Genetic and metabolic inflammation signatures in chronic inflammatory demyelinating polyneuropathy: the role of IL18 polymorphisms and short-chain fatty acids.

Introduction: Chronic inflammatory demyelinating polyneuropathy (CIDP) remains diagnostically challenging, with limited biological markers to aid phenotyping and differential diagnosis, particularly at the CIDP-diabetes mellitus (DM) interface. Methods: We investigated inflammatory genetic and metabolic readouts in CIDP by integrating interleukin 18 (IL-18) promoter variation with cytokines and short-chain fatty acids (SCFAs). 32 untreated CIDP patients and 15 controls underwent clinical scoring, nerve-conduction studies (NCS), IL-18 genotyping (rs187238, rs1946518, rs1946519), serum cytokine profiling (IL-2, tumor necrosis factor α (TNF-α), IL-18), and SCFA quantification in stool, serum, and cerebrospinal fluid (CSF). Results: No group-level differences emerged for IL-2, TNF-α, or IL-18 in serum or CSF, and CIDP subgroups (DM+ vs DM-; classical vs atypical) did not differ in NCS severity or electromyography (EMG) denervation. In contrast, IL18 promoter variation showed various associations: rs1946518 G allele correlated with peroneal nerve shorter compound motor action potential (CMAP) distal latency and lower ulnar nerve sensory nerve action potential (SNAP) amplitude. Additionally, carriers of the rs187238 C allele showed significantly higher CSF protein concentrations, whereas the rs1946518 G allele was associated with a trend toward lower CSF protein levels. Moreover, the rs187238 C and rs1946518 T alleles were associated with lower CSF butyrate levels. A haplotype analysis indicated that GGG (rs187238, rs1946518, rs1946519) aligned with shorter peroneal nerve CMAP distal latency, lower disability (INCAT), and a lower CSF protein, whereas CTT associated with higher CSF protein and lower CSF butyrate concentrations. We confirmed the presence of acetate, propionate, and butyrate in human CSF and demonstrated serum-CSF equivalence for these SCFAs, while stool concentrations were higher, as expected. Discussion: Collectively, IL18 polymorphisms and SCFAs readouts emerge as biologically grounded candidates for patient stratification in CIDP; these findings warrant validation in larger, multicenter cohorts integrating electrophysiology with CSF/serum biomarkers and microbiome profiling.