional factors (ie 32-34), and therefore neurological ones (32-34). Which brings us back to mast cells.

There are mast cells in the brain, and when they malfunction they drive neuroinflammation. This is associated with increased impulsivity (35-38 but see also 39, written by surely one of the brightest stars at Ohio State), which would be expected to raise crime rates. It is also linked to multiple neurologic and psychiatric disorders including headache, dysautonomia, depression and generalized anxiety disorder (40, 41), which are also on the rise.

Might these negative health trends have something to do with the progressive removal of natural mast cell stabilizers from our diet?

The best known of these are a group of proteolytic enzymes known as bromelain, and the polyphenols quercetin and luteolin. Bromelain appears to reduce mast cell accumulation and degranulation (ie 42, 43, but see also 44); but as the main source of bromelain is the pineapple, it is hard to make the dietary shift argument here. Quercetin and to an extent luteolin provide a better case.

One of the most prevalent of polyphenols, and present at significant levels in citrus fruits, apples, onions, tea, red wine and berry fruits, contemporary intakes of quercetin range between 5 and 500 mg/day (45), depending on dietary preferences. This is, in my view, a depletion scenario. Historical data indicates a fall of at least 80% in the intake of polyphenols, including quercetin, since pre-transitional times (45-47).

Luteolin is scarcer on the ground, and hence harder to quantify. The best food sources are radicchio and Chinese celery, with juniper berries also scoring very high marks (48).

Juniper was widely used by medieval and early modern cooks to flavour cakes and meat dishes, and by herbalists for medicinal purposes. Its first use in alcohol was as a digestive aid; but gin is no longer considered a health drink, sadly, and nobody eats juniper berries. Other than health-nuts obsessed with natural senolytics (49) …

Wherever ultra-processed foods have taken over, intakes of quercetin and luteolin have fallen due to the huge input of empty calories in the form of sugars, starches and plant oils. As quercetin and luteolin are both very good mast cell stabilizers indeed (50, 51), it is hard to argue that this aspect of dietary shift has NOT contributed to increased levels of mast cell-related pathologies and behaviours.

Perhaps the most common of these mast cell mediator disorders is Mast Cell Activation Syndrome (MCAS).

A form of mast cell malfunction involved in many autoimmune conditions (2), and linked also to many psychiatric disorders, MCAS is now reckoned by a Bonn-based research team to affect 20% of us (52). This staggering finding – if even remotely true – is yet another indictment of the modern diet and lifestyle, and feeds into my obsession of civilizational decay by diet.

A note of caution: in this paper (52), the diagnosis of MCAS was made on the basis of raised heparin blood levels, and self-reporting.

This post is not about the wider category of the mast cell disorders, which deserve a post of their own, but on the links between mast cell over-activation, other forms of illness and dietary shift. And it is a suggestion that you improve your diet to support your mast cells, in order to reduce the risk of acute symptoms and longer-term conditions.

For example, sustained over-activation of mast cells in the brain will, by imposing neuroinflammatory stress, likely increase the risk of neurodegenerative diseases such as Alzheimer’s (53). Mast cell over-activation in other tissues will promote allergy and autoimmunity, which often occur in the same patient, and which appear to share a number of common immunological, metabolic and hence dietary links (54-67).

Being allergic, for example, increases the risk of developing autoimmune problems (55); and while they involve different types of T cells, both have their origins in a range of dietary factors.

Starting with the gut, dysbiosis and the loss of normal epithelial barrier function seem to be an important part of the causative sequence of both types of immune disorder (56, 57).

It is well known that dysbiosis and epithelial barrier problems are intimately related to dietary shift, and specifically the progressive removal of prebiotics such as fermentable carbohydrates (58), omega 3 PUFA’s (59) and polyphenols (60) from our diet.

The involvement of mast cells is less well known. Mast cells are crucial to normal gut epithelial barrier function, being involved in the maintenance of tight cell junctions (61), so the removal of mast cell stabilisers from the modern diet and subsequent degradation of mast cell function will act in tandem with dysbiosis to exacerbate epithelial barrier breakdown.

These paired sequelae of dietary shift will facilitate endotoxaemia and the translocation of enteric bacteria to other sites in the body, a process implicated in the rise of autoimmune disease (6).

TH-17 cells may also be involved here. Dysbiosis caused by the modern low-fiber diet causes supra-physiological levels of inflammatory stress in the gut wall, which changes the gut’s secretory profile and the ratios, activity and differentiation of a number of immune cell sub-types. These include TH17 cells, which are implicated in driving allergy and autoimmunity, and Treg cells, several sub-types of which are protective.

A healthy (ie traditional) diet promotes Treg induction over TH17 cell development, and the optimal (non-pathogenic) types of Treg cells (62). The actives which seem to be important here include not only the prebiotic fibers but also vitamins D, E and C (62), the indoles (63), and – yet again – the omega 3 PUFA’s (64) and polyphenols (ie 65).

The modern industrial diet is low in all those protective factors, and it replaces them with a set of exacerbating ones.

It promotes obesity, itself a risk factor for immune dysfunction and autoimmunity (66), together with dysbiosis, chronic inflammatory stress, additional insults to gut barrier function from emulsifiers (67), and up-regulated TH17 activity due to excess sodium (68). The calorific density and excess intrinsic to the ultra-processed diet further disturb immune tolerance (69), and all of these contribute to the ongoing immunological train-wreckage of allergy and autoimmunity.

Physical activity comes in here too. Being a couch potato, especially if you combine this with snacking, switches on the energy sensor mTOR. This re-arranges the immune system in a way that likely increases the risk of immune-related disease (70). Over-exercise is not good either (70, 71), so moderation is the key. The best approach may be to alternate periods of activity and inactivity (69, 70), a pattern which probably reflects our evolutionary past.

What are Modern Times, however, if not Physical Inactivity + Industrial Diet?

The lifestyle factors reviewed here affirm yet again the dangers of continuing on our current course, and the need to reconfigure the truly toxic modern diet and lifestyle; if not for ourselves, then for our metabolically and epigenetically-challenged children. We should shield them from the excesses of modernity – but how?

Tipped off by Circe, wily Odysseus protected his oarsmen by stopping their ears with wax. He could hear the sirens’ song, but he could not free himself. With neither wax nor mast at hand we sail between the fleeting pleasures of ultra-processed food and the siren call of the couch, and the journey is killing us.

More prosaically, a safer way of navigating these dangerous waters is to cook your own food, and/or use the bio-hacks described in previous posts.

Given the homoeroticism on display in the painting of Odysseus’ siren-induced ecstasy, one last point. Mast cells in the central nervous system help shape the developing brain, and recent findings indicate that they influence and may even determine adult sexual behaviour (14). This is yet another metabolic intersection where the industrial diet may have contributed to today’s obsession with intersectionality.

Next week: Bureaucratic exercise, and how to circumvent it.

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