Journal of Molecular Medicine

, Volume 97, Issue 1, pp 25–35 | Cite as

Propionibacterium acnes induces discogenic low back pain via stimulating nucleus pulposus cells to secrete pro-algesic factor of IL-8/CINC-1 through TLR2–NF-κB p65 pathway

  • Yucheng Jiao
  • Ye Yuan
  • Yazhou Lin
  • Zezhu Zhou
  • Yuehuan Zheng
  • Wenjian Wu
  • Guoqing Tang
  • Yong Chen
  • Jiaqi Xiao
  • Changwei LiEmail author
  • Zhe ChenEmail author
  • Peng CaoEmail author
Original Article


Latent infection of Propionibacterium acnes was considered as a new pathogeny for low back pain (LBP); however, there is no credible animal evidence or mechanism hypothesis. This study proved that P. acnes is a causative pathogen of bacteria-induced LBP and investigated its underlying mechanism. For this, P. acnes was firstly identified in patients’ degenerated intervertebral disc (IVDs) samples. The results of patients’ Japanese Orthopaedic Association Back Pain Evaluation Questionnaire (JOABPEQ), Japanese Orthopaedic Association (JOA), and Oswestry Disability Index (ODI) scores indicated that P. acnes-positive patients showed more severe LBP and physical disability. Then, a P. acnes-inoculated lumbar IVDs model was established in rats. The results of paw/foot withdrawal threshold and qRT-PCR indicated that P. acnes-inoculated rats had obvious LBP in behavioral evaluation and over-expression of substance P (SP) and calcitonin gene-related peptide (CGRP) in IVDs. Subsequently, enzyme-linked immunosorbent assay (ELISA) results demonstrated that increased expression of IL-8 or CINC-1 (the homolog of IL-8 in rats) in the P. acnes-positive IVDs of human and rats. The CINC-1 injected animal model proved that the cytokines were able to induce LBP. Finally, the co-culture experiments showed that nucleus pulposus cells (NPCs) were able to respond to P. acnes and secreted IL-8/CINC-1 via TLR-2/NF-κB p65 pathway. In conclusion, P. acnes had strong association with LBP by stimulating NPCs to secrete pro-algesic factor of IL-8/CINC-1 via TLR2/NF-κBp65 pathway. The finding may provide a promising alternative therapy strategy for LBP in clinical.

Key messages

  • Patients with P. acnes-positive IVDs tended to have more severe LBP, physical disability, and increased IL-8 expressions.

  • P. acnes can induce LBP via IL-8/CINC-1 in IVDs.

  • P. acnes stimulate the NPCs to secrete pro-algesic factor of IL-8/CINC-1 via TLR2/NF-κBp65 pathway.


Propionibacterium acnes Intervertebral disc Low back pain Interleukin-8 Nucleus pulposus cells 



This work was supported by grants from the Science and Technology Commission of Shanghai Municipality, Shanghai, China (No. 15DZ1942604); grants from the Shanghai Bureau of Health, Shanghai, China (Nos. 20164Y0132 and 20124294); the Shanghai Sailing Program, Shanghai, China (No. 16YF1410100); the National Natural Science fund, China (NSFC No. 81702188), and the Science and Technology Bureau of Kunshan, Kunshan, China (No. KS1547).

Compliance with ethical standards

The study was approved by the Institutional Review Board of Shanghai Ruijin Hospital (Ethics Committee Reference Number: 2013-60) and every participant signed an informed consent form. All animal experiments were performed in accordance with the protocol approved by the Shanghai Jiao Tong University (SJTU) Animal Care and Use Committee [IACUC protocol number: SYXK (Shanghai) 2011-0113] and in accordance with the Ministry of Science and Technology of the People’s Republic of China Animal Care guidelines.

Conflict of interest

The authors declare that they have no competing interests.

Supplementary material

109_2018_1712_MOESM1_ESM.docx (15 kb)
Supplementary Table 1 (DOCX 15 kb)


  1. 1.
    Maher C, Underwood M, Buchbinder R (2017) Non-specific low back pain. Lancet 389(10070):736–747CrossRefGoogle Scholar
  2. 2.
    Hoy D, Bain C, Williams G, March L, Brooks P, Blyth F, Woolf A, Vos T, Buchbinder R (2012) A systematic review of the global prevalence of low back pain. Arthritis Rheum 64(6):2028–2037CrossRefGoogle Scholar
  3. 3.
    Stirling A, Worthington T, Rafiq M, Lambert PA, Elliott TS (2001) Association between sciatica and Propionibacterium acnes. Lancet 357(9273):2024–2025CrossRefGoogle Scholar
  4. 4.
    Albert HB, Kjaer P, Jensen TS, Sorensen JS, Bendix T, Manniche C (2008) Modic changes, possible causes and relation to low back pain. Med Hypotheses 70(2):361–368CrossRefGoogle Scholar
  5. 5.
    Albert HB, Sorensen JS, Christensen BS, 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(4):697–707CrossRefGoogle Scholar
  6. 6.
    Chen Z, Cao P, Zhou Z, Yuan Y, Jiao Y, Zheng Y (2016) Overview: the role of Propionibacterium acnes in nonpyogenic intervertebral discs. Int Orthop 40(6):1291–1298CrossRefGoogle Scholar
  7. 7.
    Yuan Y, Zhou Z, Jiao Y, Li C, Zheng Y, Lin Y, Xiao J, Chen Z, Cao P (2017) Histological identification of Propionibacterium acnes in nonpyogenic degenerated intervertebral discs. Biomed Res Int 2017:6192935–6192937Google Scholar
  8. 8.
    Chen Z, Zheng Y, Yuan Y, Jiao Y, Xiao J, Zhou Z, Cao P (2016) Modic changes and disc degeneration caused by inoculation of Propionibacterium acnes inside intervertebral discs of rabbits: a pilot study. Biomed Res Int 2016:9612437Google Scholar
  9. 9.
    Albert HB, Lambert P, Rollason J, Sorensen JS, Worthington T, Pedersen MB, Norgaard HS, Vernallis A, Busch F, Manniche C et al (2013) Does nuclear tissue infected with bacteria following disc herniations lead to Modic changes in the adjacent vertebrae? Eur Spine J 22(4):690–696CrossRefGoogle Scholar
  10. 10.
    Zhou Z, Chen Z, Zheng Y, Cao P, Liang Y, Zhang X, Wu W, Xiao J, Qiu S (2015) Relationship between annular tear and presence of Propionibacterium acnes in lumbar intervertebral disc. Eur Spine J 24(11):2496–2502CrossRefGoogle Scholar
  11. 11.
    Yao M, Li ZJ, Zhu S, Wang JY, Pan YF, Tian ZR, Shen LY, Cheng SD, Wang YJ, Cui XJ (2017) Simplified Chinese version of the Japanese Orthopaedic Association Back Pain Evaluation Questionnaire: cross-cultural adaptation, reliability, and validity for patients with low back pain. Spine (Phila Pa 1976) 43(20):1438–1445Google Scholar
  12. 12.
    Fairbank JC, Couper J, Davies JB, O'Brien JP (1980) The Oswestry low back pain disability questionnaire. Physiotherapy 66(8):271–273Google Scholar
  13. 13.
    Izumida S, Inoue S (1986) Assessment of treatment for low back pain. J Jpn Orthop Assoc 60:391–394Google Scholar
  14. 14.
    Yuan Y, Chen Y, Zhou Z, Jiao Y, Li C, Zheng Y, Lin Y, Xiao J, Chen Z, Cao P (2017) Association between chronic inflammation and latent infection of Propionibacterium acnes in non-pyogenic degenerated intervertebral discs: a pilot study. Eur Spine J 27:2506–2517CrossRefGoogle Scholar
  15. 15.
    Xia X, Li Z, Liu K, Wu Y, Jiang D, Lai Y (2016) Staphylococcal LTA-induced miR-143 inhibits Propionibacterium acnes-mediated inflammatory response in skin. J Investig Dermatol 136(3):621–630CrossRefGoogle Scholar
  16. 16.
    Lai A, Moon A, Purmessur D, Skovrlj B, Laudier DM, Winkelstein BA, Cho SK, Hecht AC, Iatridis JC (2016) Annular puncture with tumor necrosis factor-alpha injection enhances painful behavior with disc degeneration in vivo. Spine J 16(3):420–431CrossRefGoogle Scholar
  17. 17.
    Bertini R, Allegretti M, Bizzarri C, Moriconi A, Locati M, Zampella G, Cervellera MN, Di Cioccio V, Cesta MC, Galliera E et al (2004) Noncompetitive allosteric inhibitors of the inflammatory chemokine receptors CXCR1 and CXCR2: prevention of reperfusion injury. Proc Natl Acad Sci U S A 101(32):11791–11796CrossRefGoogle Scholar
  18. 18.
    Lai A, Moon A, Purmessur D, Skovrlj B, Winkelstein BA, Cho SK, Hecht AC, Iatridis JC (2015) Assessment of functional and behavioral changes sensitive to painful disc degeneration. J Orthop Res 33(5):755–764CrossRefGoogle Scholar
  19. 19.
    Wuertz K, Quero L, Sekiguchi M, Klawitter M, Nerlich A, Konno S, Kikuchi S, Boos N (2011) The red wine polyphenol resveratrol shows promising potential for the treatment of nucleus pulposus-mediated pain in vitro and in vivo. Spine (Phila Pa 1976) 36(21):E1373–E1384CrossRefGoogle Scholar
  20. 20.
    Chen Z, Park J, Butler B, Acosta G, Vega-Alvarez S, Zheng L, Tang J, McCain R, Zhang W, Ouyang Z et al (2016) Mitigation of sensory and motor deficits by acrolein scavenger phenelzine in a rat model of spinal cord contusive injury. J Neurochem 138(2):328–338CrossRefGoogle Scholar
  21. 21.
    Chaplan SR, Bach FW, Pogrel JW, Chung JM, Yaksh TL (1994) Quantitative assessment of tactile allodynia in the rat paw. J Neurosci Methods 53(1):55–63CrossRefGoogle Scholar
  22. 22.
    Zhongyi S, Sai Z, Chao L, Jiwei T (2015) Effects of nuclear factor kappa B signaling pathway in human intervertebral disc degeneration. Spine (Phila Pa 1976) 40(4):224–232CrossRefGoogle Scholar
  23. 23.
    Burke JG, Watson RW, McCormack D, Dowling FE, Walsh MG, Fitzpatrick JM (2002) Intervertebral discs which cause low back pain secrete high levels of proinflammatory mediators. J Bone Joint Surg Br 84(2):196–201CrossRefGoogle Scholar
  24. 24.
    Himi T, Yoshioka I, Kataura A (1997) Production and gene expression of IL-8-like cytokine GRO/CINC-1 in rat nasal mucosa. Acta Otolaryngol 117(1):123–127CrossRefGoogle Scholar
  25. 25.
    Lorenzetti BB, Veiga FH, Canetti CA, Poole S, Cunha FQ, Ferreira SH (2002) Cytokine-induced neutrophil chemoattractant 1 (CINC-1) mediates the sympathetic component of inflammatory mechanical hypersensitivitiy in rats. Eur Cytokine Netw 13(4):456–461Google Scholar
  26. 26.
    Quero L, Klawitter M, Schmaus A, Rothley M, Sleeman J, Tiaden AN, Klasen J, Boos N, Hottiger MO, Wuertz K 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(4):R94CrossRefGoogle Scholar
  27. 27.
    Burke JG, RW GW, Conhyea D, McCormack D, Dowling FE, Walsh MG, Fitzpatrick JM (2003) Human nucleus pulposis can respond to a pro-inflammatory stimulus. Spine (Phila Pa 1976) 28(24):2685–2693CrossRefGoogle Scholar
  28. 28.
    Dudli S, Liebenberg E, Magnitsky S, Miller S, Demir-Deviren S, Lotz JC (2016) Propionibacterium acnes infected intervertebral discs cause vertebral bone marrow lesions consistent with Modic changes. J Orthop Res 34(8):1447–1455CrossRefGoogle Scholar
  29. 29.
    Lin Y, Jiao Y, Yuan Y, Zhou Z, Zheng Y, Xiao J, Li C, Chen Z, Cao P (2018) Propionibacterium acnes induces intervertebral disc degeneration by promoting nucleus pulposus cell apoptosis via the TLR2/JNK/mitochondrial-mediated pathway. Emerg Microbes Infect 7(1):1CrossRefGoogle Scholar
  30. 30.
    Dudli S, Miller S, Demir-Deviren S, Lotz JC (2017) Inflammatory response of disc cells against Propionibacterium acnes depends on the presence of lumbar Modic changes. Eur Spine J 27:1013–1020CrossRefGoogle Scholar
  31. 31.
    Evans AS (1976) Causation and disease: the Henle-Koch postulates revisited. Yale J Biol Med 49(2):175–195Google Scholar
  32. 32.
    Drago L, Romano CL, Cecchinato R, Villafane JH, De Vecchi E, Lamartina C, Berjano P (2017) Are MODIC type 2 disc changes associated with low-grade infections? A pilot study. J Neurosurg Sci.
  33. 33.
    Albert HB, Manniche C, Sorensen JS, Deleuran BW (2008) Antibiotic treatment in patients with low-back pain associated with Modic changes type 1 (bone oedema): a pilot study. Br J Sports Med 42(12):969–973CrossRefGoogle Scholar
  34. 34.
    Harris AE, Hennicke C, Byers K, Welch WC (2005) Postoperative discitis due to Propionibacterium acnes: a case report and review of the literature. Surg Neurol 63(6):538–541; discussion 541 CrossRefGoogle Scholar
  35. 35.
    Richardson SM, Doyle P, Minogue BM, Gnanalingham K, Hoyland JA (2009) Increased expression of matrix metalloproteinase-10, nerve growth factor and substance P in the painful degenerate intervertebral disc. Arthritis Res Ther 11(4):R126CrossRefGoogle Scholar
  36. 36.
    Li Z, Liu H, Yang H, Wang J, Wang H, Zhang K, Ding W, Zheng Z (2014) Both expression of cytokines and posterior annulus fibrosus rupture are essential for pain behavior changes induced by degenerative intervertebral disc: an experimental study in rats. J Orthop Res 32(2):262–272CrossRefGoogle Scholar
  37. 37.
    Binch AL, Cole AA, Breakwell LM, Michael AL, Chiverton N, Cross AK, Le Maitre CL (2014) Expression and regulation of neurotrophic and angiogenic factors during human intervertebral disc degeneration. Arthritis Res Ther 16(5):416CrossRefGoogle Scholar
  38. 38.
    Freemont AJ, Peacock TE, Goupille P, Hoyland JA, O'Brien J, Jayson MI (1997) Nerve ingrowth into diseased intervertebral disc in chronic back pain. Lancet 350(9072):178–181CrossRefGoogle Scholar
  39. 39.
    Kim J, Ochoa MT, Krutzik SR, Takeuchi O, Uematsu S, Legaspi AJ, Brightbill HD, Holland D, Cunliffe WJ, Akira S et al (2002) Activation of toll-like receptor 2 in acne triggers inflammatory cytokine responses. J Immunol 169(3):1535–1541CrossRefGoogle Scholar
  40. 40.
    Brisby H (2006) Pathology and possible mechanisms of nervous system response to disc degeneration. J Bone Joint Surg Am 88(Suppl 2):68–71Google Scholar
  41. 41.
    Urban JP, Smith S, Fairbank JC (2004) Nutrition of the intervertebral disc. Spine (Phila Pa 1976) 29(23):2700–2709CrossRefGoogle Scholar
  42. 42.
    Delgado MA, Deretic V (2009) Toll-like receptors in control of immunological autophagy. Cell Death Differ 16(7):976–983CrossRefGoogle Scholar
  43. 43.
    Ellman MB, Kim JS, An HS, Chen D, Kc R, An J, Dittakavi T, van Wijnen AJ, Cs-Szabo G, Li X et al (2012) Toll-like receptor adaptor signaling molecule MyD88 on intervertebral disk homeostasis: in vitro, ex vivo studies. Gene 505(2):283–290CrossRefGoogle Scholar
  44. 44.
    Smith SM (2014) Role of toll-like receptors in helicobacter pylori infection and immunity. World J Gastrointest Pathophysiol 5(3):133–146CrossRefGoogle Scholar
  45. 45.
    Uckay I, Dinh A, Vauthey L, Asseray N, Passuti N, Rottman M, Biziragusenyuka J, Riche A, Rohner P, Wendling D et al (2010) Spondylodiscitis due to Propionibacterium acnes: report of twenty-nine cases and a review of the literature. Clin Microbiol Infect 16(4):353–358CrossRefGoogle Scholar
  46. 46.
    Capoor MN, Ruzicka F, Machackova T, Jancalek R, Smrcka M, Schmitz JE, Hermanova M, Sana J, Michu E, Baird JC et al (2016) Prevalence of Propionibacterium acnes in intervertebral discs of patients undergoing lumbar microdiscectomy: a prospective cross-sectional study. PLoS One 11(8):e0161676CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  • Yucheng Jiao
    • 1
    • 2
  • Ye Yuan
    • 1
    • 3
  • Yazhou Lin
    • 1
    • 2
  • Zezhu Zhou
    • 4
  • Yuehuan Zheng
    • 5
  • Wenjian Wu
    • 1
  • Guoqing Tang
    • 6
  • Yong Chen
    • 6
  • Jiaqi Xiao
    • 7
  • Changwei Li
    • 2
    Email author
  • Zhe Chen
    • 1
    • 2
    Email author
  • Peng Cao
    • 1
    • 2
    Email author
  1. 1.Department of Orthopedics, Ruijin Hospital, School of MedicineShanghai Jiaotong UniversityShanghaiChina
  2. 2.Shanghai Key Laboratory for Prevention and Treatment of Bone and Joint Diseases with Integrated Chinese-Western Medicine, Shanghai Institute of Traumatology and Orthopedics, Ruijin Hospital, School of MedicineShanghai Jiaotong UniversityShanghaiChina
  3. 3.Department of Orthopedics, Beijing Tsinghua Changgung HospitalTsinghua UniversityBeijingChina
  4. 4.Department of Orthopedic Surgery, Xinhua Hospital, School of MedicineShanghai Jiaotong UniversityShanghaiChina
  5. 5.Department of Orthopedics, Ruijin Hospital North, School of MedicineShanghai Jiaotong UniversityShanghaiChina
  6. 6.Kunshan Hospital of Traditional Chinese medicineKunshanChina
  7. 7.Department of Medical Microbiology and Parasitology, School of MedicineShanghai Jiaotong UniversityShanghaiChina

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