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.