Lipopolysaccharide-mediated macrophage polarization, conserved pathogenesis, and implications for peripheral neuropathy: a systematic review.

Clinical Snapshot

Key Findings

• P Value: Not reported; no inferential statistics presented

• Effect Size: Mean conditional concordance score: 0.984 (scale 0–1); M1 macrophage skew reported in 87% of studies; innate immune activation in 87%; circulating LPS in 82.6%; 11 studies demonstrated full downstream chain completeness

• Primary Outcome: Conditional concordance of in-vivo studies with a proposed 8-step LPS-mediated pathogenic pathway (gut perturbation → barrier disruption → circulating LPS → systemic inflammation → tissue interface disruption → innate immune activation → M1-like macrophage skew → tissue dysfunction) across 13 tissue systems

• Nnt Or Sensitivity: Not applicable — mechanistic evidence-mapping review; no NNT, sensitivity, specificity, or hazard ratio calculable from reported data

• Confidence Interval: Not reported; concordance expressed as mean ± SD (0.984 ± 0.053)

Clinical Application

No direct clinical intervention is proposed or evaluated. The review supports the biological plausibility of targeting the gut-immune-nerve axis in peripheral neuropathy, which could inform future trial design. Measurement of circulating LPS or endotoxin activity as a biomarker in neuropathy patients is technically feasible but not yet validated for routine clinical use. Peripheral neuropathy affects approximately 2.4% of the general Australian population and is a significant burden in the context of type 2 diabetes (affecting over 1.3 million Australians), where metabolic endotoxaemia is increasingly recognised as a pathogenic contributor. The RACGP does not currently include LPS-mediated gut-immune mechanisms in peripheral neuropathy management guidelines. No TGA-approved therapies targeting LPS-macrophage pathways for neuropathy exist. The PBS does not list any agent specifically indicated for LPS-mediated neuropathy. This review may inform future research priorities within Australian neurology and pain medicine, particularly in the context of diabetic peripheral neuropathy and post-infectious neuropathy syndromes. Clinicians should note that the evidence base is predominantly preclinical and does not yet support changes to standard neuropathy assessment or treatment pathways. The findings are relevant as a mechanistic framework for clinicians managing patients with peripheral neuropathy of uncertain aetiology, particularly those with concurrent gastrointestinal dysbiosis, metabolic endotoxaemia, or systemic inflammatory conditions. The review does not define a specific patient population for clinical intervention.

Abstract

OBJECTIVE AND DESIGN: This systematic review synthesized evidence for a conserved lipopolysaccharide (LPS)-mediated pathogenic mechanism across diverse tissues and evaluated its potential relevance to peripheral neuropathy. METHODS: Studies were identified in which LPS was the independent exposure and pro-inflammatory, M1-like macrophage activation/polarization was an outcome. Structured evidence mapping was used to code in-vivo studies for direct measurement of prespecified steps along a proposed pathway: gut perturbation→barrier disruption→circulating LPS→systemic inflammation→tissue interface disruption→innate immune activation→M1-like macrophage skew→tissue dysfunction. Conditional concordance and downstream chain completeness scores were calculated. RESULTS: Mechanistic patterns were conserved between pulmonary, cardiac, renal, lymphatic, gastrointestinal, central nervous, adipose, osseous, urologic, dental, hepatic, uterine, and pancreatic tissues. Conditional concordance with the proposed pathway was high (mean 0.984 ± 0.053). Eleven studies assessed all downstream steps from LPS exposure to tissue dysfunction, each demonstrating full chain completeness. M1 macrophage skew (87%), innate immune activation (87%), and circulating LPS (82.6%) were the most frequently reported steps. CONCLUSIONS: These findings demonstrate conservation of LPS-driven M1-like macrophage polarization and tissue injury across systems, supporting the need to further investigate the biological plausibility of a gut-immune-nerve axis contributing to peripheral neuropathy.

References

1. 1.Elson, L., Eijkelkamp, N., & Coert, J. H. (2026). Lipopolysaccharide-mediated macrophage polarization, conserved pathogenesis, and implications for peripheral neuropathy: a systematic review. Inflammation Research. https://doi.org/10.1001/jamaneurol.2022.0565 [Note: DOI as supplied by source; bibliographic inconsistency flagged — independent verification recommended]