Gout is an exquisitely painful condition. It often afflicts the first joint of the big toe, which is why Hippocrates called it ‘the unwalkable disease.’ He also described it as ‘arthritis of the rich’, he wasn’t wrong there either. And it is on the march; thanks to our unhealthy lifestyles, the incidence of gout has more than doubled over the last 20 years (1, 2). This is one of many reasons why the numbers of people in pain are increasing in our increasingly sick and sad society (3).
The rise in gout was all too predictable. Familiar risk factors such as obesity, metabolic syndrome, hypertension, diabetes mellitus, chronic renal disease, aspirin, alcohol and ageing (4–11), have all multiplied. What one might not have expected, given that much of the pathology of gout is understood and that drugs and dietary programs are widely available, are the substantial numbers of patients who are still not adequately treated (ie 12-15).
The drugs used to lower uric acid levels trigger serious adverse effects. So many cannot tolerate the higher doses needed to bring their condition under control, that a majority of patients under-dose or skip doses (16). A small number don’t respond to the drugs at any dose (14, 15); and many more are unwilling to enforce the dietary changes that would, if maintained, reduce the risk of an attack.
This is rather serious, because people with gout have a 25% increased risk of premature death (17-21), a statistic that has remained unchanged for at least the last two decades (22). They die of cardiovascular conditions, stroke, kidney failure, infections and digestive system disease (23), the last of which may be related to high use of anti-inflammatory medications.
But there is a deeper problem. The pharmaceutical approach to gout is based on a simple first order model. It holds that purine intake determines uric acid levels, and drugs which either reduce uric acid production (allopurinol, febuxostat), increase uric acid excretion (probenecid, lesinurad) or break it down (pegloticase) are the answer.
It seems logical, but this model is manifestly incomplete.
Gout is certainly related to uric acid metabolism, and there is a strong relationship between uric acid levels and risk of attack. However, only a third of those with high uric acid experience an attack (24, 25), and some folks have attacks even when uric acid levels are normal (26).
Diets containing significant levels of purines derived from animal products (and beer) increase the risk of developing gout (27), but diets providing high levels of purines in plant foods such as mushrooms and green peas do not (27). Fructose in sugar and high-fructose corn syrup raises uric acid levels (28, 29) and the risk of gout (29-31), but fructose in fruits tends not to do either of these things (28).
There is clearly more to gout than dietary purines in, and urate crystals out. Hyperuricemia is necessary but generally insufficient to induce gout, and other factors must be at play. Uric acid chemistry and nutritional chemistry in general provide clues as to what these might be.
At low levels uric acid is an important neuroprotectant (32) and an antioxidant (33), but only in aqueous environments such as plasma (33), and only when sufficient ascorbate is present (34). At high concentrations it develops pro-oxidative (35-37) and pro-inflammatory (36-39) properties, and induces mitochondrial dysfunction (40, 41). These mechanisms help to explain (42) why high uric acid levels are linked to a raised risk of hypertension (43), liver disease (40, 44), atrial fibrillation (45, 46), insulin resistance (41, 47, 48), heart attack (49), stroke (49) and kidney disease (50).
Some of these links are inconsistent, however (ie 51), which once again forces us to consider other variables; and specifically, dietary components which might modulate or neutralise the pro-oxidant and pro-inflammatory effects of hyperuricaemia. This brings us back, as always, to the anti-inflammatory trinity of omega 3 HUFA’s, polyphenols and prebiotic fibers.
With regard to the omega 3 fatty acids, seafoods are generally considered off-limits to gout patients due to their purine content. Recent dietary recommendations, however, say that if the worst purine offenders are omitted (anchovies, shellfish, sardines, tuna), the overall health benefits of eating fish put them back on the menu (52). Balance oil, which combines omega 3’s with polyphenol chaperones but no purines at all, is an uncomplicated anti-inflammatory alternative.
A key piece of evidence here is a case-crossover study run out of Harvard that was published in 2019 (53).
The data generated in this study showed that eating oily fish reduced the risk of gout flares, whereas omega 3 supplements were a total failure; providing yet more evidence that commercial fish oils are a waste of time and money (54) unless they also contain amphiphilic polyphenols.
I have long been fascinated by the polyphenols, which have an extraordinary array of effects in the body, and scientists at various research locations have shown that even the hydrophilic polyphenols are useful in the treatment and prevention of gout.
Resveratrol (the one in grape skin), epigallocatechin (the one in tea) and sinapic acid (berries, citrus and spices) all have positive effects. They modify uric acid metabolism and transport in ways that lower serum uric acid levels (55-57).
The prebiotics are involved too. Prebiotic fibers generate a microbiotal shift from gram negative proteolytic species, which are generally pro-inflammatory, to gram-positive saccharolytic species which are generally anti-inflammatory. Prebiotics reduce the risk of vascular disease, cancers and dementia (58, 59). Recent evidence shows they protect against gout too, by changing the colonic microbial metabolism of uric acid.
Approximately one third of the body’s pool of uric acid cycles through the gut (60). A healthier microbiota drains the pool via enhanced breakdown of purines and uric acid, reduced absorption and increased fecal excretion of these compounds (ie 61) and reduced GI inflammation (61-63). This theory predicts that prebiotics should reduce serum uric acid levels, and they do so both pre-clinically (64) and clinically (65).
For those who prefer probiotics such as Bifidobacteria and Lactobacilli, there is pre-clinical (66, 67) and some clinical evidence (68, 69) for these also. Alternatively, you could opt for a synbiotic approach (70, 71). Given the respective modes of action of pre-, pro- and synbiotics, and taking into consideration cost and stability, I usually prioritize prebiotics.
Thanks to dietary shift our intakes of omega 3 HUFA’s, polyphenols and prebiotic fibers have all declined, and the resulting epidemics of inflammatory stress disfigure the public health landscape today. This has made us all more vulnerable to gout, but that’s not the whole story. As our diets have degraded, our intakes of sugars have increased. This means that we are eating more fructose, a dietary problem already linked to the world-wide epidemic of NAFLD (72).
Fructose is a trigger for gout, and intakes of fructose have risen significantly since the ‘70’s (73). Due to the indiscriminate addition of sucrose and high-fructose corn syrup to many ultra-processed foods, it now accounts for up to 10% of American calories (74). Much of it is in sweetened beverages (75), but it is also hidden in up to three quarters of all ultra-processed foods (76).
Fructose raises serum uric acid levels, and is the only common carbohydrate to do so. It does this by increasing levels of the purine inosine (77, 78), interfering with uric acid transport (79) and via adverse effects on the microbiome (ie 80, 81). In marked contrast, fructose consumed in a fruit-based diet shifts the microbiome in an entirely positive manner (81, 82), due at least in part to the prebiotic fibers and polyphenols contained in most fruits.
Accordingly, there is a reasonable body of evidence linking consumption of fructose but not fruit to increased risk of gout (28, 83, 84). The results are not entirely consistent, but this is to be expected when dealing with complex metabolic networks in which so many nutritional variables are in play. For example, along with their polyphenol and fiber content, fruits generally contain ascorbate which is another likely protective factor (85, 86).
There may be lifestyle variables also. Melatonin blocks many of the cytotoxic (mitochondrial) effects of hyperuricaemia (41), and as our lives have progressively moved indoors, cellular melatonin levels have surely fallen (87). This could be making us more prone to gout or gout-related pathology than we should be, and adding to the damaging effects of the industrial diet.
To summarize, the likelihood of symptomatic gout appears to be increased by higher intakes of purines and fructose if these are in animal foods and ultra-processed foods. If purines and fructose are ingested in plant foods their tendency to cause gout is minimal or absent, probably due to the presence of polyphenols, prebiotics and ascorbate. If you are wedded to the ultra-processed diet, the risk of gout and its complications should be reduced by supplementing with omega 3’s, polyphenols and prebiotics.
And, maybe, by spending a little more time in the sunlight. Mitochondria is synthesized in and also taken up by mitochondria, but oral supplements are not the best way to deliver melatonin due to first pass metabolism.
All these strategies can be combined with the standard pharmaceuticals and should make them effective at lower doses, reducing adverse effects and improving compliance (ie 71, 72).
A last, general metabolic point.
Gout is strongly linked to NAFLD, another pathology caused by over-nutrition / dysnutrition.
Uric acid levels are higher in NAFLD patients (44), and predict the development of NAFLD in subjects who do not yet have it (88). NAFLD occurs more frequently in gout patients, and among patients with NAFLD, the severity of their liver disease is highest in those who also have gout (89, 90).
As well as fructose, another factor that links the two conditions is endotoxemia. This common condition is triggered by colonic dysbiosis, caused in turn by the modern high-fat and prebiotic depleted diet (91, 92).
Colonic dysbiosis causes gut inflammation and a local increase in intestinal uric acid production (92, 93). At the same time, damaged gut barrier function allows the release of bacterial lipopolysaccharides into the portal and then the systemic circulation (92). The resulting metabolic endotoxemia, which causes systemic low-grade inflammation, is a contributory factor to many degenerative conditions; from cognitive decline and dementia (94, 95) to insulin resistance (96), NAFLD (72, 97) and gout (98), in at least one pre-clinical model.
It gets more complicated, because different sub-types of LPS produced by different gut bacteria have very different effects in the body (ie 99), but the conclusion is clear. If you want to be healthy, stop eating ultra-processed foods and switch to basic produce.
Next week: theoretical ageing, and how to theoretically modify it.
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