News & Publications

• Beta-hydroxybutyrate produced from a ketogenic diet may improve gout symptoms (animal study) www.sciencedaily.com
  Nutrition Diet Ketosis Inflammation Arthritis NLRP3 Ketogenic Diet

  Beta-hydroxybutyrate reduces symptoms of gout.

  Gout is a painful, debilitating disease that affects more than 8 million people living in the United States. The condition arises when uric acid crystals form in and around the joints, causing inflammation, pain, and impaired mobility. Evidence from a 2017 study suggests that beta-hydroxybutyrate inhibits the activity of the NLRP3 inflammasome, reducing symptoms of gout.

  Beta-hydroxybutyrate is a type of ketone body. It forms in the liver via the breakdown of fatty acids and can be used to produce energy in the mitochondria. Beta-hydroxybutyrate also acts as a signaling molecule that alters gene expression via a wide range of molecular pathways. Ketogenic diets induce beta-hydroxybutyrate production.

  Inflammasomes are large, intracellular complexes that detect and respond to internal and external threats. Activation of inflammasomes has been implicated in a host of inflammatory disorders. The NLRP3 inflammasome, in particular, triggers the release of the proinflammatory proteins interleukin (IL)-1 beta and IL-18 and drives pyroptosis, a form of cell death that is triggered by proinflammatory signals and closely linked with inflammation.

  The study involved rats that are prone to developing gout. The investigators fed one group of the rats a normal diet and fed another group a ketogenic diet. After one week, they measured ketones present in the animals' urine. They found that the ketogenic diet induced production of beta-hydroxybutyrate, which in turn protected the animals against uric acid-induced elevations in IL-1 beta. Examination of the animals' joints revealed that the rats that ate the ketogenic diet had less joint inflammation than those fed a normal diet.

  Next, the investigators assessed the effects of beta-hydroxybutyrate on neutrophils, a type of immune cell, from both young and old humans. They found that the compound inhibited the NLRP3 inflammasome-induced IL-1 beta secretion in both young and old neutrophils, suggesting that the ketone plays a role in activating the inflammasome in neutrophils, regardless of age.

  These findings suggest that beta-hydroxybutyrate inhibits the activity of the NLRP3 inflammasome, reducing the symptoms of gout. Researchers do not know if these results translate to humans, however. Learn more about the health effects of beta-hydroxybutyrate in our overview article.

  • Link to full publication.
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• Sulforaphane inhibits activation of the NLRP3 inflammasome in mice microglia cells. www.sciencedirect.com
  Inflammation Sulforaphane NRF2 NLRP3

  Sulforaphane is a bioactive compound derived from certain cruciferous vegetables, such as broccoli and broccoli sprouts. It exerts potent anti-inflammatory properties and switches on the activity of a vast array of cellular protective proteins. A new study in mice demonstrates that sulforaphane inhibits activation of the NLRP3 inflammasome in mice microglia cells via inhibition of the NF-kB pathway and altered gene expression.

  Inflammasomes are large, intracellular complexes that detect and respond to internal and external threats. Activation of inflammasomes has been implicated in a host of inflammatory disorders. The NLRP3 inflammasome in particular triggers the release of proinflammatory cytokines interleukin-1 beta (IL-1β) and IL-18 and drives pyroptosis, a form of cell death that is triggered by proinflammatory signals and closely linked with inflammation.

  Microglia are the brain’s resident immune cells. They serve an essential role in maintaining brain microenvironment homeostasis. Acute activation of microglia modulates inflammation and neurotoxicity, but chronic activation promotes brain inflammation and damage.

  NF-kB is a family of proteins present in mammalian cells. NF-kB influences several aspects of the body’s stress response via its participation in signaling pathways that drive pro-inflammatory processes, ultimately regulating DNA transcription, cytokine production, cell survival, and immune function.

  The authors of the study triggered the activity of the NLRP3 inflammasome in mice microglia cells that had been treated with or without sulforaphane. Then they assessed the level of pyroptosis in the cells, measured expression of IL-1β and IL-18, and tracked the activity of NF-kB. They also measured the cells' mitochondrial production of reactive oxygen species and mitochondrial membrane integrity. The cells treated with sulforaphane showed less pyroptosis, reduced expression of IL-1β and IL-18, and impaired NF-kB activity than the untreated cells. Sulforaphane also reduced reactive oxygen species production and helped maintain mitochondrial membrane integrity.

  These findings suggest that sulforaphane protects the brain via inhibition of the NF-kB pathway and subsequent inhibition of the NLRP3 inflammasome.

  • Link to study abstract.
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• A pilot study to investigate the immune modulatory effects of fasting in steroid-naïve mild asthmatics www.ncbi.nlm.nih.gov
  Inflammation Fasting Allergies Asthma NLRP3

  A fasting mimetic diet blunts inflammation and intermittent fasting has shown ameliorative effects in obese asthmatics. To examine whether canonical inflammatory pathways linked with asthma are modulated by fasting we designed a pilot study in mild asthmatic subjects to assess the effect of fasting on: the NLRP3 inflammasome; Th2 cell activation and airway epithelial cell cytokine production. Subjects with documented reversible airway obstruction and stable mild asthma were recruited into this study where pulmonary function testing (PFT) and peripheral blood mononuclear cells (PBMCs) extraction was performed 24 hours after fasting, with repeated PFT-testing and blood draw 2.5 hours after refeeding. PFT’s were not changed by a prolonged fast. However, steroid-naïve mild asthmatics showed fasting-dependent blunting of the NLRP3 inflammasome. Furthermore, PBMCs from these fasted asthmatics co-cultured with human epithelial cells resulted in blunting of house dust mite-induced epithelial cell cytokine production, and reduced CD4+ T cell Th2 activation compared to refed samples. This pilot study shows that prolonged fasting blunts the NLRP3 inflammasome and Th2 cell activation in steroid-naïve asthmatics, as well as diminishes airway epithelial cell cytokine production. This identifies a potential role for nutrient-level dependent regulation of inflammation in asthma. Our findings support the evaluation of this concept in a larger study, as well as the potential development of caloric restriction interventions for the treatment of asthma.

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• Increased visceral fat impairs cognition through chronic microglial activation mediated by IL-1 beta release [animal research] www.sciencedaily.com
  Brain Inflammation Memory Fat Dementia Weight Loss NLRP3 Visceral Fat

  Scientists find that visceral fat, a type of adipose tissue that produces high levels of inflammatory signals known as adipokines, impair learning and memory in mice by setting off an inflammatory cascade mediated by the release of IL-1 beta, which crosses the blood-brain barrier leading to chronic activation of microglia.

  From the article:

  “We have identified a specific signal that is generated in visceral fat, released into the blood that gets through the blood brain barrier and into the brain where it activates microglia and impairs cognition.”

  Visceral fat as the ring leader:

  They looked further and found that just transplanting the visceral fat caused essentially the same impact as obesity resulting from a high-fat diet, including significantly increasing brain levels of interleukin-1 beta and activating microglia. Mice missing interleukin-1 beta’s receptor on the microglia also were protected from these brain ravages.

  […]

  To measure cognitive ability, the scientists looked at mice’s ability to navigate a water maze after 12 weeks on a high- or low-fat diet. They found it took the normal, or wild type, mice consuming the higher fat diet as well as the visceral transplant recipients with NLRP3 intact longer to negotiate the water maze. In fact, while they could reach a platform they could see, they had trouble finding one beneath the water’s surface that they had been taught to find. Mice with the interleukin-1 receptor knocked out, could find it just fine, Stranahan says.

  The high-fat diet, transplant mice also had weaker connections, or synapses, between neurons involved in learning and memory. Mice on a high-fat diet but missing NLRP3 were spared these changes, like mice on a low-fat diet.

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• Excess visceral fat promotes inflammation and drives cognitive decline. www.eurekalert.org
  Brain Obesity Depression Neurons Protein Metabolic Syndrome NLRP3 Visceral Fat

  Visceral fat – body fat that is stored in the abdominal cavity in close proximity to important internal organs such as the liver, pancreas, and intestines – plays a central role in the interrelationship between obesity and systemic inflammation. Excess visceral fat, often referred to as central or abdominal obesity, is a strong predictor of age-related cognitive decline. A new study in mice demonstrates that having excess visceral fat may impair cognition by activating the NLRP3 inflammasome and promoting the release of interleukin-1 beta (IL-1β).

  Inflammasomes are large, intracellular complexes that detect and respond to internal and external threats. Activation of inflammasomes has been implicated in a host of inflammatory disorders. Cryopyrin, also known as NLRP3, is a protein that drives the formation and activation of the NLRP3 inflammasome.

  Interleukin-1 beta is a proinflammatory protein present in many cells. NLRP3 inflammasome-driven release of IL-1β activates microglia, the brain’s resident immune cells. Microglia serve an essential role in maintaining brain microenvironment homeostasis. Acute activation of microglia modulates inflammation and neurotoxicity, but chronic activation promotes brain inflammation and harm.

  The authors of the study first determined that mice lacking the gene for NLRP3 did not experience visceral fat-induced brain inflammation and cognitive decline. They also determined that when visceral fat from normal, obese mice was transplanted into these mice, they exhibited higher levels of IL-1β in their hippocampus, an area of the brain associated with memory (in particular, the consolidation of short-term memories to long-term memories), learning, and spatial navigation.

  To understand the effects of IL-1β on brain function, the authors of the study fed the mice a high- or low-fat diet for 12 weeks and then assessed the animals' capacity to navigate a water maze. The mice that ate the higher-fat diet experienced greater difficulties negotiating the water maze, compared to those that ate the lower-fat diet. Examination of the animals' brains revealed that the mice that ate the high-fat diet (as well as those that received the fat transplants) had weaker synapses between the neurons involved in learning and memory.

  These findings suggest that chronic inflammation driven by excess visceral fat may contribute to cognitive decline by promoting the release of IL-1β and increasing inflammation. Inflammation drives other aspects of brain dysfunction, including those associated with depression. Watch this clip in which Dr. Charles Raison discusses how a pro-inflammatory environment can contribute to the risk of depression.

  • Link to full study (PDF).
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• Beta-hydroxybutyrate produced from a ketogenic diet, fasting, or high-intensity exercise dampens inflammation via blocking of the NLRP3 inflammasome www.sciencedaily.com
  Exercise Diet Ketosis Inflammation Fasting Immune System NLRP3 Ketogenic Diet

  From the article:

  BHB is a metabolite produced by the body in response to fasting, high-intensity exercise, caloric restriction, or consumption of the low-carbohydrate ketogenic diet. Dixit said it is well known that fasting and calorie restriction reduces inflammation in the body, but it was unclear how immune cells adapt to reduced availability of glucose and if they can respond to metabolites produced from fat oxidation.

  Working with mice and human immune cells, Dixit and colleagues focused on how macrophages – specialized immune cells that produce inflammation – respond when exposed to ketone bodies and whether that impacts the inflammasone complex.

  The team introduced BHB to mouse models of inflammatory diseases caused by NLP3. They found that this reduced inflammation, and that inflammation was also reduced when the mice were given a ketogenic diet, which elevates the levels of BHB in the bloodstream.

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