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

Causal effects of skin microbiota on intervertebral disk degeneration, low back pain and sciatica: a two-sample Mendelian randomization study | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Causal effects of skin microbiota on intervertebral disk degeneration, low back pain and sciatica: a two-sample Mendelian randomization study Yuchao Jia, Houcong Chen, Shengbo Huang, Zhenxin Huo, Baoshan Xu This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4643600/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 13 Aug, 2024 Read the published version in Journal of Orthopaedic Surgery and Research → Version 1 posted 11 You are reading this latest preprint version 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. Results MR revealed three skin microbiota associated with IVDD, five associated with LBP, and five with sciatica. Specifically, there was no significant causal relationship between skin-derived P.acnes and IVDD, LBP and sciatica; IVDD was found to increase the abundance of P.acnes. Furthermore, ASV010 [Staphylococcus (unc.)] from dry skin was a risk factor for LBP and sciatica; unclassified Acinetobacter and Acinetobacter johnsonii from dry skin environments exhibit potential protective effects against LBP and sciatica; ASV065 [Finegoldia (unc.)] from dry skin was a protective factor for IVDD and LBP. 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. Skin microbiota Intervertebral disk degeneration Low back pain Sciatica Propionibacterium acnes Mendelian randomization Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 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 typical skin microbiota[ 10 ]. The detection rate of P.acnes in the intervertebral discs of patients undergoing lumbar discectomy can reach 40%[ 11 ]. In addition, opportunistic gram-negative pathogens such as Pseudomonas aeruginosa can be detected in modic intervertebral discs, indicating that other pathogenic bacteria can cause IVDD[ 12 ]. These bacteria colonize intervertebral discs due to the lack of blood vessels, sufficient water, low oxygen tension, and pH-neutral "biofilm-like" structure in the intervertebral discs[ 13 ]. However, some studies also suggest that there is currently insufficient evidence to attribute low virulence organisms to IDD, LBP, and disability[ 14 ]. The reason for the ambiguity is the inability to determine whether the detected microorganisms are indeed infected or contaminated with the culture[ 15 ]. A cross-sectional observational study suggests no evidence to suggest a link between Cutibacterium acnes and LBP[ 16 ]. In summary, further research is needed on the relationship between low virulence organisms and IVDD. Mendelian randomization (MR) study is a new method that uses single nucleotide polymorphism (SNP) as an instrumental variable to explore the causal relationship between exposure and outcomes, effectively avoiding the influence of confounding factors and reverse causal relationships in observational studies[ 17 ]. Rajasekaran et al[ 6 ] proposed the concept of the gut/skin/spine microbiota axis, indicating that gut or skin microbiota may be a source of low virulence organisms. Our study utilized two-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[ 18 ]. 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[ 18 ]. 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 16S 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[ 19 ]. 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. Phenotype Consortium Population Case Control GWAS ID Skin microbiota KORA FF4 and PopGen European 597 - GCST90133164 - GCST90133310 IVDD FinnGen European 20,001 164,682 finn-b-M13_INTERVERTEB LBP FinnGen European 13,178 164,682 finn-b-M13_LOWBACKPAIN Sciatica FinnGen European 19,509 199,283 finn-b-M13_LOWBACKPAINOR ANDSCIATICA Instrumental variables selection and data harmonization The following steps filtered the instrumental variables: (1) SNPs are selected based on their genome-wide significance thresholds significantly associated with skin microbiota (P < 5×10 − 8 ). If the number of instrumental variables is less than 3, the threshold is relaxed to 5×10 − 6 [ 20 ]; (2) linkage disequilibrium was removed from the selected SNPs, with an r2 threshold set to < 0.001 and a clustering distance of 10000kb[ 21 ]; (3) palindromic SNPs were excluded through data harmonization[ 22 ]; (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 = r 2 (n-2)/(1-r 2 )[ 23 ]. 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[ 24 ]. 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[ 25 ]. 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[ 24 ]. When the direction of IVW is consistent with that of the supplementary method, the results are stable[ 18 ]. 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[ 25 ]. 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[ 26 ]. 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[ 27 ]. 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[ 28 ]. 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, 1,771 SNPs were selected as instrumental variables for skin microbiota, and all F-statistics were greater than 10 (Supplementary Tables S1). Causal effects of skin microbiota on IVDD Using IVW analysis as our primary approach, we identified that 3 skin microbiota taxa (two Amplicon Sequence Variant and one genus) have a causal relationship with IVDD. Specifically, ASV065 [Finegoldia (unc.)] from dry skin (OR = 0.972, 95%CI = 0.952 to 0.992, P = 0.006 ) were associated with a reduced risk of IVDD. ASV054 [Enhydrobacter (unc.)] from moist skin (OR = 1.032, 95%CI = 1.009 to 1.056, P = 0.007 ) and genus Bacteroides from dry skin (OR = 1.019, 95%CI = 1.009 to 1.028, P < 0.001 ) were identified as being association with an increased risk of IVDD (Fig. 2 ). The scatter plots demonstrate the impact of each SNP on skin microbiota and IVDD and indicate the effects of 3 skin microbiota on IVDD (Figure S1 ). The reverse MR indicates no evidence to suggest a reverse causal relationship between the above skin microbiota and IVDD. Causal effects of skin microbiota on LBP IVW analysis indicated that 5 skin microbiota taxa (five Amplicon Sequence Variants) were causally related to LBP. Specifically, ASV054 [Enhydrobacter (unc.)] from dry skin (OR = 0.990, 95%CI = 0.980 to 1.000, P = 0.044 ), ASV045 [Acinetobacter (unc.)] from dry skin (OR = 0.979, 95%CI = 0.960 to 0.998, P = 0.033 ), ASV057 [A. johnsonii] from dry skin (OR = 0.975, 95%CI = 0.952 to 0.998, P = 0.032 ) and ASV065 [Finegoldia (unc.)] from dry skin (OR = 0.981, 95%CI = 0.965 to 0.998, P = 0.032 ) were related to a reduced risk of LBP. ASV010 [Staphylococcus (unc.)] from dry skin (OR = 1.035, 95%CI = 1.013 to 1.058, P = 0.002 ) were thought to be linked to an elevated risk of LBP (Fig. 3 ). The scatter plots demonstrate the impact of each SNP on skin microbiota and LBP and indicate the effects of 5 skin microbiota on LBP (Figure S2 ). The reverse MR indicates that LBP reduces the abundance of ASV010 [Staphylococcus (unc.)] from dry skin (Supplementary Tables S3). Causal effects of skin microbiota on sciatica IVW analysis revealed the causal impact of 5 skin microbiota taxa (three Amplicon Sequence Variants, one family and one genus) on sciatica. Specifically, ASV045 [Acinetobacter (unc.)] from dry skin (OR = 0.982, 95%CI = 0.965 to 1.000, P = 0.047 ) and ASV057 [A. johnsonii] from dry skin (OR = 0.974, 95%CI = 0.952 to 0.996, P = 0.021 ) were linked to a decreased risk of sciatica. Family Rhodobacteraceae from Moist skin (OR = 1.026, 95%CI = 1.002 to 1.051, P = 0.037 ), genus Streptococcus from Moist skin (OR = 1.035, 95%CI = 1.004 to 1.067, P = 0.026 ) and ASV010 [Staphylococcus (unc.)] from dry skin (OR = 1.021, 95%CI = 1.003 to 1.040, P = 0.023 ) were considered to be associated with an increased risk of sciatica (Fig. 4 ). The scatter plots demonstrate the impact of each SNP on skin microbiota and sciatica and indicate the effects of 8 skin microbiota on sciatica (Figure S3). The reverse MR indicates no evidence to suggest a reverse causal relationship between the above skin microbiota and sciatica. 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. Although the IVW analysis results showed that P.acnes in moist skin environments (OR = 0.950, 95%CI = 0.913 to 0.989, P = 0.013) were associated with reduced risk of IVDD, the MR-Egger showed the opposite direction, indicating an unstable causal relationship. In addition, other MR results were not significant. Therefore, there was no evidence to suggest a causal relationship between P.acnes and IVDD, LBP and sciatica (Fig. 5 ). 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 = 1.615, 95%CI = 1.074 to 2.429, P = 0.021 , Fig. 6 ). 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 = 0.046). Furthermore, the MR-Egger intercept and MR-PRESSO test demonstrated no horizontal pleiotropy in all MR results. In addition, the MR leave-one-out sensitivity analysis revealed that all MR results remained stable after excluding IVs one by one (Figure S4-S6). 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 bidirectional Mendelian randomization. Our research indicated that three skin microbiota were associated with IVDD, five with LBP, and five with sciatica. Specifically, IVDD was found to increase the abundance of P.acnes. Propionibacterium acnes plays a pivotal role in maintaining skin health and homeostasis. However, they are also opportunistic pathogens closely associated with acne vulgaris[ 29 ]. Notably, Propionibacterium acnes, a species within this bacterial group, can cause infections beyond the skin. For instance, when it infiltrates intervertebral discs, it can lead to IVDD, LBP and sciatica[ 30 ]. At the same time, there is currently no direct evidence elucidating the mechanism of how P.acnes enters the intervertebral discs[ 9 ]. However, studies have revealed the existence of multiple common microbial communities shared between the intervertebral disc and the skin. This suggests that P.acnes may originate from the skin microbiota[ 6 ]. Intriguingly, despite these findings, we have yet to uncover conclusive evidence indicating that skin-derived P.acnes serves as a risk factor for IVDD. This observation contradicts the hypothesis that the presence of Propionibacterium acnes in the intervertebral discs originates solely from the skin or is the causative agent of IVDD. Furthermore, numerous studies have proposed that the detection of P. acnes in intervertebral discs may be attributed to skin contaminants[ 16 ]. 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. Numerous studies have demonstrated that Coagulase Negative Staphylococcus, akin to Propionibacterium acnes, is a Gram-positive, facultative anaerobic bacterium frequently detected in intervertebral disc (IVD) tissues[ 13 , 31 – 32 ]. In our investigation, we identified ASV010 [Staphylococcus (unc.)] as a risk factor for lower back pain (LBP) and sciatica. This bacterial group likely belongs to the Coagulase Negative Staphylococcus species[ 19 ], corroborating previous research findings. Hence, Coagulase Negative Staphylococcus in the IVD may be attributed to skin microbiota. Furthermore, a study has revealed the presence of Enhydroxide and Acinetobacter in IVD tissues[ 6 ]. Our findings suggest that Enhydroxybacter species originating from different sources exert distinct effects on IVD degeneration and LBP. Unclassified Acinetobacter and Acinetobacter johnsonii from dry skin environments exhibit potential protective effects against LBP and sciatica. Notably, Acinetobacter johnsonii infrequently causes human infections and belongs to the aerobic bacterial group[ 33 ], so its colonization in IVD may be difficult. Interestingly, Acinetobacter johnsonii negatively correlates with the secretion of IL-4 and TNF-α[ 34 ], suggesting that certain skin-derived Acinetobacter species may possess anti-inflammatory properties. The genus Bacteroides, characterized as Gram-negative, non-spore-forming, and strictly anaerobic bacteria[ 35 ], 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[ 36 ] associated with physiological joint infections[ 37 ], surprisingly demonstrates protective potential against IVDD and LBP in our findings. 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. 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. Abbreviations GWAS, genome-wide association studies; MR, Mendelian randomization; IVs, instrumental variables; IVW, inverse-variance weighted; SNP, single nucleotide polymorphism; 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. Declarations Ethical approval and consent to participate We used publicly available GWAS summary data in this study. therefore, this analysis does not require ethical approval and consent to participate. Consent for publication Not applicable. Availability of data and materials 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. Competing Interests All authors declare no competing interests Funding Tianjin Municipal Health Commission (Grant TJWJ2023XK023 to Baoshan Xu) Authors' contribut ions 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. 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Longitudinal dynamics of gut microbiota in the pathogenesis of acute graft-versus-host disease. Cancer Med. 2023;12:21567–78. http://doi.org/10.1002/cam4.6557 . Shin JH, Tillotson G, MacKenzie TN, Warren CA, Wexler HM, Goldstein EJC. Bacteroides and related species: The keystone taxa of the human gut microbiota. Anaerobe. 2024;85:102819. http://doi.org/10.1016/j.anaerobe.2024.102819 . Rosenthal ME, Rojtman AD, Frank E. Finegoldia magna (formerly Peptostreptococcus magnus): an overlooked etiology for toxic shock syndrome? Med Hypotheses. 2012;79(2):138–40. http://doi.org/10.1016/j.mehy.2012.04.013 . Levy PY, Fenollar F, Stein A, Borrione F, Raoult D. Finegoldia magna: a forgotten pathogen in prosthetic joint infection rediscovered by molecular biology. Clin Infect Dis. 2009;49(8):1244–7. http://doi.org/10.1086/605672 . Additional Declarations No competing interests reported. Supplementary Files SupplementaryFigure.docx SupplementaryTable.xlsx Cite Share Download PDF Status: Published Journal Publication published 13 Aug, 2024 Read the published version in Journal of Orthopaedic Surgery and Research → Version 1 posted Editorial decision: Revision requested 06 Jul, 2024 Reviews received at journal 06 Jul, 2024 Reviews received at journal 04 Jul, 2024 Reviews received at journal 04 Jul, 2024 Reviewers agreed at journal 02 Jul, 2024 Reviewers agreed at journal 01 Jul, 2024 Reviewers agreed at journal 30 Jun, 2024 Reviewers invited by journal 30 Jun, 2024 Editor assigned by journal 27 Jun, 2024 Submission checks completed at journal 26 Jun, 2024 First submitted to journal 26 Jun, 2024 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4643600","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":323584760,"identity":"f7326be8-5542-4957-b93e-63068c7e4d4a","order_by":0,"name":"Yuchao Jia","email":"","orcid":"","institution":"Tianjin Medical University","correspondingAuthor":false,"prefix":"","firstName":"Yuchao","middleName":"","lastName":"Jia","suffix":""},{"id":323584761,"identity":"561a17af-d2fb-4baf-b2fe-b74854d716d5","order_by":1,"name":"Houcong Chen","email":"","orcid":"","institution":"Tianjin Medical University","correspondingAuthor":false,"prefix":"","firstName":"Houcong","middleName":"","lastName":"Chen","suffix":""},{"id":323584762,"identity":"cf58fc76-66ce-4025-97a3-329fa8c641c7","order_by":2,"name":"Shengbo Huang","email":"","orcid":"","institution":"Tianjin Medical University","correspondingAuthor":false,"prefix":"","firstName":"Shengbo","middleName":"","lastName":"Huang","suffix":""},{"id":323584763,"identity":"cfbaa814-5c08-413a-8dac-d962bb59db37","order_by":3,"name":"Zhenxin Huo","email":"","orcid":"","institution":"Tianjin Hospital","correspondingAuthor":false,"prefix":"","firstName":"Zhenxin","middleName":"","lastName":"Huo","suffix":""},{"id":323584764,"identity":"c564ca72-8ee1-442e-ac67-730d531c9234","order_by":4,"name":"Baoshan Xu","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA6klEQVRIiWNgGAWjYBACAyBmBrPYmw8+gIglEKuF51iywQHStEjkmEkQpcWc/fDhzwU1dxI33Mgxq/6Yc5iBnz3HgOHnDtxaLHvS0qRnHHtmbHDmWdmNg9sOM0j2vDFg7D2Dx2EHcsyYedgOyxkcT94G1mJwI8eAmbENj5bzb4w/8/w7zGNwIMGsAKTFnqAWoAJp3jagLSdSzBjAtkgQ0GI541maNG/fYWPJM8eSJc5uS+eROPOs4GAvHi3m/MmHP/N8O5zYd7z54IfKbdZy/O3JGx/8xKMFA/CAiAMkaBgFo2AUjIJRgAUAACWwWEbl0ze2AAAAAElFTkSuQmCC","orcid":"","institution":"Tianjin Hospital","correspondingAuthor":true,"prefix":"","firstName":"Baoshan","middleName":"","lastName":"Xu","suffix":""}],"badges":[],"createdAt":"2024-06-26 15:03:05","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4643600/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4643600/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1186/s13018-024-04980-w","type":"published","date":"2024-08-13T15:57:32+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":60704477,"identity":"7127dab0-1c4a-4f37-9794-5b2d58f20231","added_by":"auto","created_at":"2024-07-19 19:09:26","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":667676,"visible":true,"origin":"","legend":"\u003cp\u003eDiagrammatic Illustration of this study. IVs, instrumental variables; IVDD, intervertebral disc degeneration; LBP, low back pain.\u003c/p\u003e","description":"","filename":"Fig1.png","url":"https://assets-eu.researchsquare.com/files/rs-4643600/v1/c7ff65958361b4c3bf4b709d.png"},{"id":60704479,"identity":"bec82b29-b6a9-499b-9519-9d98e2b4454c","added_by":"auto","created_at":"2024-07-19 19:09:26","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":994101,"visible":true,"origin":"","legend":"\u003cp\u003eForest plot shows the causal effects of skin microbiota on IVDD. ASVs, amplicon sequence variants; OR, odds ratio; CI, confidence interval.\u003c/p\u003e","description":"","filename":"Fig2.png","url":"https://assets-eu.researchsquare.com/files/rs-4643600/v1/e4ff21a3bb587cf986e0f300.png"},{"id":60705435,"identity":"59e05f29-87e8-405b-8666-fc33718e4721","added_by":"auto","created_at":"2024-07-19 19:17:26","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":1619908,"visible":true,"origin":"","legend":"\u003cp\u003eForest plot shows the causal effects of skin microbiota on LBP. ASVs, amplicon sequence variants; (A.), Acinetobacter; OR, odds ratio; CI, confidence interval.\u003c/p\u003e","description":"","filename":"Fig3.png","url":"https://assets-eu.researchsquare.com/files/rs-4643600/v1/a637eb6fd6e2ebb7fb52684f.png"},{"id":60704478,"identity":"bc244558-3bc4-4aa8-bd9b-5af960956b2f","added_by":"auto","created_at":"2024-07-19 19:09:26","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":1802318,"visible":true,"origin":"","legend":"\u003cp\u003eForest plot shows the causal effects of skin microbiota on sciatica. ASVs, amplicon sequence variants; (A.), Acinetobacter; OR, odds ratio; CI, confidence interval.\u003c/p\u003e","description":"","filename":"Fig4.png","url":"https://assets-eu.researchsquare.com/files/rs-4643600/v1/cb151f22c2de1edf47556074.png"},{"id":60706041,"identity":"4231a8be-45db-4360-bfb8-cc5c21cb8dca","added_by":"auto","created_at":"2024-07-19 19:25:26","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":1045922,"visible":true,"origin":"","legend":"\u003cp\u003eForest 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.\u003c/p\u003e","description":"","filename":"Fig5.png","url":"https://assets-eu.researchsquare.com/files/rs-4643600/v1/0b6cf0771a68168e60d5231a.png"},{"id":60704482,"identity":"928d9e25-6ade-4019-a40a-fce6e142443b","added_by":"auto","created_at":"2024-07-19 19:09:26","extension":"png","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":1362033,"visible":true,"origin":"","legend":"\u003cp\u003eForest 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.\u003c/p\u003e","description":"","filename":"Fig6.png","url":"https://assets-eu.researchsquare.com/files/rs-4643600/v1/0b3cee6e508d4b7e6adb98d0.png"},{"id":63071238,"identity":"bd56c835-bb8c-4712-a5f6-5daaa438748a","added_by":"auto","created_at":"2024-08-22 20:05:03","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":7806012,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4643600/v1/1f65eb8d-4f35-4cb5-8e68-0cdcf46ca851.pdf"},{"id":60704483,"identity":"d14feb95-8343-4a2f-8d08-5705386c56e5","added_by":"auto","created_at":"2024-07-19 19:09:26","extension":"docx","order_by":9,"title":"","display":"","copyAsset":false,"role":"supplement","size":1246388,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementaryFigure.docx","url":"https://assets-eu.researchsquare.com/files/rs-4643600/v1/cdc0f5302af83b3e894c31dc.docx"},{"id":60705433,"identity":"9dcaab33-1ecb-44e8-b18b-55c94dc4c2dc","added_by":"auto","created_at":"2024-07-19 19:17:26","extension":"xlsx","order_by":10,"title":"","display":"","copyAsset":false,"role":"supplement","size":219423,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementaryTable.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-4643600/v1/b146cb0bd15c9af131dd78f3.xlsx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Causal effects of skin microbiota on intervertebral disk degeneration, low back pain and sciatica: a two-sample Mendelian randomization study","fulltext":[{"header":"Introduction","content":"\u003cp\u003eLow back pain (LBP) is a widespread condition that carries a significant burden, causing considerable disability and frequent absenteeism from work globally[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. According to statistics, approximately 80% of all people experience back pain at some point[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. 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)[\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. 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[\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. 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[\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eResearch has shown the presence of microorganisms in intervertebral discs, and the abundance of bacteria varies between healthy and degenerative intervertebral discs[\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. The presence of low virulence bacteria may be caused by colonization and can cause subclinical intervertebral disc infections, mediating IVDD and LBP[\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. Currently, the vast majority of studies indicate that the primary pathogen of this low virulence bacterium is Propionibacterium acnes[\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e], a typical skin microbiota[\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. The detection rate of P.acnes in the intervertebral discs of patients undergoing lumbar discectomy can reach 40%[\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. In addition, opportunistic gram-negative pathogens such as Pseudomonas aeruginosa can be detected in modic intervertebral discs, indicating that other pathogenic bacteria can cause IVDD[\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. These bacteria colonize intervertebral discs due to the lack of blood vessels, sufficient water, low oxygen tension, and pH-neutral \"biofilm-like\" structure in the intervertebral discs[\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. However, some studies also suggest that there is currently insufficient evidence to attribute low virulence organisms to IDD, LBP, and disability[\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. The reason for the ambiguity is the inability to determine whether the detected microorganisms are indeed infected or contaminated with the culture[\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. A cross-sectional observational study suggests no evidence to suggest a link between Cutibacterium acnes and LBP[\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. In summary, further research is needed on the relationship between low virulence organisms and IVDD.\u003c/p\u003e \u003cp\u003eMendelian randomization (MR) study is a new method that uses single nucleotide polymorphism (SNP) as an instrumental variable to explore the causal relationship between exposure and outcomes, effectively avoiding the influence of confounding factors and reverse causal relationships in observational studies[\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. Rajasekaran et al[\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e] proposed the concept of the gut/skin/spine microbiota axis, indicating that gut or skin microbiota may be a source of low virulence organisms. Our study utilized two-sample MR to investigate the causal relationship between skin microbiota, particularly Propionibacterium acnes, and IVDD, LBP, and sciatica.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStudy design\u003c/h2\u003e \u003cp\u003eThis study complies the STROBE-MR guidelines[\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. Figure\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e 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[\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e].\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eData sources\u003c/h2\u003e \u003cp\u003eThe 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 16S 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[\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. The GWAS summary data for IVDD (ncase\u0026thinsp;=\u0026thinsp;20,001, ncontrol\u0026thinsp;=\u0026thinsp;164,682), LBP (ncase\u0026thinsp;=\u0026thinsp;13,178, ncontrol\u0026thinsp;=\u0026thinsp;164,682) and sciatica (ncase\u0026thinsp;=\u0026thinsp;19,509, ncontrol\u0026thinsp;=\u0026thinsp;199,283) were obtained from the IEU Open GWAS project. Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e shows detailed information on the data sources.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eDetailed information on the GWAS summary data for skin microbiota, IVDD, LBP and sciatica.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"6\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePhenotype\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eConsortium\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003ePopulation\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eCase\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eControl\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eGWAS ID\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSkin microbiota\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eKORA FF4\u003c/p\u003e \u003cp\u003eand PopGen\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eEuropean\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e597\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eGCST90133164 - GCST90133310\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIVDD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eFinnGen\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eEuropean\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e20,001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e164,682\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003efinn-b-M13_INTERVERTEB\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLBP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eFinnGen\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eEuropean\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e13,178\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e164,682\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003efinn-b-M13_LOWBACKPAIN\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSciatica\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eFinnGen\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eEuropean\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e19,509\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e199,283\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003efinn-b-M13_LOWBACKPAINOR\u003c/p\u003e \u003cp\u003eANDSCIATICA\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eInstrumental variables selection and data harmonization\u003c/h2\u003e \u003cp\u003eThe following steps filtered the instrumental variables: (1) SNPs are selected based on their genome-wide significance thresholds significantly associated with skin microbiota (P\u0026thinsp;\u0026lt;\u0026thinsp;5\u0026times;10\u003csup\u003e\u0026minus;\u0026thinsp;8\u003c/sup\u003e). If the number of instrumental variables is less than 3, the threshold is relaxed to 5\u0026times;10\u003csup\u003e\u0026minus;\u0026thinsp;6\u003c/sup\u003e[\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]; (2) linkage disequilibrium was removed from the selected SNPs, with an r2 threshold set to \u0026lt;\u0026thinsp;0.001 and a clustering distance of 10000kb[\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]; (3) palindromic SNPs were excluded through data harmonization[\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]; (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\u0026thinsp;=\u0026thinsp;r\u003csup\u003e2\u003c/sup\u003e (n-2)/(1-r\u003csup\u003e2\u003c/sup\u003e)[\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. Finally, we obtained the required instrumental variables.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eMendelian randomization analysis\u003c/h2\u003e \u003cp\u003eWe 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[\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. 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[\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. 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[\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. When the direction of IVW is consistent with that of the supplementary method, the results are stable[\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. Given the intimate association between Propionibacterium acnes and IVDD, LBP, and sciatica, we further investigated the impact of outcomes on exposure.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003eSensitivity analysis\u003c/h2\u003e \u003cp\u003eWe 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[\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. The MR Egger intercept test was employed to detect the presence of horizontal pleiotropy in the MR results, where P\u0026thinsp;\u0026lt;\u0026thinsp;0.05 indicated horizontal pleiotropy[\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. 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[\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]. 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[\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]. The results of these sensitivity analyses were used to evaluate the reliability of MR results.\u003c/p\u003e \u003cp\u003eAll MR results were obtained using the \"TwosampleMR\" package in the R studio software.\u003c/p\u003e \u003c/div\u003e"},{"header":"Result","content":"\u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003eInstrumental variables selection\u003c/h2\u003e \u003cp\u003eAfter the above screening steps, 1,771 SNPs were selected as instrumental variables for skin microbiota, and all F-statistics were greater than 10 (Supplementary Tables S1).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec10\" class=\"Section2\"\u003e \u003ch2\u003eCausal effects of skin microbiota on IVDD\u003c/h2\u003e \u003cp\u003eUsing IVW analysis as our primary approach, we identified that 3 skin microbiota taxa (two Amplicon Sequence Variant and one genus) have a causal relationship with IVDD. Specifically, ASV065 [Finegoldia (unc.)] from dry skin (OR\u0026thinsp;=\u0026thinsp;0.972, 95%CI\u0026thinsp;=\u0026thinsp;0.952 to 0.992, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;\u003cb\u003e0.006\u003c/b\u003e) were associated with a reduced risk of IVDD. ASV054 [Enhydrobacter (unc.)] from moist skin (OR\u0026thinsp;=\u0026thinsp;1.032, 95%CI\u0026thinsp;=\u0026thinsp;1.009 to 1.056, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;\u003cb\u003e0.007\u003c/b\u003e) and genus Bacteroides from dry skin (OR\u0026thinsp;=\u0026thinsp;1.019, 95%CI\u0026thinsp;=\u0026thinsp;1.009 to 1.028, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;\u003cb\u003e0.001\u003c/b\u003e) were identified as being association with an increased risk of IVDD (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). The scatter plots demonstrate the impact of each SNP on skin microbiota and IVDD and indicate the effects of 3 skin microbiota on IVDD (Figure \u003cspan refid=\"MOESM1\" class=\"InternalRef\"\u003eS1\u003c/span\u003e). The reverse MR indicates no evidence to suggest a reverse causal relationship between the above skin microbiota and IVDD.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003eCausal effects of skin microbiota on LBP\u003c/h2\u003e \u003cp\u003eIVW analysis indicated that 5 skin microbiota taxa (five Amplicon Sequence Variants) were causally related to LBP. Specifically, ASV054 [Enhydrobacter (unc.)] from dry skin (OR\u0026thinsp;=\u0026thinsp;0.990, 95%CI\u0026thinsp;=\u0026thinsp;0.980 to 1.000, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;\u003cb\u003e0.044\u003c/b\u003e), ASV045 [Acinetobacter (unc.)] from dry skin (OR\u0026thinsp;=\u0026thinsp;0.979, 95%CI\u0026thinsp;=\u0026thinsp;0.960 to 0.998, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;\u003cb\u003e0.033\u003c/b\u003e), ASV057 [A. johnsonii] from dry skin (OR\u0026thinsp;=\u0026thinsp;0.975, 95%CI\u0026thinsp;=\u0026thinsp;0.952 to 0.998, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;\u003cb\u003e0.032\u003c/b\u003e) and ASV065 [Finegoldia (unc.)] from dry skin (OR\u0026thinsp;=\u0026thinsp;0.981, 95%CI\u0026thinsp;=\u0026thinsp;0.965 to 0.998, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;\u003cb\u003e0.032\u003c/b\u003e) were related to a reduced risk of LBP. ASV010 [Staphylococcus (unc.)] from dry skin (OR\u0026thinsp;=\u0026thinsp;1.035, 95%CI\u0026thinsp;=\u0026thinsp;1.013 to 1.058, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;\u003cb\u003e0.002\u003c/b\u003e) were thought to be linked to an elevated risk of LBP (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). The scatter plots demonstrate the impact of each SNP on skin microbiota and LBP and indicate the effects of 5 skin microbiota on LBP (Figure \u003cspan refid=\"MOESM2\" class=\"InternalRef\"\u003eS2\u003c/span\u003e). The reverse MR indicates that LBP reduces the abundance of ASV010 [Staphylococcus (unc.)] from dry skin (Supplementary Tables S3).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003eCausal effects of skin microbiota on sciatica\u003c/h2\u003e \u003cp\u003eIVW analysis revealed the causal impact of 5 skin microbiota taxa (three Amplicon Sequence Variants, one family and one genus) on sciatica. Specifically, ASV045 [Acinetobacter (unc.)] from dry skin (OR\u0026thinsp;=\u0026thinsp;0.982, 95%CI\u0026thinsp;=\u0026thinsp;0.965 to 1.000, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;\u003cb\u003e0.047\u003c/b\u003e) and ASV057 [A. johnsonii] from dry skin (OR\u0026thinsp;=\u0026thinsp;0.974, 95%CI\u0026thinsp;=\u0026thinsp;0.952 to 0.996, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;\u003cb\u003e0.021\u003c/b\u003e) were linked to a decreased risk of sciatica. Family Rhodobacteraceae from Moist skin (OR\u0026thinsp;=\u0026thinsp;1.026, 95%CI\u0026thinsp;=\u0026thinsp;1.002 to 1.051, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;\u003cb\u003e0.037\u003c/b\u003e), genus Streptococcus from Moist skin (OR\u0026thinsp;=\u0026thinsp;1.035, 95%CI\u0026thinsp;=\u0026thinsp;1.004 to 1.067, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;\u003cb\u003e0.026\u003c/b\u003e) and ASV010 [Staphylococcus (unc.)] from dry skin (OR\u0026thinsp;=\u0026thinsp;1.021, 95%CI\u0026thinsp;=\u0026thinsp;1.003 to 1.040, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;\u003cb\u003e0.023\u003c/b\u003e) were considered to be associated with an increased risk of sciatica (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e). The scatter plots demonstrate the impact of each SNP on skin microbiota and sciatica and indicate the effects of 8 skin microbiota on sciatica (Figure S3). The reverse MR indicates no evidence to suggest a reverse causal relationship between the above skin microbiota and sciatica.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec13\" class=\"Section2\"\u003e \u003ch2\u003eCausal effects of Propionibacterium acnes on IVDD, LBP and sciatica\u003c/h2\u003e \u003cp\u003eNumerous studies have implicated Propionibacterium acnes in the pathogenesis of IVDD, LBP, and sciatica, so we further evaluated their association. Although the IVW analysis results showed that P.acnes in moist skin environments (OR\u0026thinsp;=\u0026thinsp;0.950, 95%CI\u0026thinsp;=\u0026thinsp;0.913 to 0.989, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.013) were associated with reduced risk of IVDD, the MR-Egger showed the opposite direction, indicating an unstable causal relationship. In addition, other MR results were not significant. Therefore, there was no evidence to suggest a causal relationship between P.acnes and IVDD, LBP and sciatica (Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003e). 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\u0026thinsp;=\u0026thinsp;1.615, 95%CI\u0026thinsp;=\u0026thinsp;1.074 to 2.429, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;\u003cb\u003e0.021\u003c/b\u003e, Fig.\u0026nbsp;\u003cspan refid=\"Fig6\" class=\"InternalRef\"\u003e6\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec14\" class=\"Section2\"\u003e \u003ch2\u003eSensitivity analysis\u003c/h2\u003e \u003cp\u003eWe 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\u0026thinsp;=\u0026thinsp;0.046). Furthermore, the MR-Egger intercept and MR-PRESSO test demonstrated no horizontal pleiotropy in all MR results. In addition, the MR leave-one-out sensitivity analysis revealed that all MR results remained stable after excluding IVs one by one (Figure S4-S6). The above sensitivity analysis results indicate that the MR results are stable and reliable.\u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eIn this study, we first reported the relationship between skin microbiota, particularly P.acnes, IVDD, LBP, and sciatica, using two-sample bidirectional Mendelian randomization. Our research indicated that three skin microbiota were associated with IVDD, five with LBP, and five with sciatica. Specifically, IVDD was found to increase the abundance of P.acnes.\u003c/p\u003e \u003cp\u003ePropionibacterium acnes plays a pivotal role in maintaining skin health and homeostasis. However, they are also opportunistic pathogens closely associated with acne vulgaris[\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e]. Notably, Propionibacterium acnes, a species within this bacterial group, can cause infections beyond the skin. For instance, when it infiltrates intervertebral discs, it can lead to IVDD, LBP and sciatica[\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e]. At the same time, there is currently no direct evidence elucidating the mechanism of how P.acnes enters the intervertebral discs[\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. However, studies have revealed the existence of multiple common microbial communities shared between the intervertebral disc and the skin. This suggests that P.acnes may originate from the skin microbiota[\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. Intriguingly, despite these findings, we have yet to uncover conclusive evidence indicating that skin-derived P.acnes serves as a risk factor for IVDD. This observation contradicts the hypothesis that the presence of Propionibacterium acnes in the intervertebral discs originates solely from the skin or is the causative agent of IVDD.\u003c/p\u003e \u003cp\u003eFurthermore, numerous studies have proposed that the detection of P. acnes in intervertebral discs may be attributed to skin contaminants[\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. 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.\u003c/p\u003e \u003cp\u003eNumerous studies have demonstrated that Coagulase Negative Staphylococcus, akin to Propionibacterium acnes, is a Gram-positive, facultative anaerobic bacterium frequently detected in intervertebral disc (IVD) tissues[\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e]. In our investigation, we identified ASV010 [Staphylococcus (unc.)] as a risk factor for lower back pain (LBP) and sciatica. This bacterial group likely belongs to the Coagulase Negative Staphylococcus species[\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e], corroborating previous research findings. Hence, Coagulase Negative Staphylococcus in the IVD may be attributed to skin microbiota. Furthermore, a study has revealed the presence of Enhydroxide and Acinetobacter in IVD tissues[\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. Our findings suggest that Enhydroxybacter species originating from different sources exert distinct effects on IVD degeneration and LBP. Unclassified Acinetobacter and Acinetobacter johnsonii from dry skin environments exhibit potential protective effects against LBP and sciatica. Notably, Acinetobacter johnsonii infrequently causes human infections and belongs to the aerobic bacterial group[\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e], so its colonization in IVD may be difficult. Interestingly, Acinetobacter johnsonii negatively correlates with the secretion of IL-4 and TNF-α[\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e], suggesting that certain skin-derived Acinetobacter species may possess anti-inflammatory properties. The genus Bacteroides, characterized as Gram-negative, non-spore-forming, and strictly anaerobic bacteria[\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e], 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[\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e] associated with physiological joint infections[\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e], surprisingly demonstrates protective potential against IVDD and LBP in our findings.\u003c/p\u003e \u003cp\u003eThis 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\u0026thinsp;\u0026lt;\u0026thinsp;5\u0026times;10\u003csup\u003e\u0026minus;\u0026thinsp;8\u003c/sup\u003e) for some exposed data limit the number of instrumental variables suitable for analysis. Therefore, the threshold must be relaxed to P\u0026thinsp;\u0026lt;\u0026thinsp;5\u0026times;10\u003csup\u003e\u0026minus;\u0026thinsp;6\u003c/sup\u003e. 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.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eThis 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.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eGWAS, genome-wide association studies; MR, Mendelian randomization; IVs, instrumental variables; IVW, inverse-variance weighted; SNP, single nucleotide polymorphism; 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.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthical approval and consent to participate\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eWe used publicly available\u0026nbsp;GWAS summary\u0026nbsp;data in this study.\u0026nbsp;therefore, this analysis does not require ethical approval\u0026nbsp;and consent to participate.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe 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.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting Interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll authors declare no competing interests\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTianjin Municipal Health Commission (Grant TJWJ2023XK023 to Baoshan Xu)\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026apos; contribut\u003c/strong\u003e\u003cstrong\u003eions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eYJ: 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.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgments\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eDagenais S, Caro J, Haldeman S. A systematic review of low back pain cost of illness studies in the United States and internationally. 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Finegoldia magna: a forgotten pathogen in prosthetic joint infection rediscovered by molecular biology. Clin Infect Dis. 2009;49(8):1244\u0026ndash;7. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttp://doi.org/10.1086/605672\u003c/span\u003e\u003cspan address=\"10.1086/605672\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"journal-of-orthopaedic-surgery-and-research","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"josr","sideBox":"Learn more about [Journal of Orthopaedic Surgery and Research](http://josr-online.biomedcentral.com)","snPcode":"13018","submissionUrl":"https://submission.nature.com/new-submission/13018/3","title":"Journal of Orthopaedic Surgery and Research","twitterHandle":"@MSKmedBMC","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Skin microbiota, Intervertebral disk degeneration, Low back pain, Sciatica, Propionibacterium acnes, Mendelian randomization","lastPublishedDoi":"10.21203/rs.3.rs-4643600/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4643600/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eObjective\u003c/h2\u003e \u003cp\u003eThe 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.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eWe 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.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eMR revealed three skin microbiota associated with IVDD, five associated with LBP, and five with sciatica. Specifically, there was no significant causal relationship between skin-derived P.acnes and IVDD, LBP and sciatica; IVDD was found to increase the abundance of P.acnes. Furthermore, ASV010 [Staphylococcus (unc.)] from dry skin was a risk factor for LBP and sciatica; unclassified Acinetobacter and Acinetobacter johnsonii from dry skin environments exhibit potential protective effects against LBP and sciatica; ASV065 [Finegoldia (unc.)] from dry skin was a protective factor for IVDD and LBP.\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e \u003cp\u003eThis 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.\u003c/p\u003e","manuscriptTitle":"Causal effects of skin microbiota on intervertebral disk degeneration, low back pain and sciatica: a two-sample Mendelian randomization study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-07-19 19:09:21","doi":"10.21203/rs.3.rs-4643600/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2024-07-06T22:08:27+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-07-06T22:02:34+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-07-05T00:23:32+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-07-04T09:12:01+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"261382269392700597269867744883802047163","date":"2024-07-03T01:27:26+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"304168316156372325811592813398657662912","date":"2024-07-01T05:09:21+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"117240478536590370513311250504393102154","date":"2024-07-01T01:22:01+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-07-01T01:15:57+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-06-27T04:47:18+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2024-06-27T03:53:12+00:00","index":"","fulltext":""},{"type":"submitted","content":"Journal of Orthopaedic Surgery and Research","date":"2024-06-26T15:01:48+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"journal-of-orthopaedic-surgery-and-research","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"josr","sideBox":"Learn more about [Journal of Orthopaedic Surgery and Research](http://josr-online.biomedcentral.com)","snPcode":"13018","submissionUrl":"https://submission.nature.com/new-submission/13018/3","title":"Journal of Orthopaedic Surgery and Research","twitterHandle":"@MSKmedBMC","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"d6ce88d1-526b-4572-bc87-5d26c3545b6e","owner":[],"postedDate":"July 19th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2024-08-22T19:33:01+00:00","versionOfRecord":{"articleIdentity":"rs-4643600","link":"https://doi.org/10.1186/s13018-024-04980-w","journal":{"identity":"journal-of-orthopaedic-surgery-and-research","isVorOnly":false,"title":"Journal of Orthopaedic Surgery and Research"},"publishedOn":"2024-08-13 15:57:32","publishedOnDateReadable":"August 13th, 2024"},"versionCreatedAt":"2024-07-19 19:09:21","video":"","vorDoi":"10.1186/s13018-024-04980-w","vorDoiUrl":"https://doi.org/10.1186/s13018-024-04980-w","workflowStages":[]},"version":"v1","identity":"rs-4643600","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4643600","identity":"rs-4643600","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}