INTRODUCTION
Lumbar disc herniation (LDH), defined as the displacement of nucleus pulposus (NP) tissue through the annulus fibrosus (AF) of a lumbar intervertebral disc (IVD), remains a common cause of leg pain and low back pain (LBP), with a global prevalence of about 2% [1,2]. Although pain often subsides or resolves, in most cases a considerable proportion of patients experience persistent symptoms, recurrences or flare-ups [3,4]. In such cases, the cause remains elusive. While overload-associated recurrences may have a biomechanical explanation, flare-ups often have no mechanical basis, and neither is the persistence of pain explained purely by any pathoanatomic changes. In an effort to elucidate the cause of recurrent or persistent pain, researchers have developed concepts of centralization, implicated immune system, evaluated psychosocial models, etc [3].
Research across multiple disciplines has highlighted the microbiome as a significant modulator of both systemic and local inflammatory responses, immune function, and nociception processing [5-8], consequently attracting interest from spine researchers. The microbiome refers to the diverse community of microorganisms, including bacteria, viruses, and fungi that inhabit the human body. These microbes regulate metabolism, immunity, and inflammation, and their composition and metabolites critically influence both local tissue balance and systemic homeostasis. In particular, the gut microbiome has emerged as a critical modulator, influencing multiple biological processes, even mental9 and reproductive health [10].
Growing evidence supports the presence of a “gut-disc axis,” wherein gut dysbiosis, an imprecisely defined term referring to altered microbial community composition, may influence disc homeostasis [11]. Here, the altered gut microbial families may change systemic levels of microbial metabolites and proinflammatory cytokines e.g., tumor necrosis factor (TNF)-α and interleukin (IL)-6, which are implicated in intervertebral disc degeneration (IDD) and heightened pain sensitization [12]. In addition to systemic influences, the localization of microorganisms within the spinal tissues is also increasingly being recognized for the potential microbial colonization’s role in disc health regulation. Cutibacterium acnes and other pathobionts have been identified in degenerated discs and linked to low-grade inflammation, pain sensitization, and matrix degradation processes, thus potentially influencing the progression of LDH, or worsening its symptoms [13,14]. Importantly, LDH presents a unique condition in which the otherwise largely avascular IVD is suddenly exposed to the systemic bodily systems, the local spinal microenvironment, and their respective microbiomes. This exposure may activate immune and inflammatory responses that would not typically occur in an intact IVD [15]. Yet, the connection between the microbiome and LDH remains an area of active investigation.
This scoping review aims to synthesize the current evidence from preclinical and clinical studies exploring how the gut and local disc microbiota may contribute to LDH and its associated symptoms. We will also describe the different methods utilized to isolate and characterize microbial populations and explore the different thinking behind the presence of bacteria within the IVD (contamination vs. colonization). Eventually, we will discuss the potential mechanisms involved, including systemic immunomodulation, and microbial metabolite signaling, to elucidate how microbiome-related processes may drive the initiation, progression, and persistence of symptoms in LDH.
MATERIALS AND METHODS
This systematic review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR) guidelines [16]. The corresponding checklist was followed to ensure methodological completeness (see Supplementary Checklist). The review protocol was registered in the Open Science Framework database (https://osf.io/u58cp).
1. Literature Search
A systematic search of PubMed/MEDLINE and Scopus databases was conducted on June 23, 2025 for literature published from inception to June 2025. According to the SPIDER framework, we searched for studies including subjects affected by LDH (S) focusing on the analysis of disc and/or fecal microbiota (PI) within preclinical and clinical studies with cross-sectional or cohort study designs (D) to assess causal and/or correlative relationships with the occurrence, severity, and clinical outcomes of LDH (E). Only quantitative research studies including ≥10 patients with LDH per group were included (R). Duplicates, reviews, meta-analyses, case reports, letters to the editor, cadaveric studies, technical notes, commentaries, and articles written in languages other than English were excluded from the analysis. The complete search strategy is reported in Supplementary Material 1.
2. Study Selection
The initial literature search was independently conducted by 2 reviewers (SS and JS). Any discrepancies were resolved through discussion with a third reviewer (LA). The screening process followed a sequential approach: titles and abstracts were reviewed first, followed by full-text assessment of articles that were not excluded in the initial phase. Furthermore, references cited in the included studies were examined to ensure no relevant articles were missed. The study selection process is illustrated in a PRISMA flow diagram. Due to the heterogeneity of included studies’ designs, the limited amount of quantitative data, and the preliminary nature of the reports reviewed, no formal critical appraisal was performed.
3. Data Extraction
The following data were extrapolated: author and year of publication, country, study design, sample size, age, sex, LDH level(s), and presence of Modic changes. Fecal and/or IVD samples subjected to microbiome analysis were described in terms of sample type, time of sampling, sample storage and transportation, use of contamination and technical controls, microbial identification method(s), and histological observations. Prior antibiotic use (and relative regimen), number of culture- and sequencing-positive IVDs with identified microorganisms, arguments discussing specimen contamination versus primary disc colonization, and conclusions regarding the relationship between gut/disc dysbiosis and LDH were also extracted. Data were collected in tables and critically discussed below.
RESULTS
1. Study Extraction
A total of 876 studies were obtained through the initial search; 262 duplicates were removed, and 614 titles and abstracts were screened. After excluding 575 articles, 39 full-texts were assessed. Out of these studies, 13 were excluded for the following reasons: review articles (n=2), not specific to LDH (n=9), including less than 10 patients (n=2). Eventually, 26 articles were included (Supplementary Fig. 1).
2. Study Characteristics
Included studies consisted of 20 cross-sectional analyses of prospectively enrolled patients [17-36], 1 cross-sectional analysis of retrospectively collected samples [37], 2 experimental animal studies [38,39], and 2 case-control studies [40,41]. One study included both animal experiments and a cross-sectional analysis of prospectively enrolled patients [42]. These studies were published between 2006 [22] and 2025 [40] from Israel [22], Brazil [17,18], China [20,21,27,38-40,42], USA [27,29,33,36], Sweden [23], Iran [25,26,35], Denmark [32,41], UK [28], Czech Republic [24,30,37], France [31], and Russia [34]. General study characteristics are summarized in Table 1. In all included studies, patients were diagnosed with LDH through a combination of clinical symptoms of radiculopathy, and concordant physical examination and imaging findings (e.g., magnetic resonance imaging [MRI], computed tomography [CT]).
3. Relationship Between the Gut Microbiome and LDH
Animal models indicate that gut microbiota modulation influences pain, disc homeostasis, and host signaling in LDH (Supplementary Table 1). Two studies, one using pharmacological modulators with fecal microbiota transplantation (FMT) and another testing a probiotic, reported convergent findings. In a rat annular puncture model, Li et al. [38] showed that LDH altered gut microbiota composition, with increased Oscillospirales and Ruminococcaceae and reduced Bacilli and Lactobacillales. Treatment with palmitic acid and trans-4-hydroxy-3-methoxycinnamate reversed these changes, lowered inflammatory cytokines, and reduced dorsal root ganglion activity. Importantly, antibiotic depletion abolished these beneficial benefits, confirming a central role for the microbiota. In a similar mouse model, Wang et al. [39] demonstrated that LDH also induced gut dysbiosis, marked by higher Lactobacillaceae and Lactobacillus. Furthermore, oral administration of L. paracasei S16 restored balance (increasing Lachnospiraceae and Ruminococcaceae) which was complemented by reduced pain sensitivity, preserved IVD structure, suppressed inflammatory cytokines, and enhanced autophagy, alongside changes in serum metabolites and T-cell activity. Collectively, these preclinical studies indicate that LDH itself disrupts the gut microbiota, and that targeted interventions can remodel gut dysbiosis to attenuate neuroinflammation and improve pain outcomes, with causality supported by microbiota transfer and antibiotic ablation experiments.
Beyond animal models, an initial human study implicated gut microbiota and their systemic metabolites in the pathogenesis of LDH. Aboushaala et al. [33] investigated the role of gut dysbiosis in a surgical study of patients undergoing either microdiscectomy for LDH or fusion for symptomatic lumbar IDD with lumbar degenerative spondylolisthesis (LDS), from whom stool samples were collected preoperatively for 16s rRNA sequencing. After adjusting for age, body mass index, and sex, the gut microbiota of LDH patients demonstrated a decreased Bacillota to Bacteroides ratio and a lower abundance of the proinflammatory bacterial taxa CAG-352 and Dialister compared with LDS patients. Together, these animal studies and early human investigation provide preliminary evidence that gut microbiota composition may be linked to LDH, but findings remain heterogeneous.
4. Relationship Between the Local Disc Microbiota and LDH
Attention has also turned to the possibility of a local disc microbiota, challenging the long-held assumption of IVD sterility and raising the question of whether microbial colonization or dysbiosis contributes to LDH or vice versa. For this question, our scoping review identified only one preclinical study [42], involving a rabbit model that tested whether intradiscal bacteria can colonize and aggravate IDD. Following annular incision and direct inoculation with C. acnes, the microorganism was recovered from 61% of operated IVDs, whereas none yielded growth in animals in which incision-only or intravenous C. acnes was administered. MRI showed greater degeneration in inoculated discs, particularly those culture-positive. These findings suggest that direct intradiscal presence of C. acnes can worsen IDD in an LDH model, whereas transient bacteremia alone does not establish a local disc microbiota.
Human studies have also explored the possibility of a local resident disc microbiota in LDH, aiming to determine whether microbial presence can be detected in clinical samples. Several reports have demonstrated the recovery of low-virulence organisms (most commonly C. acnes) from excised IVDs, although positivity rates and interpretations vary considerably across cohorts and methods (Table 2). Agarwal et al. [36] reported bacterial growth in 19.2% of IVD cultures, with C. acnes accounting for 13.5% and Peptostreptococcus and Staphylococcus spp. comprising the remainder. Capoor et al. [30] found C. acnes in 40% of cases, with a significant correlation between bacterial counts in culture and C. acnes genome copies detected by real-time quantitative polymerase chain reaction (qPCR). Similarly, Salehpour et al. [35] identified microbial colonization in 50% of samples, 76.6% of which contained C. acnes. Rollason et al. [28] reported C. acnes growth in 38% and coagulase-negative staphylococci (CoNS) in 8% of disc cultures, and found that 52% of C. acnes strains belonged to type II and 11% to type III. These strains are not predominant on the skin, supporting the hypothesis that C. acnes detected in the disc tissue is unlikely to originate from skin contamination. Consistent findings were reported by Lan et al. [21], who found C. acnes in 30% of discs, with lineage analysis showing 39% type II and 22% type III strains. Capoor et al. [24] reported C. acnes in 32.3% of disc samples, with a total of 44% specimens testing positive for any bacterial growth. Microscopy further confirmed the presence of bacterial biofilms in samples positive for C. acnes. Ohrt-Nissen et al. [41] identified bacterial genomes in 31% of LDH patients and in 50% of controls undergoing anterior discectomy for spinal fracture or deformity. Importantly, inflammatory cells were observed in association with bacterial aggregates in 13% of LDH patients but in none of the controls, suggesting that biofilm formation may underlie infection in a subset of LDH cases.
Studies have also investigated the local disc microbiota and its relationship to disc herniation, IDD, and Modic changes. Although C. acnes has been frequently detected in lumbar disc samples, Javanshir et al. [25] found no difference in its prevalence between patients with cervical and LDH (36.0% vs. 38.0%), suggesting a potentially shared pathophysiological mechanism across different spine regions. Similarly, Coscia et al. [19] analyzed 30 cervical and 31 lumbar discectomy samples, reporting C. acnes in 12 and 5 cases, and CoNS in 3 and 12 cases, respectively. The authors observed that disc herniation was significantly associated with positive bacterial cultures compared with controls undergoing surgery for trauma or deformity. Tang et al. [20] reported C. acnes in 31.6% of and CoNS in 1.1%, with positive cultures associated with reduced disc height and younger age. In a subsequent study, Tang et al. [27] also found that bacterial presence (C. acnes and CoNS) was significantly associated with Modic changes, although no relationship was observed with the Pfirrman classification. Conversely, Astur et al. [17] identified 7 positive disc cultures (2 C. acnes-positive) but found no differences in Modic changes pre- or post-operatively at 1 year. Similarly, Fritzell et al. [23] isolated C. acnes from 32.5% of samples and found no association between bacterial presence and Modic changes. Other investigations, however, do support a link between bacterial colonization and Modic changes. Albert et al. [32] reported C. acnes-positivity in 40% of LDH samples and a small subset colonized by anaerobic bacteria, which were associated with the onset of new Modic changes within 1- to 2-year postsurgery in 80% of patients. Likewise, Aghazadeh et al. [26] found microorganisms in 50.0% of cultures (38.3% C. acnes), with Modic changes present in 35.0% of culture-positive patients. The association between C. acnes-positive discs and Modic changes was statistically significant, further supporting a possible microbial contribution to these endplate alterations.
Conversely, other studies have reported findings against the existence of a local disc microbiota. Alexanyan et al. [34] detected only 1 C. acnes-positive culture, which was attributed to tissue contamination. Similarly, Ben-Galim et al. [22] found only 4 aerobic cultures positive for CoNS, again suggesting contamination rather than true intradiscal colonization. In a study by Li et al. [42], prophylactic cefuroxime was administered to minimize contamination. None of the disc cultures were positive for C. acnes; however, 2 samples yielded CoNS, 1 chain-forming bacterium, and 1 S. epidermidis. Using molecular approaches, Alamin et al. [29] did not find signs of bacterial genome in any of the analyzed samples. Likewise, Astur et al. [18] identified traces of 45 different bacteria general remnants, yet C. acnes was absent from all the analyses. Collectively, these mixed findings illustrate the methodological challenges and interpretive limitations that continue to obscure the true relationship between microorganisms and the IVD environment.
5. Methods of Microbial Isolation and Characterization
Given the heterogeneity of findings, it is important to consider the different methods used to detect and characterize microorganisms in disc and fecal samples (Table 3). Conventional microbiological cultures were utilized in most studies, typically under both aerobic and anaerobic conditions [17,18,20-28,30-32,34-36,42], while a few reported anaerobic cultures only [19,37]. Capoor et al. [37] recultured IVD samples obtained from 2 previous studies [28,32] on blood agar plates to assess the β-hemolytic activity of isolated C. acnes strains. Beyond standard cultures, several papers [21,25,28,32] employed biochemical identification methods for the detection of C. acnes isolates, standard biochemical panels for Staphylococcus spp., and latex agglutination for clumping factor/protein A to distinguish between S. aureus and CoNS.
The most common quantitative approach performed to identify bacterial populations was 16S rRNA PCR, utilized in 12 studies [18,20,21,23,25-28,30,32,35,41]. with 2 reporting the use of amplicon sequencing to better characterize community composition [29,33]. Target regions of the 16S gene varied between reports, including V3 [18] and V4 [18,33] regions, and several authors referenced previously published 16S sequences for comparison [32,43-46]. For higher-resolution typing, Coscia et al. [19] utilized amplified fragment length polymorphism (AFLP) to produce and compare unique fingerprints for genomes of interest, allowing to differentiate among different C. acnes strains. In 2 studies [21,28]. C. acnes isolates were confirmed by 16S PCR and further assigned to phylogroups by recA gene sequencing and monoclonal-antibody immunofluorescence typing. Fritzell et al. [23] also employed whole genome sequencing and single-nucleotide polymorphisms (SNPs) to analyze the genetic relatedness among C. acnes isolates, while Ohrt-Nissen and colleagues [41] combined 16S PCR with Sanger sequencing to identify the bacteria.
Histological analysis was performed in 7 studies [17,21,24,28,32,34,41], with Gram staining being the most frequently reported technique for detecting microorganisms [19,32,35]. Alexanyan et al. [34] used periodic acid-Schiff and toluidine blue to evaluate extracellular matrix and von Kossa staining to assess calcification; no biofilm was identified in their series. Capoor et al. [24] utilized matrix-assisted laser desorption/ionization time-of-flight mass spectrometry for taxonomic identification of isolated colonies. Additionally, confocal scanning laser microscopy with SYTO9 staining and of fluorescent in situ hybridization of selected C. acnes-positive samples was used to detect bacterial biofilm, with the same approach being replicated by Ohrt-Nissen et al. [41] Finally, 2 studies from the same group [17,18] utilized next-generation sequencing (NGS) for deep bacterial microbiome profiling, whereas Yang et al. [40] employed 2bRAD-M sequencing to accurately characterize microorganisms in samples with low microbial biomass (such as the IVD) at a species-level resolution.
6. Microbial Contamination Versus Colonization/Infection
As previously discussed, investigators used heterogeneous methods to interrogate LDH samples for microbes (Table 4). The central interpretive question, namely whether the IVD is sterile (with positive results likely representing contamination) or whether colonization, infection, or local dysbiosis may contribute to LDH, was answered differently across studies. Eight of 23 studies (34.8%) concluded that most or all positive findings reflected contamination. Reasons clustered into 2 themes: (1) matching organisms in controls (e.g., ligamentum flavum, paraspinal muscles, wound/skin swabs) or in the operating environment [17,23,31], and (2) very low culture positivity (typically <10%, including two 0% series) despite careful harvesting techniques, reportedly inconsistent with true infection [18,22,29,34]. Notably, Astur et al. [18] detected 0% positive hits through culture methods, but still detected low-biomass, environmentally associated taxa (e.g., Ralstonia, Pseudomonas, Acinetobacter) on amplicon 16S rRNA, which the authors interpreted as reagent/handling background rather than in-disc bacteria. SNP-level concordance between skin and disc strains in Fritzell et al. [23] provided additional support for contamination of skin flora in their IVD cultures.
Conversely, 13 studies (56.5%) argued for true in-disc microbial colonization/infection in at least a subset of LDH patients. Eleven of these relied on culture, often recovering C. acnes and CoNS, and 6 added molecular or phenotypic corroboration, with a higher organism burden by C. acnes [30], as well as in situ aggregates/biofilm features or hemolytic phenotypes [24,37,41], and these colonization associated with Modic changes or disc height loss [20,26,27,32]. Counter to the work of Fritzell et al. [23], 2 studies showed non-skin-dominant C. acnes genotypes (types II/III) by AFLP and recA sequencing [19,28], suggesting their samples did not originate from skin contact contamination. Still, these studies varied in control rigor, and few reported on environmental or kit-blank controls and did not include other tissues as reference controls. Finally, 2 recent sequencing-forward papers illustrated the dysbiosis/low-biomass end of the spectrum. Astur et al. [18] found sparse, reagent-like signals with no culture growth, while Yang et al. [40] using 2bRAD-M reported a wide range of species present in discal samples, highlighting a species-level shift between Modic changes and LDH, even suggesting a clear “dysbiosis” aspect to play a role in both pathologies. Collectively, signals consistent with genuine low-grade colonization (organism burden, genotype patterns, biofilm-like aggregates, clinical associations) are counter-balanced by some contamination indicators (positive tissue/air controls, skin-disc strain matching, and uniformly low culture yield under strict definitions).
DISCUSSION
This scoping review synthesizes emerging evidence that both gut and disc microbial communities are plausibly involved in the pathophysiology of LDH. Although limited by diverse designs, methods, and quality, included studies collectively showed: (1) a bidirectional relationship between LDH and the gut microbiome in preclinical models; (2) presence of low-virulence bacteria (most commonly C. acnes) in a subset of surgically excised IVDs; and (3) methodological variability and contamination risk as major obstacles to causal inference.
1. The Gut-Disc Axis: Evidence and Mechanisms
Despite their preliminary nature, animal experiments [38,39] showed that annular injury-induced LDH altered gut microbial composition and that microbiome-targeted interventions (probiotics or active herbal constituents) could reverse dysbiosis, reduce neuroinflammation, preserve IVD structure, and lower pain sensitivity. Importantly, antibiotic ablation or FMT experiments support a primary role for microbiota-mediated mechanisms in these models. These preclinical data therefore support a biologically plausible mechanistic theory in which gut microbes and their metabolites modulate the systemic inflammatory response, nociceptive pathways, and IVD homeostasis [11]. Complementary human evidence is emerging but convergent in several aspects. Indeed, a recent Mendelian randomization analysis implicated specific gut microbial taxa and blood metabolites in IDD [47], suggesting at least partially causal, metabolite-mediated pathways. On the other hand, surgical cohort stool studies showed altered fecal community structure in LDH compared with other lumbar pathologies [33].
2. Local Disc Microbiota: Colonization or Contamination?
Whether the IVD is truly sterile, or whether low-biomass colonization contributes to IDD and LDH, remains debated. Across clinical series, C. acnes remains the most frequently recovered organism and several groups have reported supportive findings. These include the identification of quantitative bacterial burden, non–skin-dominant phylogroups, hemolytic phenotypes, in situ aggregates or biofilm-like structures, that argue against simple perioperative contamination in at least a subset of IVDs (Table 2). On the other hand, opposing evidence includes many studies with minimal or no bacterial presence, frequent recovery of similar taxa from adjacent tissues, and NGS reads dominated by taxa typically associated with environmental or reagent background. Taken together, the available evidence suggests that microbes are unlikely to be universal drivers of LDH, but intradiscal colonization or localized dysbiosis may exist in a distinct phenotypic subgroup and could contribute to specific downstream features such as Modic changes, persistent inflammation, or pain sensitization [11,48].
3. LDH, Pain, and the Microbiome
The relationship between gut microbiota alterations and chronic pain has already been demonstrated in clinical contexts other than LDH. Indeed, the microbiota is able to secrete a wide array of mediators, which can exert local and systemic effects. Short-chain fatty acids (SCFAs) and bile acids influence epithelial and immune cell function, alter intestinal permeability and mucosal inflammation, and thereby modulate visceral pain thresholds in conditions such as irritable bowel syndrome and inflammatory bowel disease [49]. Nonetheless, gut dysbiosis and changes in microbiota composition, especially related to butyrate metabolism, have been implicated in chronic pain syndromes with non-visceral symptoms, such as fibromyalgia [50]. Additionally, the gut microbiota is also involved in the release of proinflammatory cytokines and neurotransmitters (e.g., serotonin, gamma-aminobutyric acid, glutamate, dopamine etc.), thus establishing a bidirectional communication between the gut and brain. In this regard, alterations of the gut microbiota have been documented in several neurological disorders, such as spinal cord injury, neuropathic pain, chronic constriction injury, and neurodegenerative diseases including Alzheimer disease, Parkinson disease, multiple sclerosis, etc [12,51]. As the pathophysiological role of gut dysbiosis and microbial colonization in tissues dogmatically considered sterile is becoming increasingly evident [52,53], a novel theory of IDD as the result of a chronic, subclinical infection has been recently proposed [11]. Rajasekaran et al. [54] demonstrated that healthy and degenerated IVDs are colonized by substantially different microbial populations, with Firmicutes, Actinobacteria and Saccharopolyspora (associated with barrier function and antibacterial properties) prevailing in the former, and Bacillus spp. and Pseudomonas spp. (correlated with infectious diseases) being abundant in the latter. Interestingly, these IVD microbial compositions are not fixed but might assumingly change based on different health conditions, diet, and both local and systemic events, across a complex brain-gut-disc axis (Fig. 1). These concepts are substantiated by a growing body of multiomics studies showing that changes in the gut microbiome observed in patients with IDD are part of a wider pattern of microbial signatures seen across several spinal conditions, including LDH, LDS, and endplate changes. Fang et al. [55] demonstrated that an increased genetic liability to the Eubacterium coprostanoligenes group lowers the odds of IDD while higher abundance of Marvinbryantia raises such a risk. Zheng et al. [47] conducted a bidirectional Mendelian randomization in individuals with IDD, also including patients with LDH. Six gut microbial taxa were identified: Comamonas B, Halomonadaceae, Lachnospirales and UBA6960 were linked to a higher risk, whereas Pseudomonadales and Blautia hansenii were associated with a lower risk. The authors next identified 21 circulating metabolites associated with IDD and showed that part of the microbial effects were mediated through systemic metabolic pathways, including amino acid and energy metabolism.
Traditionally, research on LDH has focused on mechanical root compression as the primary source of pain. However, recent clinical studies have shown that IVD inflammation is also a significant contributor to pain, even in the absence of overt nerve root compression or spinal stenosis [56,57]. When considered alongside the emerging gut-brain-disc axis theory, these findings highlight the gut microbiome as a key factor in the pathogenesis of LDH. Comamonas B and the family Halomonadaceae have been found to increase IDD (including LDH) risk, and that 9%–13% of this effect was transmitted through the tryptophan catabolites 1,3-dimethylurate and 3-hydroxy-2-methylpyridine sulfate [47]. Both metabolites enter the kynurenine pathway; downstream ligands such as quinolinic acid and 3-hydroxykynurenine excite N-methyl-D-aspartate and aryl-hydrocarbon receptors on dorsal root ganglion neurons and macrophages, thereby lowering nociceptive thresholds [58]. Although Zheng et al. [47] refer to their included IDD cohorts at times as patients with LDH, our examination of the underlying Finnish cohort (FinnGen, phenotype ID: “CD-10—M51, ICD-9—722, and ICD-8—725 [excluding ICD-9—7220|7224|7227|7228A], and ICD-8—7250”) indicates that it represents a broader population encompassing various IVD disorders, not specifically LDH. On the other hand, Blautia hansenii raised systemic histidine levels, a precursor of the inhibitory neuromodulator histamine, suggesting that the metabolome can dampen or amplify discogenic pain [59]. Another study found that microbiota-derived butyrate reinforced the blood-disc barrier, suppressed nuclear factor-kappa B signaling, and reduced the production of proinflammatory cytokines by NP cells in vitro [60].
A central debate in current research is whether specific microbes drive pathology in LDH, or whether the key mediators are their downstream metabolites. Clinical microbiome studies have shown single-genus dominance and shifts in microbial composition that induce strain-specific neuronal inflammatory responses, independent of general systemic inflammation. However, emerging evidence supports a metabolite-centric model, highlighting distinct genetic and signaling pathways that link dysbiosis to IDD. This reaffirms the gut-disc axis hypothesis in which broad microbial endotoxaemia contributes to systemic inflammation, while discrete pathobionts generate targeted pain signals within the degenerative IVD.
4. LDH, Inflammation, and Dysbiosis
Systemic inflammation resulting from gut dysbiosis has been consistently associated with its pathogenesis. Elevated levels of inflammatory cytokines have been observed in patients with LDH, suggesting that immune activation plays a contributory role in disease progression. In LDH, blood and tissue studies consistently demonstrate a shift toward the Th17 axis. Patients with ruptured discs show higher circulating IL-17–producing CD4+ cells than those with contained protrusions, and IL-17 concentrations correlate with pain intensity [61]. On the other hand, regulatory T cells (Tregs) normally restrain disc inflammation, and reduced levels of Tregs have been correlated with postoperative pain [62]. SCFAs, especially butyrate, expand colonic Tregs and signal through G-protein-coupled receptors on macrophages [63]. Lipopolysaccharide (LPS) leakage accompanying dysbiosis also provides a macrophage-priming signal [64]. Age-related microbial shifts increase intestinal permeability and systemic LPS, producing macrophages with exaggerated TNF and IL-6 output [65]. These cytokines up-regulate matrix-degrading enzymes and promote neovascular invasion, both findings associated with LDH. Once the annulus fissures, the NP meets an environment already conditioned by dysbiosis, fueling an amplified inflammatory response that degrades proteoglycans and encourages nociceptive fiber proliferation and activation [48,66]. Further studies are required to validate whether this inflammatory climate drives degeneration of the AF and cartilaginous endplate, after which commonplace mechanical loads lead to LDH. Therapeutically, restoring immune balance with next-generation probiotics that favor Treg induction, or with butyrate analogues, represents a plausible strategy to arrest the degenerative and inflammatory vicious cycle before LDH occurs.
5. Limitations in Current Evidence
This review highlighted several important limitations. First, much of the available literature is preliminary and methodologically heterogeneous: most human studies are cross-sectional or small case-control series, with only limited animal experiments and few prospective clinical investigations. Heterogeneity in sample size, patient selection, and control groups prevent robust quantitative synthesis and limits causal inference. Indeed, at the present time, the role of the microbiome in LDH and IDD is only supported by correlative rather than causative data. Second, there is substantial variability in sampling and laboratory methods across studies. Timing and technique of intraoperative sampling, perioperative antibiotic strategies, the routine (or lack of) use of negative controls (e.g., kit blanks, environmental swabs), and diverse culture and sequencing pipelines (different 16S targets, variable DNA extraction and amplification strategies) create inconsistencies that increase the risk of false-positive and false-negative results, complicating between-study comparisons. Third, the intradiscal niche presents technical challenges: low microbial biomass and potential biofilm formation hinder isolation by conventional culture, while low-biomass sequencing studies are especially vulnerable to reagent and environmental contamination. Fourth, microbial detection in most studies has been restricted to bacteria, while fungi, archaea, and viral communities remain largely unexamined, underscoring the need for more species-agnostic and comprehensive multi-kingdom microbiome profiling approaches. Fifth, the predominance of cross-sectional designs prevents assessment of temporality: it remains unclear whether dysbiosis precedes and contributes to LDH and pain, or whether disc pathology and pain alter the microbiome.
While the current evidence remains insufficient to define clear clinical applications, accumulating genetic and mechanistic data justify further investigation. Future studies could examine whether gut microbiota modulation, through diet, probiotics, or other targeted interventions [67], can influence disc health or symptom trajectories. Given that LDH often resolves spontaneously [68], approaches that reduce neuroinflammation or pain via gut-disc interactions could potentially lessen surgical needs. Microbiome- based or probiotic adjuncts may also complement standard treatments such as microdiscectomy, chemonucleolysis, or fusion to enhance recovery and tissue healing. In parallel, systematic and contamination-controlled profiling of microbial signatures within discal tissues may aid diagnostic, prognostic, and mechanistic stratification in LDH and IDD, and could potentially reveal microbial patterns indicative of an LDH-specific subphenotype [69].
CONCLUSION
The current evidence suggests the biological plausibility of microbiome-related processes in LDH, acting both through systemic mechanisms and, in a subset of patients, via local low-biomass intradiscal colonization or dysbiosis. However, the body of evidence is heterogeneous and of variable quality, and does not yet justify changes to clinical management such as routine antibiotic therapy outside clearly established infectious processes. Progress in this field will require contamination-aware, standardized, and multimodal investigations as well as mechanistic studies to clarify the pathophysiological role of the disc microbiome in LDH.
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