The ketone metabolite β-hydroxybutyrate blocks NLRP3 inflammasome-mediated inflammatory disease
Open accessAbstract
The ketone bodies β-hydroxybutyrate (BHB) and acetoacetate (AcAc) support mammalian survival during states of energy deficit by serving as alternative sources of ATP. BHB levels are elevated by starvation, caloric restriction, high-intensity exercise, or the low-carbohydrate ketogenic diet. Prolonged fasting reduces inflammation; however, the impact that ketones and other alternative metabolic fuels produced during energy deficits have on the innate immune response is unknown. We report that BHB, but neither AcAc nor the structurally related short-chain fatty acids butyrate and acetate, suppresses activation of the NLRP3 inflammasome in response to urate crystals, ATP and lipotoxic fatty acids. BHB did not inhibit caspase-1 activation in response to pathogens that activate the NLR family, CARD domain containing 4 (NLRC4) or absent in melanoma 2 (AIM2) inflammasome and did not affect non-canonical caspase-11, inflammasome activation. Mechanistically, BHB inhibits the NLRP3 inflammasome by preventing K(+) efflux and reducing ASC oligomerization and speck formation. The inhibitory effects of BHB on NLRP3 are not dependent on chirality or starvation-regulated mechanisms like AMP-activated protein kinase (AMPK), reactive oxygen species (ROS), autophagy or glycolytic inhibition. BHB blocks the NLRP3 inflammasome without undergoing oxidation in the TCA cycle, and independently of uncoupling protein-2 (UCP2), sirtuin-2 (SIRT2), the G protein-coupled receptor GPR109A or hydrocaboxylic acid receptor 2 (HCAR2). BHB reduces NLRP3 inflammasome-mediated interleukin (IL)-1β and IL-18 production in human monocytes. In vivo, BHB or a ketogenic diet attenuates caspase-1 activation and IL-1β secretion in mouse models of NLRP3-mediated diseases such as Muckle-Wells syndrome, familial cold autoinflammatory syndrome and urate crystal-induced peritonitis. Our findings suggest that the anti-inflammatory effects of caloric restriction or ketogenic diets may be linked to BHB-mediated inhibition of the NLRP3 inflammasome.
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BHB acts as a signaling molecule, reducing inflammation and oxidative stress.
“BHB acts as a signaling molecule, reducing inflammation and oxidative stress [14, 15]”
From Effectiveness and Safety of a Novel Care Model for the Management of Type 2 Diabetes at 1 Year: An Open-Label, Non-Randomized, Controlled Study (2018) · cites this paper as [15]
The paper describes BHB as a metabolic signal and reports that it suppresses NLRP3-mediated inflammation. It also says that fasting and the accompanying rise in BHB are linked to reduced oxidative stress, but does not establish that BHB itself reduces oxidative stress through signaling. The deciding passages are in the section labeled “Abstract”; page numbers are unavailable in our copy. (LLM, conf=0.86)
Experimental — accuracy not yet measuredKetone bodies inhibit the NLRP3 inflammasome and reduce IL-1beta production in monocytes.
“Additionally, increased levels of ketone bodies inhibit the Nod -like receptor pyrin domain-containing protein 3 (NLRP3) inflammasome and reduce production of interleukin-1 b in monocytes (Youm et al., 2015; Goldberg et al., 2017).”
From A kidney perspective on the mechanism of action of sodium glucose co-transporter 2 inhibitors (2021) · cites this paper as Youm et al., 2015
β-hydroxybutyrate (BHB) has an inhibitory effect on NLRP3 inflammasome.
“Specifically, the β-hydroxybutyrate (BHB), a physiological ketone body produced by the liver in condition of fasting, low blood sugar, or carbohydrate-free (like ketogenic) diet consumption had an inhibitory effect on NLRP3-inflammasome (253).”
From The gut-brain axis: how microbiota and host inflammasome influence brain physiology and pathology (2020) · cites this paper as [253]
The traditional view of β-HB as solely an energy carrier has greatly expanded to include β-HB mediated inhibition of inflammasome activation.
“The traditional view of β-HB as solely an energy carrier has greatly expanded to include β-HB mediated inhibition of inflammasome activation (Youm et al., 2015).”
From Microtubule-associated protein 1 light chain 3B, (LC3B) is necessary to maintain lipid-mediated homeostasis in the retinal pigment epithelium (2018) · cites this paper as Youm et al., 2015
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“Youm et al. (2015) discovered that the ketone metabolite β-hydroxybutyrate (BHB), but not acetoacetate or the shortchain fatty acids butyrate and acetate, reduced IL-1β, and IL-18 production by the NLRP3 inflammasome in human monocytes.”
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- Authors
- Youm, Y.-H., Nguyen, K. Y., Grant, R. W., Goldberg, E. L., Bodogai, M., Kim, D., D'Agostino, D., Planavsky, N., Lupfer, C., Kanneganti, T. D., Kang, S., Horvath, T. L., Fahmy, T. M., Crawford, P. A., Biragyn, A., Alnemri, E., & Dixit, V. D.
- Affiliations
- Yale University (US)
- Purdue University West Lafayette (US)
- National Institutes of Health (US)
- St. Jude Children's Research Hospital (US)
- Thomas Jefferson University (US)
- Sanford Burnham Prebys Medical Discovery Institute (US)
- Corresponding author
- Dixit, Vishwa Deep
- ORCID
- Venue
- Nature Medicine
- Published
- 2015-02-16
- Volume
- 21
- Issue
- 3
- Pages
- 263-269
- ISSN
- 1078-8956 (ISSN-L)
- 1546-170X
- PMC
- PMC4352123
- OpenAlex
- W2081262717
- Cited by
- 2,172
- References
- 36
- Citations by year
- 2026: 294 · 2025: 275 · 2024: 227 · 2023: 258 · 2022: 258 · 2021: 202 · 2020: 186 · 2019: 131 · 2018: 128 · 2017: 109 · 2016: 61 · 2015: 41 · 2014: 1
- FWCI
- 49.19
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature Medicine (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- BearWorks (Missouri State University) (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- University of Texas at San Antonio
- National Institutes of Health
- National Institute on Aging (R01AG045712, AG31797, R01AG031797, R01AG043608, AG043608)
- National Institute of Allergy and Infectious Diseases (AI105097, R56AI105097, R01AI105097)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK090556, DK090556)
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (R01AR055398)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Inflammasome and immune disorders
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Health Sciences › Medicine › Nephrology › Gout, Hyperuricemia, Uric Acid
- Keywords
- beta-hydroxybutyrate, ketone bodies, NLRP3 inflammasome, inflammation, ketogenic diet, caloric restriction, caspase-1, IL-1β, IL-18, potassium efflux, ASC oligomerization, urate crystals, Muckle-Wells syndrome, familial cold autoinflammatory syndrome, innate immunity
- MeSH terms
- NLR Family, Pyrin Domain-Containing 3 Protein, Adult, Aged, Animals, Carrier Proteins, Disease Models, Animal, Female, Humans, Inflammation, Male, Monocytes, Potassium, 3-Hydroxybutyric Acid, Caspase 1, Interleukin-18, Mice, Interleukin-1beta, Diet, Ketogenic, Cryopyrin-Associated Periodic Syndromes, Inflammasomes
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