Elucidating the immunomodulatory role of endocannabinoids in intervertebral disc degeneration

PurposeThe endocannabinoid system (ECS) has been well-established to play a crucial role in the regulation of several physiological processes as well as many inflammatory disease conditions. However, its role in intervertebral disc degeneration has been least explored. We aim to investigate the immunomodulatory role of endocannabinoids in regulating IVD health.MethodsThe study population included 20 healthy volunteers (controls) and 40 patients with disc degeneration (disease group) (20 Modic and 20 Non Modic). 16S metagenome sequencing of the V3-V4 region was performed for the DNA extracted from NP tissue samples of both control and disease groups. Sequencing was carried out using the Novaseq 6000 platform using 250 bp paired-end chemistry. A global metabolic profile was obtained using the uHPLC system coupled with Q Exactive Plus Hybrid Quadrupole-Orbitrap mass spectrometer.ResultsOur study revealed a higher prevalence of gram-negative bacteria, particularly opportunistic pathogens like Pseudomonas, in diseased discs (71-81%) compared to healthy controls (54%). Further investigation using metabolomics identified significant changes in the lipid profiles of diseased discs. We found that the signalling molecules of the ECS, 2-arachidonylglycerol (2-AG) and N-arachidonoylethanolamine (AEA), were significantly lower in diseased discs compared to controls (Log2FC -2.62 for 2-AG and -3.15 for AEA). Conversely, pro-inflammatory metabolites like LTA4, HPETE, HETE, and Prostaglandin G2 were elevated in diseased discs, with a Log2 fold increase greater than 2.5.ConclusionThe study reveals that the endocannabinoid metabolites (2-AG and AEA) of the ECS could be a significant molecule influencing susceptibility to infection and inflammation within the intervertebral discs, which could be a potential target for improving disc health.Level of evidenceDiagnostic: individual cross-sectional studies with consistently applied reference standard and blinding.