Causal effects of skin microbiota on intervertebral disk degeneration, low back pain and sciatica: a two-sample Mendelian randomization study.

OBJECTIVE: The purpose of this study is to use two-sample Mendelian randomization (MR) to investigate the causal relationship between skin microbiota, especially Propionibacterium acnes, and intervertebral disc degeneration (IVDD), low back pain (LBP) and sciatica. METHODS: We conducted a two-sample MR using the aggregated data from the whole genome-wide association studies (GWAS). 150 skin microbiota were derived from the GWAS catalog and IVDD, LBP and sciatica were obtained from the IEU Open GWAS project. Inverse-variance weighted (IVW) was the primary research method, with MR-Egger and Weighted median as supplementary methods. Perform sensitivity analysis and reverse MR analysis on all MR results and use multivariate MR to adjust for confounding factors. RESULTS: MR revealed five skin microbiota associated with IVDD, four associated with LBP, and two with sciatica. Specifically, P.acnes in sebaceous skin environments were associated with reduced risk of IVDD; IVDD was found to increase the abundance of P.acnes in moist skin. Furthermore, ASV010 [Staphylococcus (unc.)] from dry skin was a risk factor for LBP and sciatica; ASV045 [Acinetobacter (unc.)] from dry skin and Genus Rothia from dry skin exhibited potential protective effects against LBP; ASV065 [Finegoldia (unc.)] from dry skin was a protective factor for IVDD and LBP. ASV054 [Enhydrobacter (unc.)] from moist skin, Genus Bacteroides from dry skin and Genus Kocuria from dry skin were identified as being associated with an increased risk of IVDD. Genus Streptococcus from moist skin was considered to be associated with an increased risk of sciatica. CONCLUSIONS: This study identified a potential causal relationship between skin microbiota and IVDD, LBP, and sciatica. No evidence suggests skin-derived P.acnes is a risk factor for IVDD, LBP and sciatica. At the same time, IVDD can potentially cause an increase in P.acnes abundance, which supports the contamination theory.

METTL3 Promotes Nucleus Pulposus Cell Senescence in Intervertebral Disc Degeneration by Regulating TLR2 m6A Methylation and Gut Microbiota.

BACKGROUND: Nucleus pulposus cell (NPC) senescence in intervertebral disc (IVD) tissue is the major pathological cause of intervertebral disc degeneration (IDD). N6-methyladenosine (m6A) methylation and gut microbiota play important roles in the progression of IDD. This study investigated whether methyltransferase-like 3 (METTL3) regulates TLR2 m6A modification and gut microbiota to influence NPC senescence. METHODS: An IDD rat model was established by lumbar IVD puncture and NPCs were challenged with IL-1ß to mimic IVD injury. IDD rats and IL-1ß-exposed NPCs were treated with METTL3-interfering lentivirus and the TLR2 agonist Pam3CSK4. Compositional changes in the rat gut microbiota were analyzed and fecal microbiota transplantation procedures were used. NPC senescence, cell cycle, and the expression of senescence-associated secretory phenotype (SASP) factors were assessed. The m6A enrichment of TLR2 and the binding of IGF2BP1 to TLR2 mRNA were examined. RESULTS: METTL3 and TLR2 were highly expressed in IDD rats. METTL3 silencing attenuated senescent phenotypes and reduced secretion of SASP factors. Pam3CSK4 reversed the beneficial effects of METTL3 silencing on NPC senescence and IVD injury. METTL3 stabilized TLR2 mRNA in an IGF2BP1-dependent manner. METTL3 silencing restored specific gut microbiota levels in IDD rats, which was further reversed by administration of Pam3CSK4. Fecal microbiota from METTL3 silenced IDD rats altered the pathological phenotypes of IDD rats. CONCLUSIONS: These results demonstrate the beneficial effects of METTL3 silencing on NPC senescence and amelioration of IVD injury, involving modulation of TLR2 m6A modification and gut microbiota. These findings support METTL3 silencing as a potential therapeutic target for IDD.

Does the gut microbiome influence disc health and disease? The interplay between dysbiosis, pathobionts, and disc inflammation: a pilot study.

BACKGROUND CONTEXT: Gut microbiome alterations resulting in inflammatory responses have been implicated in many distant effects on different organs. However, its influence on disc health is still not fully investigated. PURPOSE: Our objective was to document the gut biome in healthy volunteers and patients with disc degeneration and to understand the role of gut dysbiosis on human disc health. STUDY DESIGN: Experimental case-control study. PATIENT SAMPLE: We included 40 patients with disc degeneration (DG) and 20 healthy volunteers (HV). HV comprised of age groups 30 to 60 years with no known record of back pain and no clinical comorbidities, with normal MRI. Diseased group (DG) were patients in the same age group undergoing surgery for disc disease (disc herniation-25; discogenic stenosis-15) and without instability (with Modic-20; and non-Modic-20). OUTCOME MEASURES: N/A. METHODS: We analyzed 16S V3-V4 rDNA gut metagenome from 20 healthy volunteers (HV) and compared the top signature genera from 40 patients with disc degeneration (DG) across Modic and non-Modic groups. Norgen Stool DNA Kit was used for DNA extraction from ∼200 mg of each faecal sample collected using the Norgen Stool Collection Kit.16S V3-V4 rDNA amplicons were generated with universal bacterial primers 341F and 806R and amplified with Q5 High-Fidelity DNA Polymerase. Libraries were sequenced with 250×2 PE to an average of 0.1 million raw reads per sample (Illumina Novaseq 6000). Demultiplexed raw data was assessed with FastQC, and adapter trimmed reads >Q30 reads were processed in the QIME2 pipeline. Serum C-reactive protein (CRP) was measured by the immunoturbimetry method and Fatty acid-binding protein 5 (FABP5) was measured in albumin-globulin-depleted plasma through global proteome analysis. RESULTS: We observed significant gut dysbiosis between HV and DG and also between the Modic and non-Modic groups. In the Modic group, commensals Bifidobacterium and Ruminococcus were significantly depleted, while pathobionts Streptococcus, Prevotella, and Butryvibrio were enriched. Firmicutes/Bacteroidetes ratio was decreased in DG (Modic-0.62, non-Modic-0.43) compared to HV (0.70). Bacteria-producing beneficial short-chain fatty acids were also depleted in DG. Elevated serum CRP and increased FABP5 were observed in DG. CONCLUSION: The study revealed gut dysbiosis, an altered Firmicutes/Bacteroidetes ratio, reduced SCFA-producing bacteria, and increased systemic and local inflammation in association with disc disease, especially in Modic changes. The findings have considerable importance for our understanding and prevention of disc degeneration.

Risk factors associated with low-grade virulent infection in intervertebral disc degeneration: a systematic review and meta-analysis.

BACKGROUND: An increasing number of research indicates an association between low-grade bacterial infections, particularly those caused by Propionibacterium acnes (P. acnes), and the development of intervertebral disc degeneration (IDD). However, no previous meta-analysis has systematically assessed the risk factors for low-grade bacterial infections that cause IDD. PURPOSE: This study reviewed the literature to evaluate the risk factors associated with low-grade bacterial infection in patients with IDD. STUDY DESIGN: Systematic review and meta-analysis. METHODS: The systematic literature review was conducted using the PubMed, Web of Science, Embase, and Cochrane Library databases. Eligible articles explicitly identified the risk factors for low-grade bacterial infections in IDD patients. Patient demographics and total bacterial infection rates were extracted from each study. Meta-analysis was performed using random- or fixed-effects models, with statistical analyses conducted using Review Manager (RevMan) 5.4 software.aut. RESULTS: Thirty-three studies involving 4,109 patients were included in the meta-analysis. The overall pooled low-grade bacterial infection rate was 30% (range, 24%-37%), with P. acnes accounting for 25% (range, 19%-31%). P. acnes constituted 66.7% of bacteria-positive discs. Fourteen risk factors were identified, of which 8 were quantitatively explored. Strong evidence supported male sex (odds ratio [OR] = 2.15; 95% confidence interval [CI]=1.65-2.79; p<.00001) and Modic changes (MCs) (OR=3.59; 95% CI=1.68-7.76; p=.0009); moderate evidence of sciatica (OR=2.31; 95% CI=1.33-4.00; p=.003) and younger age (OR=-3.47; 95% CI=-6.42 to -0.53; p=.02). No evidence supported previous disc surgery, MC type, Pfirrmann grade, smoking, or diabetes being risk factors for low-grade bacterial infections in patients with IDD. CONCLUSIONS: Current evidence highlights a significant association between IDD and low-grade bacterial infections, predominantly P. acnes being the most common causative agent. Risk factors associated with low-grade bacterial infections in IDD include male sex, MCs, sciatica, and younger age.

The Effect of Gut Microbiota on the Progression of Intervertebral Disc Degeneration.

OBJECTIVE: Intervertebral disc degeneration (IDD) is the main cause of back pain, and its treatment is a serious socio-economic burden. The safety and treatment of fecal microbiota transplantation (FMT) has been established. However, the relationship between FMT and IDD still unclear. We aimed to explore whether FMT plays a role in IDD to provide a reference for the treatment of IDD. METHODS: An experimental model of IDD was established using 2-month-old male Sprague-Dawley rats. FMT was performed by intragastric gavage of IDD rats with a fecal bacterial solution. Rat serum, feces, and vertebral disc tissue were collected after surgery for 2 months. The levels of TNF-α, IL-1ß, IL-6, matrix metalloproteinase (MMP)-3, MMP-13, Collagen II, and aggrecan in the serum or vertebral disc tissue were measured by an enzyme-linked immunosorbent assay, immunohistochemistry, quantitative real-time polymerase chain reaction, or western blotting. We also examined the pathology of the vertebral disc tissue using hematoxylin and eosin (HE) and safranin O-fast green staining. Finally, we examined the gut microbiota in rat feces using 16 S rRNA gene sequencing. RESULTS: We found that the expression of TNF-α, IL-1ß, IL-6, MMP-3, MMP-13, NLRP3 and Caspase-1 increased in the IDD group rats. In contrast, Collagen II and aggrecan levels were downregulated. Additionally, vertebral disc tissue was severely damaged in the IDD group, with disordered cell arrangement and uneven safranin coloration. FMT reversed the effects of IDD modeling on these factors and alleviated cartilage tissue damage. In addition, FMT increased the gut microbiota diversity and microbial abundance in rats treated with IDD. CONCLUSION: Our findings suggest that FMT has a positive effect in maintaining cellular stability in the vertebral disc and alleviating histopathological damage. It affects the diversity and abundance of gut microbiota in rats with IDD. Therefore, FMT may serve as a promising target for amelioration of IDD.

Red Light-Mediated Photoredox Catalysis Triggers Nitric Oxide Release for Treatment of Cutibacterium Acne Induced Intervertebral Disc Degeneration.

Intervertebral disc degeneration (IVDD) has been known as a highly prevalent and disabling disease, which is one of the main causes of low back pain and disability. Unfortunately, there is no effective cure to treat this formidable disease, and surgical interventions are typically applied. Herein, we report that the local administration of nitric oxide (NO)-releasing micellar nanoparticles can efficiently treat IVDD associated with Modic changes in a rat model established by infection with Cutibacterium acnes (C. acnes). By covalent incorporation of palladium(II) meso-tetraphenyltetrabenzoporphyrin photocatalyst and coumarin-based NO donors into the core of micellar nanoparticles, we demonstrate that the activation of the UV-absorbing coumarin-based NO donors can be achieved under red light irradiation via photoredox catalysis, although it remains a great challenge to implement photoredox catalysis reactions in biological conditions due to the complex microenvironments. Notably, the local delivery of NO can not only efficiently eradicate C. acnes pathogens but also inhibit the inflammatory response and osteoclast differentiation in the intervertebral disc tissues, exerting antibacterial, anti-inflammatory, and antiosteoclastogenesis effects. This work provides a feasible means to efficiently treat IVDD by the local administration of NO signaling molecules without resorting to a surgical approach.

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

Previously, we proposed the hypothesis that similarities in the inflammatory response observed in acne vulgaris and degenerative disc disease (DDD), especially the central role of interleukin (IL)-1ß, may be further evidence of the role of the anaerobic bacterium Cutibacterium (previously Propionibacterium) acnes in the underlying aetiology of disc degeneration. To investigate this, we examined the upregulation of IL-1ß, and other known IL-1ß-induced inflammatory markers and neurotrophic factors, from nucleus-pulposus-derived disc cells infected in vitro with C. acnes for up to 48 h. Upon infection, significant upregulation of IL-1ß, alongside IL-6, IL-8, chemokine (C-C motif) ligand 3 (CCL3), chemokine (C-C motif) ligand 4 (CCL4), nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF), was observed with cells isolated from the degenerative discs of eight patients versus non-infected controls. Expression levels did, however, depend on gene target, multiplicity and period of infection and, notably, donor response. Pre-treatment of cells with clindamycin prior to infection significantly reduced the production of pro-inflammatory mediators. This study confirms that C. acnes can stimulate the expression of IL-1ß and other host molecules previously associated with pathological changes in disc tissue, including neo-innervation. While still controversial, the role of C. acnes in DDD remains biologically credible, and its ability to cause disease likely reflects a combination of factors, particularly individualised response to infection.

Propionibacterium acnes Accelerates Intervertebral Disc Degeneration by Inducing Pyroptosis of Nucleus Pulposus Cells via the ROS-NLRP3 Pathway.

Our previous study verified the occurrence of Propionibacterium acnes (P. acnes), a low-virulence anaerobic bacterium, latently residing in degenerated intervertebral discs (IVDs), and the infection had a strong association with IVD degeneration. We explored whether P. acnes induces nucleus pulposus cell (NPC) pyroptosis, a more dangerous cell death process than apoptosis, and accelerates IVD degeneration via the pyroptotic products interleukin- (IL-) 1ß and IL-18. After coculturing with P. acnes, human NPCs showed significant upregulation of NOD-like receptor 3 (NLRP3), cleaved IL-1ß, cleaved caspase-1, and cleaved gasdermin D in response to the overexpression of IL-1ß and IL-18 in a time- and dose-dependent manner. In addition, the gene expression of inflammatory factors and catabolic enzymes significantly increased in normal NPCs when cocultured with pyroptotic NPCs in a transwell system, and the adverse effects were inhibited when NPC pyroptosis was suppressed. Furthermore, inoculation of P. acnes into the IVDs of rats caused significant pyroptosis of NPCs and remarkable IVD degeneration. Finally, coculture of NPCs with P. acnes induced the overexpression of reactive oxygen species (ROS) and NLRP3, while inhibition of both factors reduced NPC pyroptosis. Therefore, P. acnes induces NPC pyroptosis via the ROS-NLRP3 signaling pathway, and the pyroptotic NPCs cause an IVD degeneration cascade. Targeting the P. acnes-induced pyroptosis of NPCs may become an alternative treatment strategy for IVD degeneration in the future.

[Evidence-based implant choice in infections of the spine : Is it a gut thing, after all?] / Evidenzbasierte Implantatwahl bei Infektionen der Wirbelsäule : Ist es doch eine Bauchsache?

The choice of implant in an infection of the spine depends on what type of infection it is: discitis, spondylodiscitis, early infection after spinal surgery, or a late infection. The appropriate treatment strategies vary. In spondylodiscitis, a titanium implant may be necessary. In implant-associated early infections, surgical sanitization is often sufficient without changing the implant. In late infections, implant exchange is necessary because of biofilm.

The role of Propionibacterium acnes in and Modic type 1 changes†:†A literature review.

Propionibacterium acnes (P. acnes) is part of the normal flora of human skin, oral cavity, intestinal tract and external ear canal. However, breach in the mucosa as well as ruptured annulus fibrosus provide favorable pathway for P. acnes to nucleus pulposus where it can proliferate under anaerobic condition. In past two decades many authors have identified P. acnes in routine culture of discs. There studies showed that almost 50% of discs cultured were positive for various organism, and in vast majority of culture positive disc, P. acnes was the primary organism isolated. However, there are few studies that refute the hypothesis that P. acnes has a role in pathogenesis of Modic type 1 changes. Identification of P. acnes in culture indicates the infective patho-mechanism in the pathogenesis of Modic type 1 changes, which may be ameable to antibiotic treatment. However, it is still difficult to identify which subset of these patients (patients with low back pain with type 1 Modic change) are infective in nature. Further investigation and more clinical trails will be required for clear identification of the infective subgroup among low back patient in general. J. Med. Invest. 67 : 21-26, February, 2020.

Optimizing the safety of intradiscal platelet-rich plasma: an in vitro study with Cutibacterium acnes.

Aim: The most common risk associated with intradiscal injection of platelet-rich plasma (PRP) is discitis with Cutibacterium acnes. It is hypothesized that antimicrobial activity of PRP can be enhanced through inclusion of leukocytes or antibiotics in the injectate. Materials & methods: Multiple PRP preparations of varying platelet and leukocyte counts were co-cultured with C. acnes with or without cefazolin, with viable bacterial colony counts being recovered at 0, 4, 24 and 48 hours post-inoculation. Results: A direct correlation between C. acnes recovery and granulocyte counts were observed. Conclusion: We observed the greatest antimicrobial activity with the leukocyte-rich, high platelet PRP preparation combined with an antibiotic in the injectate. However, cefazolin did not completely clear the bacteria in this assay.

Is the discopathy associated with Modic changes an infectious process? Results from a prospective monocenter study.

BACKGROUND: The local infectious origin and the putative role of Cutibacterium acnes (CA) of a particular subtype of discopathy (Modic 1) are still debated. PURPOSE: To establish the association of CA in intervertebral disc (IVD) and Modic 1 discopathy in patients with low back pain. METHODS: The prevalence of bacteria in IVD samples obtained by anterior approach in patient with chronic low back pain harboring Modic type 1, 2 or no Modic changes was compared to that measured in IVD samples obtained by posterior approach for sciatica. From 45 patients included in the study, 77 discs samples were obtained: 58 by anterior approach (32 Modic 1/2 changes, 26 without Modic change) and 19 by posterior approach. Conventional microbial cultures, universal 16S rRNA molecular detection and a CA specific PCR were performed. RESULTS: 12 /77 (15.6%) disc samples were culture positive. Among the 10 CA positive cultures, 5 out of 58 (8.6%) were identified from specimens obtained by anterior approach and 5/19 (26.3%) from posterior approach (p = 0.046). Moreover, the percentage of CA culture positive sample was statistically no different between the patient with or without Modic changes. The CA prevalence was lower through molecular, culture-free approaches: the universal 16S rRNA PCR was positive for 6 specimens, including one CA positive sample and the CA specific PCR was positive for one specimen obtained by posterior approach. CONCLUSIONS: In spine surgery the prevalence of CA in culture was significantly higher in IVD samples collected through a posterior approach compared to an anterior approach, suggesting a contamination process. This study did not support the CA related local infectious origin of Modic 1 discopathy.

A review of microscopy-based evidence for the association of Propionibacterium acnes biofilms in degenerative disc disease and other diseased human tissue.

PURPOSE: Recent research shows an increasing recognition that organisms not traditionally considered infectious in nature contribute to disease processes. Propionibacterium acnes (P. acnes) is a gram-positive, aerotolerant anaerobe prevalent in the sebaceous gland-rich areas of the human skin. A ubiquitous slow-growing organism with the capacity to form biofilm, P. acnes, recognized for its role in acne vulgaris and medical device-related infections, is now also linked to a number of other human diseases. While bacterial culture and molecular techniques are used to investigate the involvement of P. acnes in such diseases, definitive demonstration of P. acnes infection requires a technique (or techniques) sensitive to the presence of biofilms and insensitive to the presence of potential contamination. Fortunately, there are imaging techniques meeting these criteria, in particular, fluorescence in situ hybridization and immunofluorescence coupled with confocal laser scanning microscopy, as well as immunohistochemistry. METHODS: Our literature review considers a range of microscopy-based studies that provides definitive evidence of P. acnes colonization within tissue from a number of human diseases (acne vulgaris, degenerative disc and prostate disease and atherosclerosis), some of which are currently not considered to have an infectious etiology. RESULTS/CONCLUSION: We conclude that P. acnes is an opportunistic pathogen with a likely underestimated role in the development of various human diseases associated with significant morbidity and, in some cases, mortality. As such, these findings offer the potential for new studies aimed at understanding the pathological mechanisms driving the observed disease associations, as well as novel diagnostic strategies and treatment strategies, particularly for degenerative disc disease. These slides can be retrieved under Electronic Supplementary Material.

The bacteria-positive proportion in the disc tissue samples from surgery: a systematic review and meta-analysis.

PURPOSE: The role of bacteria, especially Propionibacterium acnes (P. acnes), in human intervertebral disc diseases has raised attention in recent years. However, limited sample size of these studies and diverse bacteria-positive proportion made this topic still controversial. We aimed to review related articles and summarize the bacteria-positive proportion in these studies. METHODS: We searched the PubMed, Cochrane Library, Embase for related literature from January 2001 to May 2018, and the reference articles were also searched. The random effects or fixed effects meta-analysis was used to pool the overall positive proportion or odds ratio of these studies. RESULTS: We found 16 relevant articles and 2084 cases of the bacteria culture from surgery. Within the 16 included studies, 12 studies' results supported the infection in the discs. The pooled bacterial infection rate was 25.3%. The pooled P. acnes infection rate was 15.5%. The overall pooled P. acnes proportion in bacteria-positive discs was 56.4%. We also found that the presence of bacteria may contribute to the development of Modic change with the odds ratio as 1.27 (95% CI: 0.44-3.64), but this result is not significant due to heterogeneity, so further study is needed. CONCLUSION: The existence of bacteria in the intervertebral discs was proved by many studies. However, the variety in sample collecting and culture methods is still obvious and the positive rate also fluctuated within the studies. Standardized and reliable methods should be taken to promote the study in the future. These slides can be retrieved under Electronic Supplementary Material.

Degenerate-disc infection study with contaminant control (DISC): Application of a proposed histological scoring system.

Recent evidence into an infectious etiology of discogenic back pain/leg pain are ongoing with contradictory data in literature. We sought to validate the clinical relevance of histopathological evidence of inflammation through a previously proposed histological grading system. In this prospective cohort study, 124 consecutive patients undergoing an elective spinal decompression and/or fusion procedure involving discectomy were selected with intraoperative tissue sampling of intervertebral disc and paraspinal tissue at a single institution. The histological domains were correlated with positive disc cultures to assist in identifying relevant positive infections. Inter-observer analysis of the scoring system was also performed. There were 124 samples (36 cervical and 88 lumbar) obtained. 29 (23.4%) disc specimens and 37 (29.8%) of ligament samples demonstrated growth of C. acnes. In total, 38/124 (30.6%) of disc specimens were positive for growth of any species. There was poor association between positive disc culture and the presence of neutrophilia (p = 0.123) or chronic inflammatory changes (p = 0.092) on histopathological assessment. There was no statistical significance noted across all histological domains examined within the finalised scoring system and positive culture across disc specimens. There was moderate agreement in between observers (kappa range: 0.41-0.60) in the assessment of inflammatory changes using the proposed scoring system. The current study suggests poor correlation between histopathological evidence of chronic or acute inflammation and positive disc cultures questioning the idea that disc infection is the root cause of acute or chronic back pain/leg pain.

Cutibacterium acnes in Spine Pathology: Pathophysiology, Diagnosis, and Management.

Cutibacterium acnes, long thought to be skin flora of pathological insignificance, has seen a surge in interest for its role in spine pathology. C acnes has been identified as a pathogen in native spine infection and osteomyelitis, which has implications in the management compared with more commonly recognized pathogens. In addition, It has also been recognized as a pathogen in postoperative and implant-associated infections. Some evidence exists pointing to C acnes as an unrecognized source of otherwise aseptic pseudarthrosis. Recently, it is hypothesized that low virulent organisms, in particular C acnes, may play a role in degenerative disk disease and the development of Modic end plate changes found in MRI. To this end, controversial implications exist in terms of the use of antibiotics to treat certain patients in the setting of degenerative disk disease. C acnes continues to remain an expanding area of interest in spine pathology, with important implications for the treating spine surgeon.

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.

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.

The Relationship Between Low-Grade Infection and Degenerative Disk Disease: A Review of Basic Science and Clinical Data.

Low back pain resulting from intervertebral disk degeneration is a cause of substantial disability and productivity loss. Over the past few years, growing evidence exists which suggests that low-grade bacterial infection, particularly infection with Cutibacterium acnes, may be associated with degenerative disk disease in the lumbar spine. Positive cultures are obtained in approximately 30% of intervertebral disk specimens removed at the time of surgery. In addition, one randomized trial has shown that antibiotic therapy for low back pain in patients with disk degeneration can slow the progression of degeneration and improve pain and disability levels. Although these results are encouraging, the link between infection and disk degeneration remains controversial. Investigators have attempted to address the limitations of clinical research by using translational methods and animal models. These methods have shown that seeding of the disk with bacteria can lead to increased local inflammation and an in vivo phenotype that is similar to human disk degeneration. This review seeks to provide an overview of the clinical, translational, and animal model data linking infection to disk degeneration. We review mechanisms for disk degeneration in the setting of infection and explore areas for future investigation.

Latent infection of low-virulence anaerobic bacteria in degenerated lumbar intervertebral discs.

BACKGROUND: The existence of latent low-virulence anaerobic bacteria in degenerated intervertebral discs (IVDs) remains controversial. In this study, the prevalence of low-virulence anaerobic bacteria in degenerated IVDs was examined, and the correlation between bacterial infection and clinical symptoms was analysed. METHODS: Eighty patients with disc herniation who underwent discectomy were included in this study. Under a stringent protocol to ensure sterile conditions, 80 disc samples were intraoperatively retrieved and subjected to microbiological culture. Meanwhile, tissue samples from the surrounding muscle and ligaments were harvested and cultured as contamination markers. The severity of IVD degeneration and the prevalence of Modic changes (MCs) were assessed according to preoperative MRI analysis. RESULTS: Of the 80 cultured discs, 54 were sterile, and 26 showed the presence of bacteria: Propionibacterium acnes (21 cases) and coagulase-negative staphylococci (5 cases). MRI revealed that the presence of bacteria was significantly associated with MCs (P<0.001). However, there was no significant association between bacterial infection and the severity of IVD degeneration (P = 0.162). CONCLUSIONS: Our findings further validated the presence of low-virulence anaerobic bacteria in degenerated IVDs, and P. acnes was the most frequent bacterium. In addition, the latent infection of bacteria in IVDs was associated with Modic changes. Therefore, low-virulence anaerobic bacteria may play a crucial role in the pathophysiology of MCs and lumbar disc herniation.

Association between Type 1 Modic Changes and Propionibacterium Acnes Infection in the Cervical Spine: An Observational Study.

BACKGROUND AND PURPOSE: Research on the association between Propionibacterium acnes in the disc space and type 1 Modic changes in adjacent vertebrae is limited and has produced mixed results. The prevalence of bacteria in intervertebral discs contradicts the prior understanding that skeletal areas in the human anatomy are sterile; yet it opens new treatment possibilities. We investigated the relationship of P acnes and type 1 Modic changes in the cervical spine. MATERIALS AND METHODS: Over a 36-month period, we collected intraoperative biopsies of patients undergoing a routine cervical spine operation for degenerative disc diseases. The disc material was cultured aerobically and anaerobically for 7 days. All preoperative MR images were evaluated for Modic changes by a board-certified neuroradiologist. Medical records were reviewed for other spine interventions before the operation. RESULTS: The study population consisted of 48 patients. Of these, 14 patients tested positive for P acnes (29%) at ≥1 level. Additionally, 13 patients had type 1 Modic changes (27%) at ≥1 level; 54% (95% CI, 27%-84%) of patients who had type 1 Modic changes were also positive for P acnes compared with 20% (95% CI, 7%-33%) of patients without type 1 Modic changes. The difference between these proportions was 34% (95% CI, 4%-64%). The Fisher exact test produced a P value of .03 for the association between P acnes and MC1, and .53 for the association between P acnes and prior procedures. CONCLUSIONS: We conclude that P acnes was prevalent in the degenerated cervical spine and that type 1 Modic changes were predictive of a culture positive for P acnes. We also found that the prevalence of P acnes was not associated with previous interventions. If these results are validated by future studies, they could have a major impact on the standard of care for back and neck pain.