Gut Microbiota Alterations in Adolescent Idiopathic Scoliosis Are Associated with Aberrant Bone Homeostasis

Abstract

Objective: Low bone mineral density is the major prognostic factor for adolescent idiopathic scoliosis (AIS), but the underlying mechanisms remain unclear. Accumulating evidence suggests that gut microbiota (GM) have the potential to affect bone development, and the GM signatures are altered in AIS patients. However, the effect of GM alterations on aberrant bone homeostasis in AIS remains unclear. This study aims to investigate the GM profile in AIS patients with different bone mineral density (BMD) and explore the association between GM, osteopenia, and aberrant bone turnover.

Methods: A total of 126 patients with AIS who received surgical treatment were retrospectively included in this study. We analyzed the composition of the GM by 16S rRNA sequencing and BMD by dual X-ray absorptiometry. Based on the BMD of the femur neck, the patients were divided into the osteopenia group (OPN) if the Z score < −1, and the normal (NOR) group if the Z score ≥ −1 SD compared to the healthy control. For the 16S rRNA sequencing, the raw reads were filtered to remove low-quality reads, and operational taxonomic units were identified with the Uparse program. Weighted UniFrac distance matrix for the beta-diversity metrics and principal coordinate analysis (PCoA) was performed, and the statistical comparisons were made with permutational multivariate analysis of variance (PERMANOVA) and analysis of similarity (ANONISM). Linear discriminant analysis effect size (LEfSe) was used to identify the enriched species in two groups. The “Random forest” was applied to determine the optimal biomarker for OPN according to the mean decrease in Gini value. The metabolic function was predicted by the Tax4Fun analysis. The Pearson correlation coefficient was used to evaluate the associations between GM species, bone turnover markers, and BMD.

Results: The serum β-CTX was increased in the OPN group (n = 67) compared to the NOR group (n = 59). Patients in OPN groups showed significantly decreased α diversity indicated by the Shannon index. Principal coordinate analysis (PCoA) analysis showed significant clustering of GM between OPN and NOR groups. At genus level, the Escherichia-Shigella and Faecalibacterium were significantly enriched in the OPN group compared to that in the NOR group (p < 0.05), whereas the abundance of Prevotella was significantly decreased (p = 0.0012). The relative abundance of Megamonas and Prevotella was positively correlated with the femur BMD. The abundance of Escherichia-Shigella was negatively correlated with femur BMD and positively correlated with serum β-CTX levels. Functional analysis revealed significant differences in starch and sucrose metabolism, pyruvate and cysteine, and methionine metabolism between NOR and OPN groups.

Conclusion: The alterations of GM in AIS patients are correlated with osteopenia. The association between enriched species, BMD, and bone turnover markers provides novel diagnostic and therapeutic targets for the clinical management of AIS.

Keywords

Adolescent idiopathic scoliosis / Bone turnover / Gut microbiota / Osteopenia

References

[1] WeinsteinSL, DolanLA, ChengJC, Danielsson A, MorcuendeJA. Adolescent idiopathic scoliosis. Lancet. 2008;371(9623):1527–1537.

[2] ChengJC, Castelein RM, ChuWC, DanielssonAJ, DobbsMB, GrivasTB, et al. Adolescent idiopathic scoliosis. Nat Rev Dis Primers. 2015;1(1):1–21.

[3] TakahashiY, KouI, TakahashiA, Johnson TA, KonoK, KawakamiN, et al. A genome-wide association study identifies common variants near LBX1 associated with adolescent idiopathic scoliosis. Nat Genet. 2011;43(12):1237–1240.

[4] HallerG, Alvarado D, McCallK, et al. A polygenic burden of rare variants across extracellular matrix genes among individuals with adolescent idiopathic scoliosis. Hum Mol Genet. 2016;25(1):202–209.

[5] SharmaS, GaoX, LondonoD, et al. Genome-wide association studies of adolescent idiopathic scoliosis suggest candidate susceptibility genes. Hum Mol Genet. 2011;20(7):1456–1466.

[6] KouI, Takahashi Y, JohnsonTA, TakahashiA, GuoL, DaiJ, et al. Genetic variants in GPR126 are associated with adolescent idiopathic scoliosis. Nat Genet. 2013;45(6):676–679.

[7] ZhaoL, RoffeyDM, ChenS. Genetics of adolescent idiopathic scoliosis in the post-genome-wide association study era. Ann Transl Med. 2015;3(Suppl 1):S35.

[8] LeboeufD, Letellier K, AlosN, EderyP, Moldovan F. Do estrogens impact adolescent idiopathic scoliosis? Trends Endocrinol Metab. 2009;20(4):147–152.

[9] GirardoM, Bettini N, DemaE, CervellatiS. The role of melatonin in the pathogenesis of adolescent idiopathic scoliosis (AIS). Eur Spine J. 2011;20(Suppl 1):S68–S74.

[10] LiuZ, TamEM, SunGQ, et al. Abnormal leptin bioavailability in adolescent idiopathic scoliosis: an important new finding. Spine. 2012;37(7):599–604.

[11] MaryaS, TambeAD, MillnerPA, Tsirikos AI. Adolescent idiopathic scoliosis: a review of aetiological theories of a multifactorial disease. Bone Jt J. 2022;104(8):915–921.

[12] WangZW, LeeWY, LamTP, et al. Defining the bone morphometry, micro-architecture and volumetric density profile in osteopenic vs non-osteopenic adolescent idiopathic scoliosis. Eur Spine J. 2017;26(6):1586–1594.

[13] LiuH, LiuZ, ManCW, et al. The effect of exogenous melatonin on reducing scoliotic curvature and improving bone quality in melatonin-deficient C57BL/6J mice. Sci Rep. 2019;9(1):6202.

[14] LiX, HungVWY, YuFWP, Hung ALH, NgBKW, ChengJCY, et al. Persistent low-normal bone mineral density in adolescent idiopathic scoliosis with different curve severity: a longitudinal study from presentation to beyond skeletal maturity and peak bone mass. Bone. 2019;133:115217.

[15] LeeWT, CheungCS, TseYK, et al. Generalized low bone mass of girls with adolescent idiopathic scoliosis is related to inadequate calcium intake and weight bearing physical activity in peripubertal period. Osteoporosis Int. 2005;16(9):1024–1035.

[16] NgSY, Bettany-Saltikov J, CheungIYK, ChanKKY. The role of vitamin D in the pathogenesis of adolescent idiopathic scoliosis. Asian Spine J. 2018;12(6):1127–1145.

[17] LiJ, HoWTP, LiuC, ChowSKH, IpM, YuJ, et al. The role of gut microbiota in bone homeostasis: a systematic review of preclinical animal studies. Bone Jt Res. 2021;10(1):51–59.

[18] SchirmerM, Franzosa EA, Lloyd-PriceJ, McIverLJ, Schwager R, PoonTW, et al. Dynamics of metatranscription in the inflammatory bowel disease gut microbiome. Nat Microbiol. 2018;3(3):337–346.

[19] BlacherE, Bashiardes S, ShapiroH, RothschildD, MorU, Dori-BachashM, et al. Potential roles of gut microbiome and metabolites in modulating ALS in mice. Nature. 2019;572(7770):474–480.

[20] ForslundK, Hildebrand F, NielsenT, et al. Disentangling type 2 diabetes and metformin treatment signatures in the human gut microbiota. Nature. 2015;528(7581):262–266.

[21] LorenzoJ. From the gut to bone: connecting the gut microbiota with Th17 T lymphocytes and postmenopausal osteoporosis. J Clin Invest. 2021;131(5):e146619.

[22] O'ToolePW, Marchesi JR, HillC. Next-generation probiotics: the spectrum from probiotics to live biotherapeutics. Nat Microbiol. 2017;2(5):1–6.

[23] ShenN, ChenN, ZhouX, Zhao B, HuangR, LiangJ, et al. Alterations of the gut microbiome and plasma proteome in Chinese patients with adolescent idiopathic scoliosis. Bone. 2019;120:364–370.

[24] DanL, La Hong J, YangZY, et al. Food frequency questionnaire for Chinese children aged 12-17 years: validity and reliability. Biomed Environ Sci. 2019;32(7):486–495.

[25] SunX, WuT, LiuZ, ZhuZ, QianB, Zhu F, et al. Osteopenia predicts curve progression of adolescent idiopathic scoliosis in girls treated with brace treatment. J Pediatr Orthop. 2013;33(4):366–371.

[26] HungVWY, QinL, CheungCSK, Lam TP, NgBKW, TseYK, et al. Osteopenia: a new prognostic factor of curve progression in adolescent idiopathic scoliosis. J Bone Jt Surg Am. 2005;87(12):2709–2716.

[27] HungV, QinL, CheungC, et al. Osteopenia: a new prognostic factor of curve progression in adolescent idiopathic scoliosis. J Bone Jt Surg. 2005;87(12):2709–2716.

[28] WangJ, ChenQ, AiY, HuangY, ZhuC, DingH, et al. Vertebral bone quality score as a novel predictor of proximal junctional kyphosis after thoracic adolescent idiopathic scoliosis surgery. Eur Spine J. 2023;32:3996–4002.

[29] LiX-F, LiH, LiuZ-D, Dai L-Y. Low bone mineral status in adolescent idiopathic scoliosis. Eur Spine J. 2008;17:1431–1440.

[30] YangY, ChenZ, HuangZ, Tao J, LiX, ZhouX, et al. Risk factors associated with low bone mineral density in children with idiopathic scoliosis: a scoping review. BMC Musculoskeletal Disorders, 2023;24(1):1–12.

[31] HerdeaA, Dragomirescu M-C, UliciA, LunguCN, Charkaoui A. Controlling the progression of curvature in children and adolescent idiopathic scoliosis following the Administration of Melatonin, calcium, and vitamin D. Children. 2022;9(5):758.

[32] HeJ, XuS, ZhangB, Xiao C, ChenZ, SiF, et al. Gut microbiota and metabolite alterations associated with reduced bone mineral density or bone metabolic indexes in postmenopausal osteoporosis. Aging. 2020;12(9):8583–8604.

[33] ChengJ, ZhongW-L, ZhaoJ-W, Zhai JH, ChenC, ChaoAJ, et al. Alterations in the composition of the gut microbiota affect absorption of cholecalciferol in severe osteoporosis. J Bone Miner Metab. 2022;40(3):478–486.

[34] WangZ, ChenK, WuC, ChenJ, PanH, LiuY, et al. An emerging role of Prevotella histicola on estrogen deficiency-induced bone loss through the gut microbiota-bone axis in postmenopausal women and in ovariectomized mice. Am J Clin Nutr. 2021;114(4):1304–1313.

[35] LaiB, JiangH, GaoY, ZhouX. Causal effects of gut microbiota on scoliosis: a bidirectional two-sample mendelian randomization study. Heliyon. 2023;9(11):e21654.

[36] ChengB, WenY, YangX, Cheng S, LiuL, ChuX, et al. Gut microbiota is associated with bone mineral density: an observational and genome-wide environmental interaction analysis in the UK biobank cohort. Bone Jt Res. 2021;10(11):734–741.

[37] PacielloI, SilipoA, Lembo-FazioL, et al. Intracellular Shigella remodels its LPS to dampen the innate immune recognition and evade inflammasome activation. Proc Natl Acad Sci U S A. 2013;110(46):E4345–E4354.

[38] Garcia-RiberaS, Amat-Bou M, ClimentE, LlobetM, Chenoll E, CorripioR, et al. Specific dietary components and gut microbiota composition are associated with obesity in children and adolescents with prader–willi syndrome. Nutrients. 2020;12(4):1063.

[39] LyuZ, HuY, GuoY, LiuD. Modulation of bone remodeling by the gut microbiota: a new therapy for osteoporosis. Bone Res. 2023;11(1):31.

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