The ketone bodies β-hydroxybutyrate (BHB) and acetoacetate (AcAc) support mammalian survival during states of energy deficit by serving as alternative sources of ATP1. BHB levels are elevated by starvation, caloric restriction, high-intensity exercise, or the low-carbohydrate ketogenic diet2. 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 unknown2,3,4,5,6. 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.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.


  1. 1.

    & Ketone bodies as signaling metabolites. Trends Endocrinol. Metab. 25, 42–52 (2014).

  2. 2.

    , & Ketone body metabolism and cardiovascular disease. Am. J. Physiol. Heart Circ. Physiol. 304, H1060–H1076 (2013).

  3. 3.

    , & Blunted febrile response to intravenous endotoxin in starved rats. J. Appl. Physiol. 67, 963–969 (1989).

  4. 4.

    et al. Alternate day calorie restriction improves clinical findings and reduces markers of oxidative stress and inflammation in overweight adults with moderate asthma. Free Radic. Biol. Med. 42, 665–674 (2007).

  5. 5.

    et al. Calorie restriction in humans inhibits the PI3K/AKT pathway and induces a younger transcription profile. Aging Cell 12, 645–651 (2013).

  6. 6.

    & How metabolism generates signals during innate immunity and inflammation. J. Biol. Chem. 288, 22893–22898 (2013).

  7. 7.

    , & The inflammasomes: guardians of the body. Annu. Rev. Immunol. 27, 229–265 (2009).

  8. 8.

    & Mechanisms and functions of inflammasomes. Cell 157, 1013–1022 (2014).

  9. 9.

    , & Mechanisms of NOD-like receptor-associated inflammasome activation. Immunity 39, 432–441 (2013).

  10. 10.

    , & Activation and regulation of the inflammasomes. Nat. Rev. Immunol. 13, 397–411 (2013).

  11. 11.

    , , & The inflammasome: a caspase-1-activation platform that regulates immune responses and disease pathogenesis. Nat. Immunol. 10, 241–247 (2009).

  12. 12.

    et al. The NLRP3 inflammasome instigates obesity-induced inflammation and insulin resistance. Nat. Med. 17, 179–188 (2011).

  13. 13.

    et al. Activation of the NLRP3 inflammasome by islet amyloid polypeptide provides a mechanism for enhanced IL-1β in type 2 diabetes. Nat. Immunol. 11, 897–904 (2010).

  14. 14.

    et al. NLRP3 is activated in Alzheimer's disease and contributes to pathology in APP/PS1 mice. Nature 493, 674–678 (2013).

  15. 15.

    , , , & Gout-associated uric acid crystals activate the NALP3 inflammasome. Nature 440, 237–241 (2006).

  16. 16.

    et al. NLRP3 inflammasomes are required for atherogenesis and activated by cholesterol crystals. Nature 464, 1357–1361 (2010).

  17. 17.

    et al. Fatty acid-induced NLRP3-ASC inflammasome activation interferes with insulin signaling. Nat. Immunol. 12, 408–415 (2011).

  18. 18.

    et al. Cutting edge: critical role for PYCARD/ASC in the development of experimental autoimmune encephalomyelitis. J. Immunol. 184, 4610–4614 (2010).

  19. 19.

    et al. Canonical Nlrp3 inflammasome links systemic low-grade inflammation to functional decline in aging. Cell Metab. 18, 519–532 (2013).

  20. 20.

    et al. Noncanonical inflammasome activation by intracellular LPS independent of TLR4. Science 341, 1246–1249 (2013).

  21. 21.

    , , , & Cytoplasmic LPS activates caspase-11: implications in TLR4-independent endotoxic shock. Science 341, 1250–1253 (2013).

  22. 22.

    et al. Suppression of oxidative stress by β-hydroxybutyrate, an endogenous histone deacetylase inhibitor. Science 339, 211–214 (2013).

  23. 23.

    , , & The ketone body β-hydroxybutyric acid influences agouti-related peptide expression via AMP-activated protein kinase in hypothalamic GT1–7 cells. J. Endocrinol. 213, 193–203 (2012).

  24. 24.

    & Ketone bodies stimulate chaperone-mediated autophagy. J. Biol. Chem. 280, 25864–25870 (2005).

  25. 25.

    et al. K+ efflux is the common trigger of NLRP3 inflammasome activation by bacterial toxins and particulate matter. Immunity 38, 1142–1153 (2013).

  26. 26.

    et al. (D)-beta-Hydroxybutyrate inhibits adipocyte lipolysis via the nicotinic acid receptor PUMA-G. J. Biol. Chem. 280, 26649–26652 (2005).

  27. 27.

    et al. Activation of Gpr109a, receptor for niacin and the commensal metabolite butyrate, suppresses colonic inflammation and carcinogenesis. Immunity 40, 128–139 (2014).

  28. 28.

    , , , & Impact of peripheral ketolytic deficiency on hepatic ketogenesis and gluconeogenesis during the transition to birth. J. Biol. Chem. 288, 19739–19749 (2013).

  29. 29.

    et al. Microtubule-driven spatial arrangement of mitochondria promotes activation of the NLRP3 inflammasome. Nat. Immunol. 14, 454–460 (2013).

  30. 30.

    & The ketogenic diet: metabolic influences on brain excitability and epilepsy. Trends Neurosci. 36, 32–40 (2013).

  31. 31.

    et al. Unified polymerization mechanism for the assembly of ASC-dependent inflammasomes. Cell. 156, 1193–1206 (2014).

  32. 32.

    et al. Cryopyrin and pyrin activate caspase-1, but not NF-κB, via ASC oligomerization. Cell Death Differ. 13, 236–249 (2006).

  33. 33.

    , , , & Pathogen-associated molecular patterns on biomaterials: a paradigm for engineering new vaccines. Trends Biotechnol. 29, 294–306 (2011).

  34. 34.

    , , , & Gout-associated uric acid crystals activate the NALP3 inflammasome. Nature 440, 237–241 (2006).

  35. 35.

    et al. Inflammasome-mediated disease animal models reveal roles for innate but not adaptive immunity. Immunity 30, 875–887 (2009).

  36. 36.

    et al. NLRP6 negatively regulates innate immunity and host defence against bacterial pathogens. Nature 488, 389–393 (2012).

Download references


We thank M. Koch, Y. Kui, P. Chang and D. Albarado for technical assistance, and V. M. Dixit (Genentech) and R. Medzhitov (Yale School of Medicine) for helpful discussions and for providing knockout mice. Salmonella typhimurium and Francisella tularensis (U112) were provided by D. Monack (Stanford University School of Medicine) and J. Teale (University of Texas at San Antonio). M.B. and A.B. were supported by the National Institute on Aging–Intramural Research Program. D.D'A. was supported by the Office of Naval Research (ONR) Grant N000141310062. V.D.D. was supported in part by the grants from National Institutes of Health (AG043608, AG31797, DK090556 and AI105097).

Author information

Author notes

    • Yun-Hee Youm
    •  & Kim Y Nguyen

    These authors contributed equally to this work.


  1. Section of Comparative Medicine and Program on Integrative Cell Signaling and Neurobiology of Metabolism, Yale School of Medicine, New Haven, Connecticut, USA.

    • Yun-Hee Youm
    • , Kim Y Nguyen
    • , Emily L Goldberg
    • , Tamas L Horvath
    •  & Vishwa Deep Dixit
  2. Department of Nutrition Sciences, Purdue University, West Lafayette, Indiana.

    • Ryan W Grant
  3. Laboratory of Molecular Biology and Immunology, National Institute on Aging, National Institutes of Health (NIH), Baltimore, Maryland, USA.

    • Monica Bodogai
    •  & Arya Biragyn
  4. Department of Biomedical Engineering, Yale University, New Haven, Connecticut, USA.

    • Dongin Kim
    •  & Tarek M Fahmy
  5. Department of Molecular Pharmacology and Physiology, University of South Florida, Tampa, Florida, USA.

    • Dominic D'Agostino
  6. Department of Geology and Geophysics, Yale University, New Haven, Connecticut, USA.

    • Noah Planavsky
  7. Department of Immunology, St. Jude Children's Hospital, Memphis, Tennessee, USA.

    • Christopher Lupfer
    •  & Thirumala D Kanneganti
  8. Department of Biochemistry and Molecular Biology, Thomas Jefferson University, Philadelphia, Pennsylvania, USA.

    • Seokwon Kang
    •  & Emad Alnemri
  9. Diabetes and Obesity Research Center, Sanford-Burnham Medical Research Institute, Orlando, Florida, USA.

    • Peter A Crawford
  10. Department of Immunobiology, Yale School of Medicine, New Haven, Connecticut, USA.

    • Vishwa Deep Dixit


  1. Search for Yun-Hee Youm in:

  2. Search for Kim Y Nguyen in:

  3. Search for Ryan W Grant in:

  4. Search for Emily L Goldberg in:

  5. Search for Monica Bodogai in:

  6. Search for Dongin Kim in:

  7. Search for Dominic D'Agostino in:

  8. Search for Noah Planavsky in:

  9. Search for Christopher Lupfer in:

  10. Search for Thirumala D Kanneganti in:

  11. Search for Seokwon Kang in:

  12. Search for Tamas L Horvath in:

  13. Search for Tarek M Fahmy in:

  14. Search for Peter A Crawford in:

  15. Search for Arya Biragyn in:

  16. Search for Emad Alnemri in:

  17. Search for Vishwa Deep Dixit in:


Y. H.Y. and K.Y.N. designed and conducted the majority of in vitro and all in vivo experiments, analyzed and interpreted the data, and participated in writing the manuscript. R.W.G. participated in design and conduct of inflammasome activation experiments. E.L.G. performed ASC speck and neutrophil assays. M.B. and A.B. performed the human monocytes experiments. D.K. and T.M.F. synthesized the BHB–nanolipogels and conducted control experiments to determine the dose response. D.D'A. formulated the ketone diester diet. N.P. conducted the ICP-MS experiments to determine K+ efflux. C.L. and T.D.K. conducted the F. tularensis and S. typhimurium infection experiments. T.L.H. designed the experiments and provided essential reagents for experiments involving mitochondrial ROS and UCP2. P.A.C. generated the macrophage-specific, Scot-deficient mice and contributed to experiment design. S.K. and E.A. designed and conducted the ASC oligomerization experiments. V.D.D. conceived and supervised the project, interpreted the data, and wrote the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Vishwa Deep Dixit.

Supplementary information

PDF files

  1. 1.

    Supplementary Text and Figures

    Supplementary Figures 1–8

About this article

Publication history






Further reading