Okay, maybe saying a diet composed of just doughnuts could save you from gout was maybe a wee bit of a stretch. But a diet composed mainly of fats accompanied by a small amount of carbohydrates actually stands a fair chance at coming to your aid. This unique regiment is known as the ketogenic diet. If you ever had a biology class in high school, you learned that glucose is the main energy source for the billions of cells in your body. Whereas that is largely the general trend, there are several instances where this doesn’t always happen. Due to the composition of the ketogenic diet, the body believes it is going through a period of starvation since there is not an abundant amount of glucose around. In response to this, the body produces a higher amount of these molecules known as ketone bodies that are used as alternative fuels for the cell. B-hydroxybutyrate (BHB) and acetoacetate (AcAc) are two of the most famous ketone bodies. In a recent paper published this February, the Goldberg et al. team examined how these ketone bodies, specifically BHB, were able to alleviate some of the symptoms of gout.
As a refresher, gout is a metabolic disorder that leads to painful inflammation of the joints and can lead to immobility if it was severe enough (“Diseases and Conditions Gout” 2017). An accumulation of small crystals in the joints are the cause of this disease (Goldberg et al. 2017). Since gout is an extreme inflammatory condition, Goldberg and her team focused on the known pro-inflammatory molecules that centered around this disease, primarily interleukin- 1b, IL-1b for short. IL-1b is responsible for causing an inflammatory response in order to protect the body during an immune response for a pathogen attack (Lopez-Castejon and Brough 2011). This pro-inflammatory goes awry in gout and leads to intense pain and fever (Goldberg et al. 2017). Another crucial aspect of gout that was investigated was the NLRP3 inflammasome. This inflammasome is composed of several different inflammatory caspases that once activated lead to an increase downstream products such as IL-1b (Baroja-Mazo et al. 2014). With a series of experiments, Goldberg et al. were able to connect how BHB was able to block the activity of the inflammasome and how ketones may be able to regulate the inflammation of gout.
One of the first things the authors did was examine how BHB interferes with the proposed gout mechanism. With an increase of the crystals in the joint, neutrophils are drawn there via an inflammasome and become activated. The authors believe to cause the pain and swelling. A deeper look into this pathway revealed that a cytoplasmic protein, found predominantly in neutrophils, are one of the activators for the inflammasome. When BHB was introduced to the situation, it was able to block this activation and in turn prevent IL-1b to be secreted and cause intense inflammation.
Now that is was noted what BHB had to contribute, it was a compelling reason why to look into how a ketogenic diet may be able to help against gout. The authors talked about how there are already IL-1b antagonists that have worked in clinical trials, but the downside was how expensive they are and the potential harmful side effects. Because of these complications, these antagonists’ uses have been extremely limited and therefore need another method which is capable of limiting the secretion of IL-1b and other pro-inflammatory agents. The authors created a biological model which gave rats gout in their knees. Following this, these rats were put on a one week ketogenic diet and had their BHB production significantly increased. The rats were examined again after the diet and were found to have their IL-1b levels and knee swelling decreased. Tissue samples from the rat subjects with gout in their knees were taken and stained to compare between rats that were on the special diet and those who were not. Those not on the diet displayed lesions and soft tissue inflammation. The samples taken from rats on the ketogenic diet revealed diminished lesion sites and inflammation. The authors concluded that the diet was able to decrease the severity of the gouty inflammation, but not alleviate it completely.
As dangerous it can be to have these joint inflammations, inflammation is a body’s natural defense to bacterial infections. The question became if these increased levels of BHB affected inflammation due to an infection. Fortunately, there was no inflammatory response change in a rat on the ketogenic diet that was infected with Staphylococcus aureus. This suggests that there is specificity for how BHB can affect inflammation.
Further experiments were conducted to further understand how BHB affects gouty inflammation. The authors found that IL-1b can be secreted in two main ways, one being of an inflammasome-dependent process and the other being an inflammasome-independent process. As stated above, BHB does interact with the inflammasome and prevent IL-1b from being secreted. But unfortunately, BHB did not appear to have any effect on the inflammasome-independent pathway.
In addition to the cellular mechanistic character of BHB, Goldberg et al. also found that BHB acted to prevent this gouty inflammation in a genetic manner as well. It was found to inhibit the phosphorylation of the DNA transcription factor NF –KB. This particular transcription factor was linked by the authors to being fundamental in the signaling event for inflammasome activation. This supports how BHB specially deals with the inflammasome to hinder gouty inflammation.
Before Goldberg et al.’s investigation, this entire mechanism was not well explored. Gout is a disease that affects 4% of the adult population with the 10% prevalence in the elderly about 60 years old. Between sequencing the human genome in 2001 and the major technological advancements made between then and now, we are capable in both prolonging someone’s lifespan as well as their quality of life. Sure, pharmaceuticals are a huge field and develop what seems like endless drugs, but that is not always the answer. Sometimes a more natural approach is more effective. This a case were there drugs that are capable of reducing gout’s inflammation, but a high monetary and health cost. By analyzing and having a better understanding of BHB’s effects on gout, a diet change might be able to be incorporated into the battle. Our bodies are capable of magnificent feats, so why not take advantage of that and let it suit us better rather than pumping endless manufactured drugs into our systems when it is not absolutely necessary.
Figure 1. This is the basic overview of how the pro-inflammatory IL-1B is produced and secreted out of the cell and produce that inflammatory response. BHB functions by inhibiting the caspase 1 cleavage and prevent a mature IL-1B from being able to be secreted.
Baroja-Mazo, Alberto, Fatima Martín-Sánchez, Ana I. Gomez, Carlos M. Martínez, Joaquín Amores-Iniesta, Vincent Compan, Maria Barberà-Cremades, et al. 2014. “The NLRP3 Inflammasome Is Released as a Particulate Danger Signal That Amplifies the Inflammatory Response.” Nature Immunology 15 (8): 738–48. doi:10.1038/ni.2919.
Goldberg, Emily L., Jennifer L. Asher, Ryan D. Molony, Albert C. Shaw, Caroline J. Zeiss, Chao Wang, Ludmilla A. Morozova-Roche, Raimund I. Herzog, Akiko Iwasaki, and Vishwa Deep Dixit. 2017. “β-Hydroxybutyrate Deactivates Neutrophil NLRP3 Inflammasome to Relieve Gout Flares.” Cell Reports 18 (9): 2077–87. doi:10.1016/j.celrep.2017.02.004.