Gout is a rheumatic disease that affects more than 8 million people in the United States. It is caused by either an excessive production or insufficient excretion of uric acid. In gout, the uric acid crystals sediment in tissues and fluids, triggering the body's immune cells. This results in disabling pain, inflammation, and fever.
These episodes of immune cell reactivation, also known as flares, are triggered by a protein complex called the NLRP3 inflammasome.
New research from the laboratory of Vishwa Deep Dixit - professor of comparative medicine and immunobiology at Yale School of Medicine in New Haven, CT - suggests that the so-called ketogenic diet may help to relieve the symptoms of gout.
A ketogenic diet is low in carbohydrates and typically used to lose weight. Ketogenic diets work by inducing "physiological ketosis" in the body - a state of the metabolism where the body's reserves of glucose are no longer enough for the body's central nervous system.
The central nervous system then needs an alternative source of energy, so it makes the liver turn fats into fatty acids and ketone bodies.
The new study - published in the journal Cell Reports - suggests that one of these ketone bodies, the beta-hydroxybutyrate (BHB), may alleviate urate crystal-induced gout.
Ketogenic diet increases BHB, protects against gout-related inflammation
The research team developed a new model of gout flares in rodents.
As the researchers explain, these flares are triggered by the NLRP3 inflammasome. With the help of neutrophils - the most common type of white blood cell - NLRP3 activates the IL-1B pro-inflammatory cytokine, leading to episodes of intense pain, fever, and the destruction of joints.
In the rodent model, researchers induced gout by injecting 1.25 milligrams of monosodium urate into rats' knees. Researchers measured knee thickness and performed pathology analyses on the rats' ligaments and menisci.
The rodents were kept in pathogen-free conditions and fed a ketogenic diet 1 week before starting the experiments. Scientists measured the levels of BHB in the rodents' blood.
The scientists also examined human subjects. They recruited healthy, steroid-free adults aged between 18 and 45, as well as older adults aged 65 and over. Participants were not fasting when their peripheral blood was collected.
Dixit and colleagues also conducted statistical analyses and performed all of the experiments at least twice.
The team found that a ketogenic diet raised BHB levels, which in turn inhibited the NLRP3 inflammasome. As a consequence, the symptoms of urate crystal-induced gout were alleviated, without negatively impacting the immune system or its ability to defend against bacterial infections.
Additionally, BHB blocked IL-1B in the neutrophils of both mice and humans, regardless of age. Dixit and colleagues conclude that:
"Collectively, our studies show that BHB, a known alternate metabolic fuel, is also an anti-inflammatory molecule that may serve as a treatment for gout."
Emily Goldberg, co-author on the study, associate research scientist, and clinical veterinarian in comparative medicine, explains the findings:
"In isolated neutrophils, [BHB] completely blocked NLRP3 inflammasome activation, even when provided at low concentrations that are physiologically achievable through dietary modification."
She also suggests that targeting the NLRP3 inflammasome to reduce inflammation during a flare may improve the gout patients' symptoms. However, she admits that more studies are needed to test this possibility.