GDF-15 reflects host physiological stress rather than tumor progression in colorectal cancer patients

GDF-15 (growth differentiation factor 15) is a stress-responsive cytokine within the TGF-beta (transforming growth factor-beta) superfamily that is secreted in response to tissue injury and cellular stress. It increases under various pathological conditions, including cardiovascular, renal, and malignant diseases. In colorectal cancer (CRC), plasma GDF-15 levels are elevated compared with healthy individuals, and higher concentrations have been associated with worse prognosis. However, whether GDF-15 reflects tumor characteristics or host physiology remains unclear. This study aimed to clarify the clinical significance of GDF-15 in CRC by integrating analyses of plasma levels, tumor tissue expression, and gut microbiota composition. Seventy patients with CRC who underwent surgery between November 2021 and September 2023 were enrolled. Plasma GDF-15 levels were examined in relation to age, serum albumin (Alb), tumor stage, and other comprehensive nutritional and clinical parameters. GDF-15 expression in tumor tissue was evaluated by immunohistochemistry, and a semiquantitative histoscore (H-score) was calculated using the digital pathology software QuPath. Preoperative fecal samples were analyzed by 16S rRNA sequencing. For microbiota analysis, patients were classified into high and low plasma GDF-15 groups based on the median value, and microbial diversity and composition were compared between the groups. Plasma GDF-15 correlated positively with age (r = 0.58, p < 0.001) and negatively with Alb (r = -0.54, p < 0.0001). Levels were higher in advanced T categories (T3+4 vs. T1+2, p < 0.05) and higher stages (II-IV vs. I, p < 0.05); however, these associations disappeared after adjustment for age and Alb (T category, p = 0.72; stage, p = 0.86). These findings indicate that plasma GDF-15 reflects host physiological stress rather than tumor progression. GDF-15 expression in tumor tissue, assessed by H-score, showed no correlation with plasma GDF-15 (r = 0.06, p = 0.62), age (r = 0.09, p = 0.47), or Alb (r = -0.09, p = 0.48), and did not vary by tumor depth (p = 0.97) or stage (p = 0.75). Gut microbiota analysis revealed no difference in alpha-diversity. In contrast, beta-diversity differed significantly in both weighted and unweighted UniFrac analyses (p < 0.05), indicating compositional shifts associated with elevated plasma GDF-15. In conclusion, GDF-15 functions as a host-derived marker that reflects systemic physiological stress associated with aging and malnutrition rather than tumor burden. Furthermore, concurrent microbial alterations in patients with elevated GDF-15 suggest a potential role for GDF-15 as an integrative biomarker linking host physiological stress to intestinal environmental changes in colorectal cancer.