The gut–disc axis in intervertebral disc degeneration: microbial metabolites, immunometabolic remodeling, and regulated cell death

Intervertebral disc degeneration (IDD) involves interactions among mechanical injury, inflammation, and metabolic dysfunction. The proposed gut–disc axis extends this framework to intestinal microbial signals, but the strength and tissue relevance of the supporting evidence vary considerably. This narrative review examines whether microbial metabolites could influence IDD through pyroptosis, a gasdermin-mediated form of lytic regulated cell death, and ferroptosis, an iron-dependent form of regulated cell death driven by lipid peroxidation. We distinguish human microbial associations, experimental findings in disc tissues, mechanisms demonstrated in other organs, and computational predictions. Selected microbial metabolites regulate inflammatory and antioxidant pathways in non-disc models, whereas disc studies establish the relevance of mitochondrial dysfunction, iron handling, and local metabolite-dependent protein modifications. These findings support mechanistic hypotheses but do not establish that defined gut-derived metabolites reach the disc and causally regulate either death program. We also assess microbiome-directed interventions and local therapeutic strategies, emphasizing that efficacy against a downstream disc pathway does not demonstrate a microbial initiating mechanism. Clinical intervention evidence remains limited and does not establish structural disease modification. Translation requires verified metabolite exposure, cell-specific target engagement, functional validation of cell death, and longitudinal assessment of imaging, pain, and disability. This evidence-based distinction provides a framework for prioritizing testable gut–disc mechanisms and clinically relevant interventions.