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

Journal of Orthopaedic Surgery and Research volume 19, Article number: 476 (2024) Cite this article

Abstract

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.

Introduction

Low back pain (LBP) is a widespread condition that carries a significant burden, causing considerable disability and frequent absenteeism from work globally [1, 2]. According to statistics, approximately 80% of all people experience back pain at some point [3]. Intervertebral disc degenerative IVDD is a common spinal degenerative disease characterized by a gradual decrease of proteoglycan content and water content in the nucleus pulposus (NP) [4]. This pathological process may ultimately lead to the rupture of the intervertebral disc, making the disc more prone to protrusion. When such protrusion compresses the spinal cord or nerve roots, it can cause symptoms of LBP [4]. Notably, when the nerve roots in the L4-S1 region are compressed, patients often exhibit sciatica symptoms. Therefore, IVDD is not only an essential pathological basis for lower back pain (LBP) but also a critical factor in causing sciatica [5].

Research has shown the presence of microorganisms in intervertebral discs, and the abundance of bacteria varies between healthy and degenerative intervertebral discs [6]. The presence of low-virulence bacteria may be caused by colonization and can cause subclinical intervertebral disc infections, mediating IVDD and LBP [7, 8]. Currently, the vast majority of studies indicate that the primary pathogen of this low-virulence bacterium is Propionibacterium acnes [9], a Gram-positive, oxygen-tolerant anaerobic bacterium and an average bacterial population distributed in the skin. It belongs to an opportunistic pathogen that can cause infections outside of the skin, such as in bones and joints [10]. In 2001, Stirling et al. [11]. first detected P.acnes in degenerated intervertebral disc tissue and proposed that P.acnes may be one of the causes of intervertebral disc degeneration. Subsequently, multiple studies have explored the connection between them. A meta-analysis study reviewed 4109 patients and found that the low-grade bacterial infection rate was 30% (24 -37%), with P.acnes being the most common, accounting for 66.7% of bacterial-positive intervertebral discs [12]. Therefore, many researchers support the correlation between P.acnes and IVDD, LBP, and sciatica. However, some researchers oppose the impact of low-virulence bacteria on intervertebral discs and propose contamination theories. In short, current surgical or radiological guidance cannot wholly separate intervertebral disc tissue [13]. P.acnes can be cultured not only in intervertebral disc tissue, but also in muscle tissue, ligamentum flavum, and even operating room air [14], resulting in symbiotic bacterial contamination in the skin or muscles. A meta-analysis suggests that there is currently insufficient evidence to attribute low-virulence organisms to IDD, LBP, and disability [15]. There is still controversy over the relevant theories at present.

P.acnes, as a symbiotic bacterium located on the skin or oral cavity [10], may invade the circulatory system and colonize intervertebral discs when the skin or mucosa ruptures [9, 16]. Similarly, other skin microbiota, such as coagulase-negative Staphylococcus (CoNS) [17], may colonize intervertebral discs or indirectly affect intervertebral disc degeneration through a similar process. Rajasekaran et al. [6]. proposed the concept of the skin-spine microbiota axis. They found 29 common bacteria between the skin and IVD microbiota, indicating that the skin microbiota may be the source of the intervertebral disc microbiota. However, the impact and potential mechanisms of these skin microbiota on IVDD, LBP and sciatica are still unclear, and the intermediate processes are complex and susceptible to contamination theory, confounding factors and reverse causality [18]. Mendelian randomization (MR) provides an effective method for inferring causal relationships by utilizing genetic variation as an instrumental variable (IV). It imitates the causal reasoning of randomized controlled trials, effectively minimizing the influence of confounding factors and reversing the causal bias often encountered in observational studies [19, 20]. Therefore, MR provides a precise tool to address the limitations above. Our study utilized dual sample MR to investigate the causal relationship between skin microbiota, particularly Propionibacterium acnes, and IVDD, LBP, and sciatica.

Methods

Study design

This study complies the STROBE-MR guidelines [21]. Figure 1 illustrates the study’s overall framework. Our analysis used two-sample MR to assess the potential causal relationships between skin microbiota and IVDD, LBP and sciatica. Mendelian randomization depends on three crucial assumptions: firstly, that the chosen instrumental variables exhibit a robust association with the exposures being studied; secondly, that these instrumental variables are not influenced by confounding factors that might impact both exposures and outcomes; and thirdly, that there is no direct link between the instrumental variables and the outcomes themselves [21].

Fig. 1
figure 1

Diagrammatic Illustration of this study. IVs, instrumental variables; IVDD, intervertebral disc degeneration; LBP, low back pain

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Data sources

The summary statistics for 150 skin microbiota were derived from the GWAS catalog (GWAS ID from GCST90133164 to GCST90133310). This extensive study encompassed the sequencing data of the 16 S rRNA gene, collected from meta-analyses of two population-based GWAS in Germany, including 1656 skin samples taken from dry skin (dorsal and volar forearm), moist (antecubital fossa) and sebaceous (retroauricular folds and forehead) skin microenvironment. The skin microbiota encompassed three phyla, four classes, seven orders, seven families, fifteen genera and forty-three ASV [22]. The GWAS summary data for IVDD (ncase = 20,001, ncontrol = 164,682), LBP (ncase = 13,178, ncontrol = 164,682) and sciatica (ncase = 19,509, ncontrol = 199,283) were obtained from the IEU Open GWAS project. Table 1 shows detailed information on the data sources.

Table 1 Detailed information on the GWAS summary data for skin microbiota, IVDD, LBP and Sciatica
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Instrumental variables selection and data harmonization

The following steps filtered the instrumental variables: (1) SNPs were selected based on their genome-wide significance thresholds significantly associated with skin microbiota (P < 5 × 10− 8). However, the number of instrumental variables for some skin microbiota was less than 3 and was no longer suitable for further MR analysis. Therefore, for this part of exposre, we used a liberal significance threshold (5 × 10− 6) [23]; (2) linkage disequilibrium was removed from the selected SNPs, with an r2 threshold set to < 0.001 and a clustering distance of 10000kb [24]; (3) palindromic SNPs were excluded through data harmonization [25]; (4) the F-statistic was computed for each instrumental variable (IV), and those having an F-statistic value below ten were excluded to reduce weak instrument bias. The calculation of the F-statistic was based on the formula: F = r2 (n-2)/(1-r2) [26]. (5) The LDtrait tool (https://ldlink.nih.gov/?tab=ldtrait) was used to examine each IV and excluded SNPs associated with confounding factors [27]. Finally, we obtained the required instrumental variables.

Mendelian randomization analysis

We used a two-sample MR to assess the effects of skin microbiota on IVDD, LBP, and sciatica. The primary research method used was inverse variance weighting (IVW). Without directional pleiotropy, the IVW method can provide a relatively stable and accurate causal assessment by combining the Wald estimates of each IV [28]. When the Cochran Q test suggests the existence of potential heterogeneity, a random-effects IVW model is employed. Conversely, in cases where significant heterogeneity is absent, a fixed effects IVW model is utilized [29]. In addition, MR-Egger and weighted median serve as supplementary methods for estimating causal effects. MR-Egger is based on the assumption of InSIDE. This method can provide relatively robust estimates and evaluate horizontal pleiotropy through intercept terms. Weighted median can provide a robust estimate of causal effects, even with up to 50% of invalid IVs [28]. When the direction of IVW is consistent with that of the supplementary method, the results are stable [21]. To investigate the direct effects of skin microbiota on IVDD, LBP and sciatica, we used multivariate Mendelian randomization (MVMR), an MR method that allows for the co-detection of multiple risk factors, to adjust for potential confounding effects of BMI and smoking status [30]. Given the intimate association between Propionibacterium acnes and IVDD, LBP, and sciatica, we further investigated the impact of outcomes on exposure.

Sensitivity analysis

We conducted a sensitivity analysis on all obtained MR results, including heterogeneity and horizontal pleiotropy analysis. Specifically, Cochran’s Q statistics for the IVW method were used to evaluate whether MR results had heterogeneity, and when Q_pval was less than 0.05, it indicated the existence of heterogeneity [29]. The MR Egger intercept test was employed to detect the presence of horizontal pleiotropy in the MR results, where P < 0.05 indicated horizontal pleiotropy [31]. Additionally, the MR-PRESSO test was utilized to identify and exclude outliers, an additional means to detect horizontal pleiotropy. After excluding outliers, MR analysis will be conducted again [32]. The Leave-one-out sensitivity analysis was to remove each SNP one by one and subsequently perform the MR analysis again to identify influential outliers [33]. The results of these sensitivity analyses were used to evaluate the reliability of MR results.

All MR results were obtained using the “TwosampleMR” package in the R studio software.

Result

Instrumental variables selection

After the above screening steps, 553 (genome-wide significance threshold, P < 5 × 10− 8) and 994 (liberal significance threshold, P < 5 × 10− 6) SNPs were selected as instrumental variables for skin microbiota, and all F-statistics were greater than 10 (Supplementary Tables S1).

At the genome-wide significance threshold (5 × 10− 8), Causal effects of skin microbiota on IVDD LBP and sciatica

Using IVW analysis as our primary approach, we identified 6 skin microbiota taxa (five Amplicon Sequence Variant and one genus) that have a causal relationship with IVDD, LBP, and sciatica at the genome-wide significance threshold (5 × 10− 8). Specifically, ASV065 [Finegoldia (unc.)] from dry skin (OR = 0.968, 95%CI = 0.945 to 0.992, P = 0.008) was associated with a reduced risk of IVDD. Besides, ASV045 [Acinetobacter (unc.)] from dry skin (OR = 0.977, 95%CI = 0.957 to 0.997, P = 0.023), ASV065 [Finegoldia (unc.)] from dry skin (OR = 0.976, 95%CI = 0.957 to 0.995, P = 0.013) and Genus Rothia from dry skin (OR = 0.966, 95%CI = 0.933 to 1.000, P = 0.049) were related to a reduced risk of LBP. ASV010 [Staphylococcus (unc.)] from dry skin (OR = 1.038, 95%CI = 1.015 to 1.062, P = 0.001) was thought to be linked to an elevated risk of LBP. Moreover, ASV010 [Staphylococcus (unc.)] from dry skin (OR = 1.024, 95%CI = 1.005 to 1.044, P = 0.014) were considered to be associated with an increased risk of sciatica (Fig. 2). The scatter plots illustrates the causal relationships between 6 skin microbiota and IVDD, LBP and sciatica (Figure S1). The reverse MR indicates no evidence to suggest a reverse causal relationship between the above MR result (Supplementary Tables S3).

Fig. 2
figure 2

Forest plot shows the causal effects of skin microbiota on IVDD, LBP and sciatica at the genome-wide significance threshold (5 × 10− 8). ASVs, amplicon sequence variants; OR, odds ratio; CI, confidence interval

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At the liberal significance threshold (5 × 10− 6), Causal effects of skin microbiota on IVDD LBP and sciatica

IVW analysis indicated that 5 skin microbiota taxa (two Amplicon Sequence Variants and three Genus) were causally related to IVDD, LBP and sciatica at the liberal significance threshold (5 × 10− 6). ASV001 [P.acnes] from sebaceous skin environments (OR = 0.955, 95%CI = 0.914 to 0.997, P = 0.038) were associated with reduced risk of IVDD. ASV054 [Enhydrobacter (unc.)] from moist skin (OR = 1.032, 95%CI = 1.009 to 1.056, P = 0.007), Genus Bacteroides from dry skin (OR = 1.020, 95%CI = 1.010 to 1.031, P < 0.001) and Genus Kocuria from dry skin (OR = 1.009, 95%CI = 1.001 to 1.018, P = 0.034) were identified as being association with an increased risk of IVDD. Besides, Genus Streptococcus from moist skin (OR = 1.035, 95%CI = 1.004 to 1.067, P = 0.026) was considered to be associated with an increased risk of sciatica (Fig. 3). The scatter plots illustrate the causal relationships between 5 skin microbiota and IVDD, LBP and sciatica (Figure S2). The reverse MR indicates no evidence to suggest a reverse causal relationship between the above MR result. (Supplementary Tables S3)

Fig. 3
figure 3

Forest plot shows the causal effects of skin microbiota on IVDD, LBP and sciatica at the liberal significance threshold (5 × 10− 6). ASVs, amplicon sequence variants; OR, odds ratio; CI, confidence interval

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Causal effects of Propionibacterium acnes on IVDD, LBP and Sciatica

Numerous studies have implicated Propionibacterium acnes in the pathogenesis of IVDD, LBP and sciatica, so we further evaluated their association. The IVW analysis showed that P.acnes in sebaceous skin environments (OR = 0.955, 95%CI = 0.914 to 0.997, P = 0.038) were associated with reduced risk of IVDD. In addition, other MR results were not significant. Therefore, there was no evidence to suggest skin-derived P.acnes was a risk factor for IVDD, LBP, and sciatica (Fig. 4). However, when exploring the causal effects of IVDD, LBP and sciatica on P.acnes, we found that IVDD increased the abundance of P.acnes derived from moist skin (OR = 1.800, 95%CI = 1.131 to 2.866, P = 0.013, Fig. 5).

Fig. 4
figure 4

Forest plot shows the causal effects of Propionibacterium acnes on IVDD, LBP and sciatica. ASVs, amplicon sequence variants; IVDD, intervertebral disc degeneration; LBP, low back pain

Full size image
Fig. 5
figure 5

Forest plot shows the causal effects of IVDD, LBP and sciatica on Propionibacterium acnes. ASVs, amplicon sequence variants; IVDD, intervertebral disc degeneration; LBP, low back pain

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MVMR

To determine whether the statistically significant skin microbiota we had observed directly or indirectly affected the risk of IVDD, LBP and sciatica through confounding factors, we had conducted additional MVMR analysis to adjust for the effects of BMI and smoking. We found that after adjusting for BMI and smoking, the impact of Genus Bacteroides and Kocuria from dry skin on IVDD were still significant. In contrast, the impact of ASV065 [Finegoldia (unc.)] from dry skin on IVDD and various skin microbiota on LBP and sciatica were no longer significant. In addition, the impact of P.acnes in sebaceous skin environments on IVDD was attenuated with adjustment of BMI (Fig. 6).

Fig. 6
figure 6

Forest plot illustrates the effects of skin microbiota on IVDD, LBP and sciatica, with adjustments made for confounding factors including BMI and smoking using MVMR

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Sensitivity analysis

We conducted a sensitivity analysis on all MR results. Specifically, Cochran’s Q test using the IVW method revealed heterogeneity in the MR results of ASV065 [Finegoldia (unc.)] from dry skin on IVDD (Q_pval = 0.038). Furthermore, the MR-Egger intercept and MR-PRESSO test demonstrated no horizontal pleiotropy in all MR results (Supplementary Tables S2). In addition, the MR leave-one-out sensitivity analysis revealed that all MR results remained stable after excluding IVs one by one (Figure S3-S4). The above sensitivity analysis results indicate that the MR results are stable and reliable.

Discussion

In this study, we first reported the relationship between skin microbiota, particularly P.acnes, IVDD, LBP, and sciatica, using two-sample Mendelian randomization. Our research indicated five skin microbiota were associated with IVDD, four with LBP, and two with sciatica. Specifically, IVDD was found to increase the abundance of P.acnes in moist skin. The sensitivity analysis results indicate that our MR results are stable and reliable, and the reverse MR results indicate that there is no reverse causal relationship between our MR results.

Propionibacterium acnes plays a pivotal role in maintaining skin health and homeostasis. However, they are also opportunistic pathogens closely associated with acne vulgaris [34]. When it infiltrates intervertebral discs, it can lead to IVDD, LBP and sciatica [10]. Senker et al. [35] found that 38.78% of samples cultured for intervertebral disc bacteria were positive, with P.acnes (18.05%) being one of the most commonly detected microorganisms. Albert et al. [36]. found that among 61 patients with lumbar disc herniation, 46% of them found microorganisms in the IVD tissue, with the most common being P.acnes. In addition, a randomized, controlled, double-blind trial was conducted on 162 patients with discogenic back pain, and the relief of back pain in the antibiotic treatment group was significantly higher than that in the placebo group [37]. Injecting p.acnes into the intervertebral discs of mice and rabbits can cause intervertebral disc modic changes [38, 39]. Therefore, P.acnes is likely associated with intervertebral disc degeneration.

Propionibacterium acnes may enter the intervertebral disc through multiple pathways. One possible method is for P.acnes to enter through the circulatory system [36]. P.acnes have the opportunity to invade the bloodstream when the skin or mucous membranes are damaged [9, 16]. Due to the aerobic environment of human blood, P.acnes has not shown any harm to the human body at this time. When the annulus fibrosus breaks, neovascularisation will provide a potential pathway for P.acnes to enter the nucleus pulposus [40]. The lack of blood vessels, sufficient water, low oxygen pressure, and pH-neutral “biofilm-like” structure in the intervertebral disc provides a suitable environment for the survival of P. acnes [17]. Another possible pathway is through the action of macrophages. Macrophages may engulf Propionibacterium acnes and accumulate around the ruptured annulus fibrosus [41, 42]. Finally, P.acnes entering the intervertebral disc may also originate from iatrogenic infections. Surgery or injections may introduce bacteria into the intervertebral disc [43].

Although there are multiple possible pathways, further research is needed to clarify the exact mechanism by which P.acnes enters intervertebral discs. When the abundance of P.acnes distributed on the skin increases, regardless of the potential mechanism through which P.acnes enters the intervertebral disc. It is possible to increase the risk of its colonization in the intervertebral disc. However, we concluded that P.acnes derived from the skin is not a risk factor for intervertebral disc degeneration. In other words, skin-derived P.acnes may be challenging to colonize intervertebral discs or may not significantly promote intervertebral disc degeneration. However, we cannot completely deny the impact of P.acnes on intervertebral disc degeneration. This is because P.acnes is widely distributed and may have other sources or enter the intervertebral disc through other means. For example, P.acnes is a resident bacterial community in the oral cavity [10]. Brushing teeth can cause P.acnes to enter the bloodstream, forming bacteremia [44]. The nucleus pulposus is in an anaerobic environment, and when the intervertebral disc degenerates, protrudes, or the annulus fibrosus ruptures, neovascularisation can be formed locally, becoming the entrance for P.acnes to enter the degenerated intervertebral disc [40]. P.acnes are classified into types I, II, and III, with type I further divided into four subtypes: IA1, IA2, IB, and IC [45]. Rollason et al. [46]. found a positive rate of 38% for P.acnes in 64 intervertebral disc specimens, with type II P.acnes accounting for the majority. However, the P.acnes that colonizes the skin are mainly type I, further indicating that these P.acnes may not originate from the skin.

Our research indicated that P.acnes derived from sebaceous glands can have a protective effect on IVDD. It may cause adaptive immunity, making it more difficult for P.acnes from other sources or other pathogens to evade the immune system and colonize the IVD [47]. In addition, studies have shown that the relative abundance of P.acnes in the skin of patients with acne vulgaris is comparable to that of healthy individuals. However, there are differences in classification [48]. Type IA1 is the primary strain type in the hair follicles of acne patients [49]. Different types of P.ances play various roles in IVDD. However, the GWAS summary data of this study did not strictly classify P.ances, which may be another reason why P.ances was not related to IVDD, LBP, and sciatica in this study.

Furthermore, numerous studies have proposed that the detection of P. acnes in intervertebral discs may be attributed to skin contaminants [50]. Carricajo et al. [14]. found only 2 cases of P.acnes infection in 54 lumbar disc tissue testing cases. Still, the detection rate of Propionibacterium acnes was as high as 29.6% in the control group samples of operating room air, yellow ligament, and muscle. Out of 120 samples obtained under strict aseptic conditions, 116 were sterile, 4 tested positive for coagulase-negative Staphylococcus aureus, and no samples tested positive for P.ances, supporting the contamination theory [51]. A recent prospective cohort study showed that less than 2% of patients with intervertebral disc herniation can detect the presence of infectious bacteria. P.acnes was not detected in any intervertebral disc tissue, and there was no significant correlation between positive tissue infection and any clinical prognostic factors [52]. Using anterior surgery with relatively less contamination, 379 intervertebral disc samples were cultured, and only 2 cases were cultured for P.acnes, while 4 cases were cultured for other bacteria, suggesting contamination [53]. Our research adds to this discourse, revealing that IVDD promotes an increased abundance of Propionibacterium acnes on the skin through specific undisclosed mechanisms. This finding supports the contamination theory, suggesting that the high abundance of P.acnes detected in cultures may originate from the skin.

Coagulase-negative staphylococci, such as S.epidermidis, S.capitis and S.hominis [54, 55], are the second most commonly detected group of bacteria after P.acnes [17]. Arndt et al. [56]. found that 16 out of 40 intervertebral discs tested positive for coagulase-negative staphylococci. Due to the similar characteristics of CoNS and P.acnes, they may implant into intervertebral discs resembling biofilms through a similar process [17]. In our study, ASV010 [Staphylococcus (unc.)] was identified as a risk factor for lower back pain (LBP) and sciatica. This bacterial community may belong to CoNS [22], which confirms previous research findings. S.epidermidis is the most common CoNS, which appropriately regulates protective immune responses when encountering pathogens [55]. The protease Esp produced by it can interfere with forming Staphylococcus aureus biofilm but can also degrade human complement component C5 and fibrinogen [57]. S.epidermidis can cause host diseases through virulence factors such as proteases (serine and cysteine proteases), lipases, and hemolysins [54]. After injecting S.epidermidis into the cervical intervertebral disc of mice, the intervertebral discs and subchondral bone structures are destroyed, and bone fusion occurs after discitis [58]. S.hominis is the second most common CoNS in healthy human skin [59] and is considered as a beneficial commensal bacterium that plays a vital role in maintaining skin health [60]. S.capitis infection has been described as associated with prosthetic joint infection [61]. However, although these bacterial communities belong to CoNS, we found no association between them and IVDD, LBP or sciatica in our study. There are numerous types of CoNS, and future research should attempt to distinguish the effects of different bacterial genera in CoNS on IVDD, as they may play various roles.

Furthermore, a study revealed the presence of Enhydroxide, Acinetobacter, Kocuria, Rothia and Streptococcus in IVD tissues [6]. The abundance of Enhydroactor is associated with psoriasis and diabetic foot ulcer [62, 63]. Our research indicates that Enhydroxybacter has the potential to increase the risk of IVDD. Unclassified Acinetobacter from dry skin environments exhibit potential protective effects against LBP and sciatica. Notably, Acinetobacter infrequently causes human infections and belongs to the aerobic bacterial group [64], so its colonization in IVD may be difficult. Interestingly, Acinetobacter johnsonii negatively correlates with the secretion of IL-4 and TNF-α [65], suggesting that certain skin-derived Acinetobacter species may possess anti-inflammatory properties. Kocuria species are catalase-positive and coagulase-negative Gram-positive coccoid bacteria [66]. Although it is relatively rare, it can cause serious infection [66]. We found that genus Kocuria is a risk factor for intervertebral disc degeneration. However, identifying Kocuria is complex, and there is a high possibility of misidentifying Kocuria as a coagulase-negative Staphylococcus based on Gram staining, catalase, and coagulase negativity [67]. In future research, attention should be paid to distinguishing between the two and being alert to their potential harm to intervertebral disc degeneration. Rothia spp. have been shown to interact with other microbiota through nitrate production, cross-feeding, and release of antimicrobial secondary metabolites to reduce the relative abundance of pathogens and maintain human health [68]. This may explain why it has a protective effect on LBP. Streptococcus alactolyticus and Streptococcus anginosus were found to only exist in degenerated intervertebral discs and not in healthy intervertebral discs [6], and their colonization in intervertebral discs may be harmful. The genus Bacteroides, characterized as Gram-negative, non-spore-forming, and strictly anaerobic bacteria [69], poses a potential risk for colonizing the IVD, thus explaining its association as a risk factor for IVDD. Finegoldia, an anaerobic bacterium considered an opportunistic pathogen [70] associated with physiological joint infections [71], surprisingly demonstrates protective potential against IVDD and LBP in our findings. From the MVMR results, we can conclude that the influence of skin microbiota on LBP and sciatica is easily influenced by BMI and smoking. Genius Bacteroides and Kocuria are not affected by the confounding effects of BMI and smoking, and P.acnes may be confounded by BMI.

This study also has limitations. Firstly, due to data limitations, we can only establish the association between skin microbiota, rather than the microbiota within IVD, and IVDD, LBP, and sciatica through MR. Therefore, we cannot completely deny the role of P.acnes in intervertebral disc degeneration, and previous studies have found that P.acnes in IVD may have other sources. Secondly, strict genome-wide significance thresholds (P < 5 × 10− 8) for some exposed data limit the number of instrumental variables suitable for analysis. Therefore, the threshold must be relaxed to P < 5 × 10− 6. However, this may reduce the accuracy of these results. Furthermore, our results only apply to the European population, and their applicability to other races is uncertain. In addition, the exposed sample only contains 597 cases, and the small sample size may affect the accuracy of the results. Furthermore, although we controlled for potential confounding factors for each IV, the results of MVMR suggest that BMI and smoking status may still contribute to confounding our findings. Therefore, future research must carefully consider and control these potential confounding factors to obtain more accurate and reliable results.

Conclusion

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.

Data availability

The GWAS data used in this study are publicly available and can be obtained from GWAS Catalog (https://www.ebi.ac.uk/gwas/); IEU Open GWAS (https://gwas.mrcieu.ac.uk/datasets/); The summary data analyzed in this study can be obtained from articles and supplementary materials.

Abbreviations

GWAS:

Genome-wide association studies

MR:

Mendelian randomization

IVs:

Instrumental variables

IVW:

Inverse-variance weighted

SNP:

Single nucleotide polymorphism

MVMR:

Multivariate Mendelian randomization

MR-PRESSO:

MR pleiotropy residual sum and outlier

OR:

Odds ratio

CI:

Confidence interval

ASVs:

Amplicon sequence variants

IVDD:

Intervertebral disc degeneration

LBP:

Low back pain

CoNS:

Coagulase-negative Staphylococcus

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Tianjin Municipal Health Commission (Grant TJWJ2023XK023 to Baoshan Xu).

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  1. Yuchao Jia and Houcong Chen contributed equally to this work.

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  1. Department of Graduate School, Tianjin Medical University, Tianjin, 300070, China

    Yuchao Jia, Houcong Chen, Shengbo Huang & Zhenxin Huo

  2. Department of Minimally Invasive Spine Surgery, Tianjin Hospital, Tianjin University, Tianjin, 300211, China

    Baoshan Xu

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YJ: designed the study; YJ, HC, SH and ZH: writing - original draft preparation; YJ and HC: formal analysis and investigation; All authors: writing - review and editing; BX: supervision. All authors agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

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Jia, Y., Chen, H., Huang, S. et al. Causal effects of skin microbiota on intervertebral disk degeneration, low back pain and sciatica: a two-sample Mendelian randomization study. J Orthop Surg Res 19, 476 (2024). https://doi.org/10.1186/s13018-024-04980-w

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Journal of Orthopaedic Surgery and Research

ISSN: 1749-799X