β-hydroxybutyric acid (β-HBA) is a water soluble small molecule and the main component of ketone body. Upon facing energy shortage, free fatty acids in liver are oxidized and decomposed in mitochondria to produce β-HBA. β-HBA is a carbon source providing energy for extrahepatic tissues such as brain, heart, and skeletal muscles. Intestinal flora is the key component of regulating the host lipid metabolism and other metabolic activities of human body. The imbalance of intestinal flora may lead to the disorders of fatty acid metabolism having impact on cardiovascular, nervous, metabolic systems, etc. This work discusses the potential regulatory mechanism of intestinal flora involved in producing β-HBA through metabolic pathway, molecular mechanism of β-HBA production, physiological effects in animals, and relation between intestinal flora and fatty acid metabolism. These outcomes can provide reference for further work on β-HBA production in treating diseases, especially for cancer treatment in terms of the energy metabolism. 

1. Linke A, Zhao G, Recchia FA, et al. Shift in metabolic substrate uptake by the heart during development of alloxan-induced diabetes. American Journal of Physiology Heart and Circulatory Physiology 2003; 285(3): H1007–H1014. doi: 10.1152/ajpheart.00528.2002.

2. Lapidot A, Haber S. Effect of endogenous beta-hydroxybutyrate on brain glucose metabolism in fetuses of diabetic rabbits, studied by (13)C magnetic resonance spectroscopy. Developmental Brain Research 2002; 135(1–2): 87–99. doi: 10.1016/s0165-3806(02)00347-4.

3. Thomas RM, Jobin C. Microbiota in pancreatic health and disease: The next frontier in microbiome research. Nature Reviews Gastroenterology & Hepatology 2020; 17: 53–64. doi: 10.1038/s41575-019-0242-7.

4. Moran-Ramos S, Lopez-Contreras BE, Villarruel-Vazquez R, et al. Environmental and intrinsic factors shaping gut microbiota composition and diversity and its relation to metabolic health in children and early adolescents: A population-based study. Gut Microbes 2020; 11(4): 900–917. doi: 10.1080/19490976.2020.1712985.

5. Yao A, Li Z, Lyu J, et al. On the nutritional and therapeutic effects of ketone body D-β-hydroxybutyrate. Applied Microbiology and Biotechnology 2021; 105(16–17): 6229–6243. doi: 10.1007/s00253-021-11482-w.

6. Cuenoud B, Hartweg M, Godin JP, et al. Metabolism of exogenous D-Beta-Hydroxybutyrate, an energy substrate avidly consumed by the heart and kidney. Frontiers in Nutrition 2020; 7: 13. doi: 10.3389/fnut.2020.00013.

7. Puchalska P, Crawford PA. Metabolic and signaling roles of ketone bodies in health and disease. Annual Review of Nutrition 2021; 41: 49–77. doi: 10.1146/annurev-nutr-111120-111518.

8. Sharma S, Sarathlal KC, Taliyan R. Epigenetics in neurodegenerative diseases: The role of histone deacetylases. CNS Neurol Disord Drug Targets 2019; 18(1): 11–18. doi: 10.2174/1871527317666181004155136.

9. Kong G, Huang Z, Ji W, et al. The ketone metabolite β-Hydroxybutyrate attenuates oxidative stress in spinal cord injury by suppression of class I histone deacetylases. Journal of Neurotrauma 2017; 34(18): 2645–2655. doi: 10.1089/neu.2017.5192.

10. Lu Y, Zhou X, Zhao W, et al. Epigenetic inactivation of Acetyl-CoA Acetyltransferase 1 promotes the proliferation and metastasis in nasopharyngeal carcinoma by blocking ketogenesis. Frontiers in Oncology 2021; 11: 667673. doi: 10.3389/fonc.2021.667673.

11. Benjamin DI, Both P, Benjamin JS, et al. Fasting induces a highly resilient deep quiescent state in muscle stem cells via ketone body signaling. Cell Metabolism 2022; 34(6): 902–918.e6. doi: 10.1016/j.cmet.2022.04.012.

12. Ji L, He Q, Liu Y, et al. Ketone body β-Hydroxybutyrate prevents myocardial oxidative stress in septic cardiomyopathy. Oxidative Medicine and Cellular Longevity 2022; 2022: 2513837. doi: 10.1155/2022/2513837.

13. Spigoni V, Cinquegrani G, Iannozzi NT, et al. Activation of G protein-coupled receptors by ketone bodies: Clinical implication of the ketogenic diet in metabolic disorders. Frontiers in Endocrinology 2022; 13: 972890. doi: 10.3389/fendo.2022.972890.

14. Fu SP, Liu BR, Wang JF, et al. β-Hydroxybutyric acid inhibits growth hormone-releasing hormone synthesis and secretion through the GPR109A/extracellular signal-regulated 1/2 signalling pathway in the hypothalamus. Journal of Neuroendocrinology 2015; 27(3): 212–222. doi: 10.1111/jne.12256.

15. Wu Y, Gong Y, Luan Y, et al. BHBA treatment improves cognitive function by targeting pleiotropic mechanisms in transgenic mouse model of Alzheimer’s disease. The FASEB Journal 2020; 34(3): 1412–1429. doi: 10.1096/fj.201901984R.

16. Gambhir D, Ananth S, Veeranan-Karmegam R, et al. GPR109A as an anti-inflammatory receptor in retinal pigment epithelial cells and its relevance to diabetic retinopathy. Investigative Ophthalmology & Visual Science 2012; 53(4): 2208–2217. doi: 10.1167/iovs.11-8447.

17. Zhang S, Li Z, Zhang Y, et al. Ketone body 3-Hydroxybutyrate ameliorates atherosclerosis via receptor Gpr109a-Mediated calcium influx. Advanced Science 2021; 8(9): 2003410. doi: 10.1002/advs.202003410.

18. Abdelrahman AA, Powell FL, Jadeja RN, et al. Expression and activation of the ketone body receptor HCAR2/GPR109A promotes preservation of retinal endothelial cell barrier function. Experimental Eye Research 2022; 221: 109129. doi: 10.1016/j.exer.2022.109129.

19. Bai Y, Han Q, Dong B, et al. PPARα contributes to the therapeutic effect of hydrogen gas against sepsis-associated encephalopathy with the regulation to the CREB-BDNF signaling pathway and hippocampal neuron plasticity-related gene expression. Brain Research Bulletin 2022; 184: 56–67. doi: 10.1016/j.brainresbull.2022.03.015.

20. Guo Q, Liu S, Wang S, et al. Beta-hydroxybutyric acid attenuates neuronal damage in epileptic mice. Acta Histochemica 2019; 121(4): 455–459. doi: 10.1016/j.acthis.2019.03.009.

21. Ferst JG, Glanzner WG, Gutierrez K, et al. Supplementation of oleic acid, stearic acid, palmitic acid and β-hydroxybutyrate increase H3K9me3 in endometrial epithelial cells of cattle cultured in vitro. Animal Reproduction Science 2021; 233: 106851. doi: 10.1016/j.anireprosci.2021.106851.

22. Kaiser G, Gerst F, Michael D, et al. Regulation of forkhead box O1 (FOXO1) by protein kinase B and glucocorticoids: Different mechanisms of induction of beta cell death in vitro. Diabetologia 2013; 56: 1587–1595. doi: 10.1007/s00125-013-2863-7.

23. Luo S, Yang M, Han Y, et al. β-Hydroxybutyrate against Cisplatin-Induced acute kidney injury via inhibiting NLRP3 inflammasome and oxidative stress. International Immunopharmacology 2022; 111: 109101. doi: 10.1016/j.intimp.2022.109101.

24. Hirata Y, Shimazaki S, Suzuki S, et al. β-hydroxybutyrate suppresses NLRP3 inflammasome-mediated placental inflammation and lipopolysaccharide-induced fetal absorption. Journal of Reproductive Immunology 2021; 148: 103433. doi: 10.1016/j.jri.2021.103433.

25. Şahin E, Bektur Aykanat NE, Kacar S, et al. β-Hydroxybutyrate, one of the three main ketone bodies, ameliorates acute pancreatitis in rats by suppressing the NLRP3 inflammasome pathway. Turkish Journal Gastroenterology 2021; 32(8): 702–711. doi: 10.5152/tjg.2021.191062.

26. Wu Y, Teng Y, Zhang C, et al. The ketone body β-hydroxybutyrate alleviates CoCrMo alloy particles induced osteolysis by regulating NLRP3 inflammasome and osteoclast differentiation. Journal of Nanobiotechnology 2022; 20: 120. doi: 10.1186/s12951-022-01320-0.

27. Trotta MC, Maisto R, Guida F, et al. The activation of retinal HCA2 receptors by systemic beta-hydroxybutyrate inhibits diabetic retinal damage through reduction of endoplasmic reticulum stress and the NLRP3 inflammasome. PLoS One 2019; 14: e0211005. doi: 10.1371/journal.pone.0211005.

28. Qiao Q, Sun C, Han C, et al. Endoplasmic reticulum stress pathway PERK-eIF2α confers radioresistance in oropharyngeal carcinoma by activating NF-κB. Cancer Science 2017; 108: 1421–1431. doi: 10.1111/cas.13260.

29. Kuter KZ, Olech Ł, Głowacka U, Paleczna M. Increased beta-hydroxybutyrate level is not sufficient for the neuroprotective effect of long-term ketogenic diet in an animal model of early parkinson’s disease. Exploration of brain and liver energy metabolism markers. International Journal of Molecular Sciences 2021; 22(14): 7556. doi: 10.3390/ijms22147556.

30. Ma X, Dong Z, Liu J, et al. β-Hydroxybutyrate exacerbates hypoxic injury by inhibiting HIF-1α-Dependent glycolysis in cardiomyocytes-adding fuel to the fire?. Cardiovascular Drugs and Therapy 2022; 36: 383–397. doi: 10.1007/s10557-021-07267-y.

31. Ari C, Koutnik AP, DeBlasi J, et al. Delaying latency to hyperbaric oxygen-induced CNS oxygen toxicity seizures by combinations of exogenous ketone supplements. Physiological Reports 2019; 7(1): e13961. doi: 10.14814/phy2.13961.

32. Jiang Z, Yin X, Wang M, et al. β-Hydroxybutyrate alleviates pyroptosis in MPP+/MPTP-induced Parkinson’s disease models via inhibiting STAT3/NLRP3/GSDMD pathway. International Immunopharmacology 2022; 113: 109451. doi: 10.1016/j.intimp.2022.109451.

33. Sun W, Wen M, Liu M, et al. Effect of β-hydroxybutyrate on behavioral alterations, molecular and morphological changes in CNS of multiple sclerosis mouse model. Frontiers in Aging Neuroscience 2022; 14: 1075161. doi: 10.3389/fnagi.2022.1075161.

34. Huang J, Chai X, Wu Y, et al. β-Hydroxybutyric acid attenuates heat stress-induced neuroinflammation via inhibiting TLR4/p38 MAPK and NF-κB pathways in the hippocampus. The FASEB Journal 2022; 36: e22264. doi: 10.1096/fj.202101469rr.

35. Mirzaei V, Eidi A, Manaheji H, et al. β-Hydroxybutyrate diminishes the apoptotic cell death and demyelination via altering bax, Caspase-3, and Bcl2 levels in the spinal cord of mice with MOG-Induced encephalomyelitis. Neurochemical Journal 2022; 16: 322–333. doi: 10.1134/S1819712422030072.

36. Li Y, Zhang X, Ma A, Kang Y. Rational application of β-Hydroxybutyrate attenuates ischemic stroke by suppressing oxidative stress and mitochondrial-dependent apoptosis via activation of the Erk/CREB/eNOS pathway. ACS Chemical Neuroscience 2021; 12: 1219–1227. doi: 10.1021/acschemneuro.1c00046.

37. Si J, Wang Y, Xu J, Wang J. Antiepileptic effects of exogenous β-hydroxybutyrate on kainic acid-induced epilepsy. Experimental and Therapeutic Medicine 2020; 20: 177. doi: 10.3892/etm.2020.9307.

38. Weis EM, Puchalska P, Nelson AB, et al. Ketone body oxidation increases cardiac endothelial cell proliferation. EMBO Molecular Medicine 2022; 14: e14753. doi: 10.15252/emmm.202114753.

39. Ji L, Deng Y, Li T. Effect of ketone body β-Hydroxybutyrate to attenuate inflammation-induced mitochondrial oxidative stress in vascular endothelial cells (Chinese). Journal of Sichuan University (Medical Sciences) 2021; 52: 954–959. doi: 10.12182/20211160202.

40. Flores-Guerrero JL, Westenbrink BD, Connelly MA, et al. Association of beta-hydroxybutyrate with development of heart failure: Sex differences in a Dutch population cohort. European Journal of Clinical Investigation 2021; 51(5): e13468. doi: 10.1111/eci.13468.

41. Yu Y, Yu Y, Zhang Y, et al. Treatment with D-β-hydroxybutyrate protects heart from ischemia/reperfusion injury in mice. European Journal of Pharmacology 2018; 829: 121–128. doi: 10.1016/j.ejphar.2018.04.019.

42. Chiang YF, Nguyen NTK, Hsia SM, et al. Protective potential of β-Hydroxybutyrate against glucose-deprivation-induced neurotoxicity involving the modulation of autophagic flux and the monomeric Aβ level in Neuro-2a cells. Biomedicines 2023; 11(3): 698. doi: 10.3390/biomedicines11030698.

43. Oka SI, Tang F, Chin A, et al. β-Hydroxybutyrate, a Ketone body, potentiates the antioxidant defense via thioredoxin 1 upregulation in cardiomyocytes. Antioxidants (Basel) 2021; 10(7): 1153. doi: 10.3390/antiox10071153.

44. Zhang Y, Yu C, Du L, Deng Q. β-Hydroxybutyric acid inhibits activation of nuclear factor-κB signaling pathway in lipopolysaccharide-stimulated neutrophils from cows (Chinese). Chinese Journal of Animal Nutrition 2022; 34: 1268–1275.

45. Zuo M, Meng C, Song Q, et al. Beta-Hydroxybutyric acid inhibits renal tubular reabsorption via the AKT/DAB2/Megalin signalling pathway. Journal of Diabetes Research 2022; 2022: 3411123. doi: 10.1155/2022/3411123.

46. Wang FX, Xu CL, Su C, et al. β-Hydroxybutyrate attenuates painful diabetic neuropathy via restoration of the aquaporin-4 polarity in the spinal glymphatic system. Frontiers in Neuroscience 2022; 16: 926128. doi: 10.3389/fnins.2022.926128.

47. García-Caballero M, Zecchin A, Souffreau J, et al. Role and therapeutic potential of dietary ketone bodies in lymph vessel growth. Nature Metabolism 2019; 1: 666–675. doi: 10.1038/s42255-019-0087-y.

48. Soto-Mota A, Norwitz NG, Evans RD, Clarke K. Exogenous d-β-hydroxybutyrate lowers blood glucose in part by decreasing the availability of L-alanine for gluconeogenesis. Endocrinology Diabetes & Metabolism 2022; 5(1): e00300. doi: 10.1002/edm2.300.

49. Dmitrieva-Posocco O, Wong AC, Lundgren P, et al. β-Hydroxybutyrate suppresses colorectal cancer. Nature 2022; 605: 160–165. doi: 10.1038/s41586-022-04649-6.

50. Cui W, Luo W, Zhou X, et al. Dysregulation of ketone body metabolism is associated with poor prognosis for clear cell renal cell carcinoma patients. Frontiers in Oncology 2019; 9: 1422. doi: 10.3389/fonc.2019.01422.

51. Shang S, Wang L, Zhang Y, et al. The beta-hydroxybutyrate suppresses the migration of glioma cells by inhibition of NLRP3 inflammasome. Cellular and Molecular Neurobiology 2018; 38(8): 1479–1489. doi: 10.1007/s10571-018-0617-2.

52. Hwang CY, Choe W, Yoon KS, et al. Molecular mechanisms for ketone body metabolism, signaling functions, and therapeutic potential in cancer. Nutrients 2022; 14(22): 4932. doi: 10.3390/nu14224932.

53. Koronowski KB, Greco CM, Huang H, et al. Ketogenesis impact on liver metabolism revealed by proteomics of lysine β-hydroxybutyrylation. Cell Reports 2021; 36: 109487. doi: 10.1016/j.celrep.2021.109487.

54. Feng S, Wang H, Liu J, et al. Multi-dimensional roles of ketone bodies in cancer biology: Opportunities for cancer therapy. Pharmacological Research 2019; 150: 104500. doi: 10.1016/j.phrs.2019.104500.

55. Chen J, Li Z, Zhang Y, et al. Mechanism of reduced muscle atrophy via ketone body (D)-3-hydroxybutyrate. Cell and Bioscience 2022; 12: 94. doi: 10.1186/s13578-022-00826-2.

56. Bendridi N, Selmi A, Balcerczyk A, Pirola L. Ketone bodies as metabolites and signalling molecules at the crossroad between inflammation and epigenetic control of cardiometabolic disorders. International Journal of Molecular Sciences 2022; 23(23): 14564. doi: 10.3390/ijms232314564.

57. Hirschberger S, Gellert L, Effinger D, et al. Ketone bodies improve human CD8+ cytotoxic T-Cell immune response during COVID-19 infection. Frontiers in Medicine (Lausanne) 2022; 9: 923502. doi: 10.3389/fmed.2022.923502.

58. Ansaldo E, Farley TK, Belkaid Y. Control of immunity by the microbiota. Annual Review of Immunology 2021; 39: 449–479. doi: 10.1146/annurev-immunol-093019-112348.

59. Rooks MG, Garrett WS. Gut microbiota, metabolites and host immunity. Nature Reviews Immunology 2016; 16: 341–352. doi: 10.1038/nri.2016.42.

60. Eckburg PB, Bik EM, Bernstein CN, et al. Diversity of the human intestinal microbial flora. Science 2005; 308: 1635–1638. doi: 10.1126/science.1110591.

61. Vogt NM, Kerby RL, Dill-McFarland KA, et al. Gut microbiome alterations in Alzheimer’s disease. Scientific Reports 2017; 7(1): 13537. doi: 10.1038/s41598-017-13601-y.

62. Ziemons J, Smidt ML, Damink SO, Rensen SS. Gut microbiota and metabolic aspects of cancer cachexia. Best Practice & Research Clinical Endocrinology & Metabolism 2021; 35(3): 101508. doi: 10.1016/j.beem.2021.101508.

63. Chakaroun RM, Olsson LM, Bäckhed F. The potential of tailoring the gut microbiome to prevent and treat cardiometabolic disease. Nature Reviews Cardiology 2023; 20: 217–235. doi: 10.1038/s41569-022-00771-0.

64. Li HB, Xu ML, Xu XD, et al. Faecalibacterium prausnitzii attenuates CKD via butyrate-renal GPR43 axis. Circulation Research 2022; 131(9): e120–e134. doi: 10.1161/CIRCRESAHA.122.320184.

65. Larsen N, Vogensen FK, van den Berg FW, et al. Gut microbiota in human adults with type 2 diabetes differs from non-diabetic adults. PLoS One 2010; 5(2): e9085. doi: 10.1371/journal.pone.0009085.

66. Zhai T, Ren W, Wang P, Zheng L. Lactobacillus rhamnosus GG protects against atherosclerosis by improving ketone body synthesis. Applied Microbiology Biotechnology 2022; 106(24): 8233–8243. doi: 10.1007/s00253-022-12265-7.

67. Djukovic A, Garzón MJ, Canlet C, et al. Lactobacillus supports clostridiales to restrict gut colonization by multidrug-resistant enterobacteriaceae. Nature Communications 2022; 13: 5617. doi: 10.1038/s41467-022-33313-w.

68. Quan LH, Zhang C, Dong M, et al. Myristoleic acid produced by enterococci reduces obesity through brown adipose tissue activation. Gut 2020; 69(7): 1239–1247. doi: 10.1136/gutjnl-2019-319114.

69. Liao JF, Cheng YF, Li SW, et al. Lactobacillus plantarum PS128 ameliorates 2,5-Dimethoxy-4-iodoamphetamine-induced tic-like behaviors via its influences on the microbiota-gut-brain-axis. Brain Research Bulletin 2019; 153: 59–73. doi: 10.1016/j.brainresbull.2019.07.027.

70. Kumar P, Monin L, Castillo P, et al. Intestinal interleukin-17 receptor signaling mediates reciprocal control of the gut microbiota and autoimmune inflammation. Immunity 2016; 44: 659–671. doi: 10.1016/j.immuni.2016.02.007.

71. Howard EJ, Lam TKT, Duca FA. The Gut microbiome: Connecting diet, glucose homeostasis, and disease. Annual Review of Medicine 2022; 73: 469–481. doi: 10.1146/annurev-med-042220-012821.

72. Takei H, Narushima S, Suzuki M, et al. Characterization of long-chain fatty acid-linked bile acids: A major conjugation form of 3β-hydroxy bile acids in feces. Journal of Lipid Research 2022; 63(10): 100275. doi: 10.1016/j.jlr.2022.100275.

73. Ma C, Han M, Heinrich B, et al. Gut microbiome-mediated bile acid metabolism regulates liver cancer via NKT cells. Science 2018; 360(6391): eaan5931. doi: 10.1126/science.aan5931.

74. Zhao Z, Deng S, Lv Z, Yang J. Cellular innate biological nano confinements control cancer metastasis through materials seizing and signaling regulating. Technology in Cancer Research & Treatment 2023; 22. doi: 10.1177/15330338231158917.