The pathogenesis of degenerative disc disease is a complex and multifactorial process in which genetics, mechanical trauma, altered loading and nutrition present significant etiological factors. Infection of the intervertebral disc with the anaerobic bacterium Propionibacterium acnes is now also emerging as a potentially new etiological factor. This human commensal bacterium is well known for its long association with the inflammatory skin condition acne vulgaris. A key component of inflammatory responses to P. acnes in acne appears to be interleukin (IL)-1β. Similarly, in degenerative disc disease (DDD) there is compelling evidence for the fundamental roles of IL-1β in its pathology. We therefore propose that P. acnes involvement in DDD is biologically very plausible, and that IL-1β is the key inflammatory mechanism driving the host response to P. acnes infection. Since there is a solid theoretical basis for this phenomenon, we further propose that the relationship between P. acnes infection and DDD is causal.

Central European Institute of Technology Masaryk University Brno Czechia

Department of Biomedicine Aarhus University Aarhus Denmark

Division of Cell Matrix Biology and Regenerative Medicine Faculty of Biology Medicine and Health The University of Manchester Manchester United Kingdom

Laboratory of Bacterial Pathogenesis and Immunology Rockefeller University New York NY United States

Northern Ireland Centre for Stratified Medicine School of Biomedical Sciences Ulster University Londonderry United Kingdom

School of Life and Health Sciences Aston University Birmingham United Kingdom

Spine Center UCSF Medical Center San Francisco CA United States

Zobrazit více v PubMed

Agak G. W., Qin M., Nobe J., Kim M. H., Krutzik S. R., Tristan G. R., et al. . (2014). Propionibacterium acnes induces an IL-17 response in acne vulgaris that is regulated by vitamin A and vitamin D. J. Invest. Dermatol. 134, 366–373. 10.1038/jid.2013.334 PubMed DOI PMC

Albert H. B., Sorensen J. S., Christensen B. S., Manniche C. (2013). Antibiotic treatment in patients with chronic low back pain and vertebral bone edema (Modic type 1 changes): a double-blind randomized clinical controlled trial of efficacy. Eur. Spine J. 22, 697–707. 10.1007/s00586-013-2675-y PubMed DOI PMC

Birkenmaier C. (2013). Should we start treating chronic low back pain with antibiotics rather than with pain medications? Korean J. Pain 26, 327–335. 10.3344/kjp.2013.26.4.327 PubMed DOI PMC

Capoor M. N., Ruzicka F., Machackova T., Jancalek R., Smrcka M., Schmitz J. E., et al. . (2016). Prevalence of Propionibacterium acnes in intervertebral discs of patients undergoing lumbar microdiscectomy: a prospective cross-sectional study. PLoS ONE 11:e0161676. 10.1371/journal.pone.0161676 PubMed DOI PMC

Capoor M. N., Ruzicka F., Schmitz J. E., James G. A., Machackova T., Jancalek R., et al. . (2017). Propionibacterium acnes biofilm is present in intervertebral discs of patients undergoing microdiscectomy. PLoS ONE 12:e0174518. 10.1371/journal.pone.0174518 PubMed DOI PMC

Chen Z. H., Jin S. H., Wang M. Y., Jin X. L., Lv C., Deng Y. F., et al. . (2015). Enhanced NLRP3, caspase-1, and IL- 1beta levels in degenerate human intervertebral disc and their association with the grades of disc degeneration. Anat. Rec. 298, 720–726. 10.1002/ar.23059 PubMed DOI

Coscia M. F., Denys G. A., Wack M. F. (2016). Propionibacterium acnes, coagulase-negative Staphylococcus, and the “Biofilm-like” intervertebral disc. Spine 41, 1860–1865. 10.1097/BRS.0000000000001909 PubMed DOI PMC

Denk F., Bennett D. L., McMahon S. B. (2017). Nerve growth factor and pain mechanisms. Annu. Rev. Neurosci. 40, 307–325. 10.1146/annurev-neuro-072116-031121 PubMed DOI

Dinarello C. A., Simon A., van der Meer J. W. (2012). Treating inflammation by blocking interleukin-1 in a broad spectrum of diseases. Nat. Rev. Drug Discov. 11, 633–652. 10.1038/nrd3800 PubMed DOI PMC

Dudli S., Liebenberg E., Magnitsky S., Miller S., Demir-Deviren S., Lotz J. C. (2016). Propionibacterium acnes infected intervertebral discs cause vertebral bone marrow lesions consistent with Modic changes. J. Orthop. Res. 34, 1447–1455. 10.1002/jor.23265 PubMed DOI

Fenini G., Contassot E., French L. E. (2017). Potential of IL-1, IL-18 and inflammasome inhibition for the treatment of inflammatory skin Diseases. Front. Pharmacol. 8:278. 10.3389/fphar.2017.00278 PubMed DOI PMC

Freemont A. J., Peacock T. E., Goupille P., Hoyland J. A., O'Brien J., Jayson M. I. (1997). Nerve ingrowth into diseased intervertebral disc in chronic back pain. Lancet 350, 178–181. PubMed

Ganko R., Rao P. J., Phan K., Mobbs R. J. (2015). Can bacterial infection by low virulent organisms be a plausible cause for symptomatic disc degeneration? A systematic review. Spine 40, E587–E592. 10.1097/BRS.0000000000000832 PubMed DOI

Gorth D. J., Mauck R. L., Chiaro J. A., Mohanraj B., Hebela N. M., Dodge G. R., et al. . (2012). IL-1ra delivered from poly(lactic-co-glycolic acid) microspheres attenuates IL-1beta-mediated degradation of nucleus pulposus in vitro. Arthritis Res. Ther. 14:R179. 10.1186/ar3932 PubMed DOI PMC

Gruber H. E., Hoelscher G. L., Bethea S., Hanley E. N., Jr. (2012). Interleukin 1-beta upregulates brain-derived neurotrophic factor, neurotrophin 3 and neuropilin 2 gene expression and NGF production in annulus cells. Biotech. Histochem. 87, 506–511. 10.3109/10520295.2012.703692 PubMed DOI

Hart L. G., Deyo R. A., Cherkin D. C. (1995). Physician office visits for low back pain. Frequency, clinical evaluation, and treatment patterns from a U.S. national survey. Spine 20, 11–19. 10.1097/00007632-199501000-00003 PubMed DOI

Holmberg A., Lood R., Mörgelin M., Söderquist B., Holst E., Collin M., et al. . (2009). Biofilm formation by Propionibacterium acnes is a characteristic of invasive isolates. Clin. Microbiol. Infect. 15, 787–795. 10.1111/j.1469-0691.2009.02747.x PubMed DOI

Jahns A. C., Lundskog B., Ganceviciene R., Palmer R. H., Golovleva I., Zouboulis C. C., et al. . (2012). An increased incidence of Propionibacterium acnes biofilms in acne vulgaris: a case-control study. Br. J. Dermatol. 167, 50–58. 10.1111/j.1365-2133.2012.10897.x PubMed DOI

Kistowska M., Gehrke S., Jankovic D., Kerl K., Fettelschoss A., Feldmeyer L., et al. . (2014). IL-1beta drives inflammatory responses to propionibacterium acnes in vitro and in vivo. J. Invest. Dermatol. 134, 677–685. 10.1038/jid.2013.438 PubMed DOI

Lasigliè D., Traggiai E., Federici S., Alessio M., Buoncompagni A., Accogli A., et al. . (2011). Role of IL-1 beta in the development of human T(H)17 cells: lesson from NLPR3 mutated patients. PLoS ONE 6:e20014. 10.1371/journal.pone.0020014 PubMed DOI PMC

Le Maitre C. L., Freemont A. J., Hoyland J. A. (2005). The role of interleukin-1 in the pathogenesis of human intervertebral disc degeneration. Arthritis Res. Ther. 7, R732–R745. 10.1186/ar1732 PubMed DOI PMC

Le Maitre C. L., Hoyland J. A., Freemont A. J. (2007). Interleukin-1 receptor antagonist delivered directly and by gene therapy inhibits matrix degradation in the intact degenerate human intervertebral disc: an in situ zymographic and gene therapy study. Arthritis Res. Ther. 9:R83. 10.1186/ar2282 PubMed DOI PMC

Li Z. J., Choi D. K., Sohn K. C., Seo M. S., Lee H. E., Lee Y., et al. . (2014). Propionibacterium acnes activates the NLRP3 inflammasome in human sebocytes. J. Invest. Dermatol. 134, 2747–2756. 10.1038/jid.2014.221 PubMed DOI

Magnitsky S., Dudli S., Tang X., Kaur J., Diaz J., Miller S., et al. (2017). Quantification of propionic acid in the bovine spinal disk after infection of the tissue with P. Acnes bacteria. Spine 43, E634–E638. 10.1097/BRS.0000000000002448 PubMed DOI PMC

McDowell A., Nagy I., Magyari M., Barnard E., Patrick S. (2013). The opportunistic pathogen Propionibacterium acnes: insights into typing, human disease, clonal diversification and CAMP factor evolution. PLoS ONE 8:e70897. 10.1371/journal.pone.0070897 PubMed DOI PMC

Moradi Tuchayi S., Makrantonaki E., Ganceviciene R., Dessinioti C., Feldman S. R., Zouboulis C. C. (2015). Acne vulgaris. Nat. Rev. Dis. Primers 1:15029. 10.1038/nrdp.2015.29 PubMed DOI

Nazipi S., Stødkilde-Jørgensen K., Scavenius C., Bruggemann H. (2017). The Skin bacterium Propionibacterium acnes employs two variants of hyaluronate lyase with distinct properties. Microorganisms 5:57. 10.3390/microorganisms5030057 PubMed DOI PMC

Quero L., Klawitter M., Schmaus A., Rothley M., Sleeman J., Tiaden A. N., et al. . (2013). Hyaluronic acid fragments enhance the inflammatory and catabolic response in human intervertebral disc cells through modulation of toll-like receptor 2 signalling pathways. Arthritis Res. Ther. 15:R94. 10.1186/ar4274 PubMed DOI PMC

Risbud M. V., Shapiro I. M. (2014). Role of cytokines in intervertebral disc degeneration: pain and disc content. Nat. Rev. Rheumatol. 10, 44–56. 10.1038/nrrheum.2013.160 PubMed DOI PMC

Sanford J. A., Zhang L. J., Williams M. R., Gangoiti J. A., Huang C. M., Gallo R. L. (2016). Inhibition of HDAC8 and HDAC9 by microbial short-chain fatty acids breaks immune tolerance of the epidermis to TLR ligands. Sci. Immunol. 1:eaah4609. 10.1126/sciimmunol.aah4609 PubMed DOI

Sardana K., Verma G. (2017). Propionibacterium acnes and the Th1/Th17 axis, implications in acne pathogenesis and treatment. Indian J. Dermatol. 62, 392–394. 10.4103/ijd.IJD_483_16 PubMed DOI PMC

Shaheen B., Gonzalez M. (2011). A microbial aetiology of acne: what is the evidence? Br. J. Dermatol. 165, 474–485. 10.1111/j.1365-2133.2011.10375.x PubMed DOI

Shan Z., Zhang X., Li S., Yu T., Liu J., Zhao F. (2017). Propionibacterium acnes incubation in the discs can result in time-dependent modic changes: a long-term rabbit model. Spine 42, 1595–1603. 10.1097/BRS.0000000000002192 PubMed DOI

Stirling A., Worthington T., Rafiq M., Lambert P. A., Elliott T. S. (2001). Association between sciatica and Propionibacterium acnes. Lancet 357, 2024–2025. 10.1016/S0140-6736(00)05109-6 PubMed DOI

Ugge H., Udumyan R., Carlsson J., Andrén O., Montgomery S., Davidsson S., et al. . (2018). Acne in late adolescence and risk of prostate cancer. Int. J. Cancer 142, 1580–1585. 10.1002/ijc.31192 PubMed DOI PMC

Unna P. G. (1895). The histological pathology of diseases of the skin. Br. J. Dermatol. 7, 83–85. 10.1111/j.1365-2133.1895.tb16839.x DOI

Urquhart D. M., Zheng Y., Cheng A. C., Rosenfeld J. V., Chan P., Liew S., et al. . (2015). Could low grade bacterial infection contribute to low back pain? A systematic review. BMC Med. 13:13. 10.1186/s12916-015-0267-x PubMed DOI PMC

Vos T., Flaxman A. D., Naghavi M., Lozano R., Michaud C., Ezzati M., et al. . (2012). Years lived with disability (YLDs) for 1160 sequelae of 289 diseases and injuries 1990-2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet 380, 2163–2196. 10.1016/S0140-6736(12)61729-2 PubMed DOI PMC

Wang J., Tian Y., Phillips K. L., Chiverton N., Haddock G., Bunning R. A., et al. . (2013). Tumor necrosis factor alpha- and interleukin-1beta-dependent induction of CCL3 expression by nucleus pulposus cells promotes macrophage migration through CCR1. Arthritis Rheum. 65, 832–842. 10.1002/art.37819 PubMed DOI PMC

Wuertz K., Haglund L. (2013). Inflammatory mediators in intervertebral disk degeneration and discogenic pain. Global Spine J. 3, 175–184. 10.1055/s-0033-1347299 PubMed DOI PMC

Yang W., Yu X. H., Wang C., He W. S., Zhang S. J., Yan Y. G., et al. . (2015). Interleukin-1beta in intervertebral disk degeneration. Clin. Chim. Acta 450, 262–272. 10.1016/j.cca.2015.08.029 PubMed DOI

Pro-Inflammatory and Neurotrophic Factor Responses of Cells Derived from Degenerative Human Intervertebral Discs to the Opportunistic Pathogen Cutibacterium acnes