The Effect of Raising Ketones Directly With MCT Oil on Inflammation in Healthy Young Adults
Condition: MCT Oil Supplementation
Study type: Interventional

Summary: 
      Ketogenic diets are gaining support as a method to lower inflammation within the body, but
      studies have not been able to show the way by which this occurs. Ketones, which are molecules
      made by the body as a source of energy during carbohydrate restriction, have been shown to
      have the ability to alter the number and types of messages that immune cells send to each
      other, and thus have the potential to lower inflammation. To determine whether raising
      ketones independent of diet reduce inflammation, 20 healthy, young men and women will follow
      a 14-day "normal" diet combined with MCT oil supplements. Based on previous research, the
      investigators expect that raising ketones will reduce immune cell pro-inflammatory signaling.
    

Detailed description: 
      The potential for a ketogenic diet to reduce inflammation has become increasingly popular in
      recent years, but direct scientific evidence to demonstrate that ketones impact inflammatory
      mechanisms in humans does not exist. B-hydroxybutyrate (B-OHB) is the most abundant
      circulating ketone and recent evidence indicates that B-OHB may be able to act as a direct
      signal to inhibit cellular pathways involved in inflammation.

      B-OHB can be raised naturally by induction of nutritional ketosis, which is a normal
      physiological response to severe reductions in carbohydrate or caloric intake. In this state,
      free fatty acids are converted to ketone bodies (primarily B-hydroxybutyrate [B-OHB]) by the
      liver in order to provide essential fuel for metabolically active tissues. However,
      determining the direct effects of B-OHB in human ketogenic diet studies is difficult due to
      the numerous metabolic adaptations that occur in nutritional ketosis (e.g., reduced insulin,
      elevated free fatty acids, stable glucose) and the propensity for participants to lose body
      and fat mass over longer period.

      B-OHB can also be raised independent of diet by supplementation with medium chain
      triglyceride (MCT) oil, allowing for induction of ketosis without the additional metabolic
      adaptations. In addition to being an important fuel source, recent interest has focused on a
      potential signaling role for B-OHB with cell culture and animal studies describing
      anti-inflammatory, anti-oxidant, and anti-cancer effects. The cellular pathways through which
      B-OHB is proposed to reduce inflammation, include the NLPR3 inflammasome and histone
      deacetylases (HDACs), both of which play important roles in regulating cellular inflammation.
      The NLRP3 inflammasome pathway is an immune complex which, upon activation, initiates
      downstream pro-inflammatory cascades including the activation of caspase-1 and interleukin
      (IL)-1B. These pro-inflammatory cascades have been implicated in the propagation of sterile
      inflammation, which has been identified as a major contributor to certain chronic
      inflammatory diseases such as type 2 diabetes and atherosclerosis. HDACs are enzymes
      typically found within the nucleus and have the ability to regulate signaling through innate
      immune pathways. B-OHB has been shown to have the ability to inhibit HDACs, and consequently
      has the potential to decrease oxidative stress and inflammation. The NLRP3 inflammasome and
      HDACs are responsive to the intracellular nutritional milieu and thus their activity may be
      able to be modulated through increases in B-OHB.

      The use of MCT oil supplements will allow the investigators to raise blood B-OHB independent
      of diet, and thus directly test the immunomodulatory effects of B-OHB in healthy, adult
      males. This fundamental research is needed to understand whether ketones have direct
      immunomodulatory effects or if it is the widespread systemic metabolic adaptation to a
      ketogenic diet that might impact inflammatory processes.

      The overall objective of this pilot study is to determine if directly raising B-OHB through
      supplementation with MCT oil impacts innate immune cell function and/or phenotype. Based on
      previous cell culture and animal research showing that B-OHB can reduce pro-inflammatory
      signaling, it is hypothesized that raising B-OHB with MCT oil supplementation will result in
      a attenuation of caspase-1 activation and mature IL-1B secretion, both markers of NLRP3
      inflammasome activation. Additionally, it is hypothesized that raised B-OHB will result in
      greater histone acetylation, as B-OHB has been shown to be an HDAC inhibitor.
    

Intervention name(s): MCT Oil Supplementation
Intervention type(s): Dietary Supplement
Intervention description(s): Participants consume MCT oil (97-99% octanoic acid) twice per day for 14 days. Dosing will begin at 5ml/dose for Days 1-2, 10ml for Days 3-4, and 15ml for the remainder of the intervention.
Intervention model: Single Group Assignment
Intervention model description: All participants complete the supplementation condition.
Masking: None (Open Label)
Primary purpose: Other
Keywords: NLR Family, Pyrin Domain-Containing 3 Protein; Caspase 1; 3-Hydroxybutyric Acid; Histone Deacetylase Inhibitors; MCT Oil