Gut‑disc axis: A cause of intervertebral disc degeneration and low back pain?

European Spine Journal (2022) 31:917–925

Low back pain (LBP), a widely prevalent and costly disease around the world, is mainly caused by intervertebral disc (IVD) degeneration (IDD). Although numerous factors may trigger this degenerative process, microbiome dysbiosis has recently been implicated as one of the likely causes. However, the exact relationship between the microbiome and IDD is not well understood. This review summarizes the potential mechanisms and discusses microbiome dysbiosis’s possible influence on IDD and LBP.

Methods Prospective literature review.

Results Alterations in microbiome composition and host responses to the microbiota causing pathological bone development and involution, led to the concept of gut-bone marrow axis and gut-bone axis. Moreover, the concept of the gut-disc axis was also proposed to explain the microbiome’s role in IDD and LBP. According to the existing evidence, the microbiome could be an important factor for inducing and aggravating IDD through changing or regulating the outside and inside microenvironment of the IVD. Three potential mechanisms by which the gut microbiota can induce IVD and cause LBP are: (1) translocation of the bacteria across the gut epithelial barrier and into the IVD, (2) regulation of the mucosal and systemic immune system, and (3) regulation of nutrient absorption and metabolites formation at the gut epithelium and its diffusion into the IVD. Furthermore, to investigate whether IVD is initiated by pathogenic bacteria and establish the correlation between the presence of certain microbial groups with the disease in question, microbiome diversity analysis based on16S rRNA data can be used to characterise stool/blood microbiota from IVD patients.

Conclusion Future studies on microbiome, fungi and viruses in IDD is necessary to revolutionize our thinking about their possible role in the development of IVD diseases. Furthermore, we believe that inflammation inhibition and interruption of amplification of cascade reaction in IVD by targeting the gut and IVD microbiome is worthwhile for the treatment of IDD and LBP.

Level of Evidence I Diagnostic: individual cross-sectional studies with the consistently applied reference standard and blinding.

Aneurysm Wall Enhancement Is Associated With Decreased Intrasaccular IL-10 and Morphological Features of Instability

Neurosurgery 89:664–671, 2021

High-resolution vessel wall imaging plays an increasingly important role in assessing the risk of aneurysm rupture.

OBJECTIVE: To introduce an approach toward the validation of the wall enhancement as a direct surrogate parameter for aneurysm stability.

METHODS: A total of 19 patients harboring 22 incidental intracranial aneurysms were enrolled in this study. The aneurysms were dichotomized according to their aneurysm to- pituitary stalk contrast ratio using a cutoff value of 0.5 (nonenhancing < 0.5; enhancing ≥ 0.5). We evaluated the association of aneurysm wall enhancement with morphological characteristics, hemodynamic features, and inflammatory chemokines directly measured inside the aneurysm.

RESULTS: Differences in plasma concentration of chemokines and inflammatory molecules, morphological, and hemodynamic parameters were analyzed using the Welch test or Mann-Whitney U test. The concentration  IL-10 in the lumen of intracranial aneurysms with low wall enhancement was significantly increased compared to aneurysms with strong aneurysm wall enhancement (P = .014). The analysis of morphological and hemodynamic parameters showed significantly increased values for aneurysm volume (P=.03), aneurysm area (P=.044), maximal diameter (P=.049), and nonsphericity index (P=.021) for intracranial aneurysms with strong aneurysm wall enhancement. None of the hemodynamic parameters reached statistical significance; however, the total viscous shear force computed over the region of low wall shear stress showed a strong tendency toward significance (P = .053).

CONCLUSION: Aneurysmal wall enhancement shows strong associations with decreased intrasaccular IL-10 and established morphological indicators of aneurysm instability.


Aspirin associated with decreased rate of intracranial aneurysm growth

J Neurosurg 133:1478–1485, 2020

Aspirin has emerged as a potential agent in the prevention of rupture of intracranial aneurysms (IAs). In this study, the authors’ goal was to test if aspirin is protective against aneurysm growth in patients harboring multiple IAs ≤ 5 mm.

METHODS The authors performed a retrospective review of a prospectively maintained database covering the period July 2009 through January 2019. Patients’ data were included if the following criteria were met: 1) the patient harbored multiple IAs; 2) designated primary aneurysms were treated by surgical/endovascular means; 3) the remaining aneurysms were observed for growth; and 4) a follow-up period of at least 5 years after the initial treatment was available. Demographics, earlier medical history, the rupture status of designated primary aneurysms, aneurysms’ angiographic features, and treatment modalities were gathered.

RESULTS The authors identified 146 patients harboring a total of 375 IAs. At the initial encounter, 146 aneurysms were treated and the remaining 229 aneurysms (2–5 mm) were observed. During the follow-up period, 24 (10.48%) of 229 aneurysms grew. All aneurysms observed to grow later underwent treatment. None of the observed aneurysms ruptured. Multivariate analysis showed that aspirin was significantly associated with a decreased rate of growth (odds ratio [OR] 0.19, 95% confidence interval [CI] 0.05–0.63). Variables associated with an increased rate of growth included hypertension (OR 14.38, 95% CI 3.83–53.94), drug abuse (OR 11.26, 95% CI 1.21–104.65), history of polycystic kidney disease (OR 9.48, 95% CI 1.51–59.35), and subarachnoid hemorrhage at presentation (OR 5.91, 95% CI 1.83–19.09).

CONCLUSIONS In patients with multiple IAs, aspirin significantly decreased the rate of aneurysm growth over time. Additional prospective interventional studies are needed to validate these findings.

Lumbar disc extrusions reduce faster than bulging discs due to an active role of macrophages in sciatica

Acta Neurochirurgica (2020) 162:79–85

This retrospective observational histological study aims to associate the size and type of disc herniation with the degree of macrophage infiltration in disc material retrieved during disc surgery in patients with sciatica.

Methods Disc tissue of 119 sciatica patients was embedded in paraffin and stained with hematoxylin and CD68. Tissue samples were categorized as mild (0–10/cm2), moderate (10–100/cm2), and considerable (> 100/cm2) macrophage infiltration. All 119 patients received an MRI at baseline, and 108 received a follow-up MRI at 1-year. MRIs were reviewed for the size and type of the disc herniations, and for Modic changes in the vertebral endplates.

Results Baseline characteristics and duration of symptoms before surgery were comparable in all macrophage infiltration groups. The degree of macrophage infiltration was not associated with herniation size at baseline, but significantly associated with reduction of size of the herniated disc at 1-year post surgery. Moreover, the degree of macrophage infiltration was higher in extrusion in comparison with bulging (protrusion) of the disc. Results were comparable in patients with and without Modic changes.

Conclusion Macrophage infiltration was positively associated with an extruded type of disc herniation as well as the extent of reduction of the herniated disc during 1-year follow-up in patients with sciatica. This is an indication that the macrophages play an active role in reducing herniated discs. An extruded disc herniation has a larger surface for the macrophages to adhere to, which leads to more size reduction.

The Role of Hypoxia in Angiogenesis and Extracellular Matrix Regulation of Intervertebral Disc Cells During Inflammatory Reactions

Neurosurgery 81:867–875, 2017

The intervertebral disc (IVD) is an avascular structure, and is therefore stable under hypoxic conditions. Previous studies have demonstrated that hypoxia might be related to symptomatic degenerative disc diseases (DDDs); however, the pathomechanism is still poorly understood.

OBJECTIVE: To identify the effect of hypoxia on the production of inflammatory mediators, angiogenic factors, and extracellularmatrix-regulating enzymes of IVD cells during inflammatory reactions.

METHODS: Human nucleus pulposus (NP) and annulus fibrosus (AF) cells harvested during surgery for DDDs were cultured in macrophage conditioned media or interleukin (IL)-1β-stimulated media under hypoxic (2%) and normoxic (21%) conditions. Hypoxiainducible factor-1α transcription factor activation was analyzed by western blotting. IL-6, IL-8, vascular endothelial growth factor (VEGF), vascular cell adhesion molecule (VCAM), matrix metalloproteinase (MMP)-1,MMP-3, tissue inhibitor ofmetalloprotease (TIMP)-1, and TIMP-2 in conditioned media weremeasured by an enzyme-linked immunosorbent assay.

RESULTS: NP cells expressed higher hypoxia-inducible factor-1α in the IL-1β-stimulated group under hypoxic condition. MMP-1 was significantly increased in the AF cells under hypoxic condition; TIMP-1 and TIMP-2 were significantly decreased in both naïve NP and AF cells during hypoxia. Both cells in macrophage conditioned media significantly diminished the production of IL-6 and VCAM, while VEGF significantly increased during hypoxia. After 1 ng/mL IL-1β stimulation, IL-8, VEGF, MMP-1, and MMP-3 were significantly increased in both cell types during hypoxia, while VCAM, TIMP-1, and TIMP-2 were decreased.

CONCLUSION: We found that hypoxia can enhance the angiogenic ability of IVD during inflammatory reactions, and cause progress in development of DDD via extracellular matrix regulation in this in vitro study.

The Mechanism of Ligamentum Flavum Hypertrophy

Ligamentum Flavum Hypertrophy

Neurosurgery 77:274–282, 2015

Biochemical alterations associated with mechanical stress have been explored as an initiating step in the pathological progression of ligamentum flavum hypertrophy (LFH); however, this mechanism remains poorly understood. Recently, the inflammation induced after mechanical stress and the subsequent response of ligamentum flavum (LF) cells have been implicated in LFH pathology.

OBJECTIVE: To investigate the hypothesis that angiogenesis may be a critical link between hypertrophy and a series of stimulating events, including mechanical stress.

METHODS: LF from 20 lumbar spinal canal stenosis (LSCS) patients and 16 non-LSCS patients (control group) were collected during surgery. Patient demographic and radiographic data were obtained. The levels of angiogenic factors (vascular endothelial growth factor [VEGF], angiopoietin-1, vascular cell adhesion molecule, and basic fibroblast growth factor) in the LF were investigated by using an enzyme-linked immunosorbent assay. Angiogenesis was also quantified by immunohistochemical detection of CD34-positive capillaries. The correlations among clinical factors, including radiographic factors, angiogenic factors, and angiogenesis, were statistically analyzed.

RESULTS: The LSCS group was older and exhibited a longer symptom duration, wider segmental motion, and thicker LF than the control group. The LSCS group showed significantly higher tissue concentrations of VEGF (P , .001) that positively correlated with LF thickness (r = 0.557, P , .001) and segmental motion (r = 0.586, P , .001). The LSCS group showed significantly more CD34-positive capillaries than the control group (P = .004).

CONCLUSION: The LSCS group showed greater segmental motion, higher VEGF concentrations, and more CD34-positive capillaries than the control group. These data indicate that VEGF-mediated angiogenesis following mechanical stress may be a critical step within the series of pathological events in LFH.

Randomized, double-blind, placebo-controlled, pilot trial of high-dose methylprednisolone in aneurysmal subarachnoid hemorrhage

J Neurosurg 112:681–688, 2010. DOI: 10.3171/2009.4.JNS081377

The object of this study was to determine the efficacy of methylprednisolone in reducing symptomatic vasospasm and poor outcomes after subarachnoid hemorrhage (SAH).

Methods. Ninety-five patients with proven SAH were recruited into a double-blind, placebo-controlled, random- ized trial. Starting within 6 hours after angiographic diagnosis of aneurysm rupture, placebo or methylprednisolone, 16 mg/kg, was administered intravenously every day for 3 days to 46 and 49 patients, respectively. Deterioration, defined as development of a focal sign or decrease of more than 1 point on the Glasgow Coma Scale for more than 6 hours, was investigated by using clinical criteria and transcranial Doppler ultrasonography, cerebral angiography, or CT when appropriate. The end points were incidence of symptomatic vasospasm (delayed ischemic neurological deficits associated with angiographic arterial narrowing or accelerated flow on Doppler ultrasonography, or both) and outcome 1 year after entry into the study according to a simplified Rankin scale (Functional Outcome Scale [FOS]) in living patients and the Glasgow Outcome Scale in all patients included.

Results. All episodes of deterioration and all living patients with a 1-year outcome were assessed by a review committee. In patients treated with methylprednisolone, the incidence of symptomatic vasospasm was 26.5% com- pared with 26.0% in those given placebo. Poor outcomes according to FOS were significantly reduced in the Meth- ylprednisolone Group at 1 year of follow-up; the risk difference was 19.3% (95% CI 0.5–37.9%). The outcome was poor in 15% (6/40) of patients in the Methylprednisolone Group versus 34% (13/38) in the Placebo Group.

Conclusions. A safe and simple treatment with methylprednisolone did not reduce the incidence of symptomatic vasospasm but improved ability and functional outcome at 1 year after SAH.