Medical Stress Hormones in Hospitalized Patients Drive Resistance Gene Activation in the Emerging Human Pathogen Elizabethkingia anophelis: Evidence for a Neuroendocrine–Resistome Axis

Background: Elizabethkingia anophelis has emerged as a rare multidrug-resistant human pathogen in hospitalized patients. Severe medical illness was accompanied by elevated stress hormones, which were suspected to influence bacterial resistance gene expression. However, their role in transcriptional activation of resistance determinants in this pathogen had not been clarified. Aim: This study investigated whether medical stress hormones in hospitalized patients were associated with activation of key resistance genes in Elizabethkingia anophelis and evaluated the presence of a Neuroendocrine–Resistome Axis. Patients and Methods: A total of 42 hospitalized patients with confirmed E. anophelis infection and 40 matched controls were enrolled. Serum cortisol, norepinephrine, and epinephrine were quantified using targeted UPLC–MS/MS. Clinical isolates were exposed ex vivo to physiological hormone concentrations. Expression of blaB, blaCME, catB, and vsr1 was measured by RT-qPCR and normalized to rpoB. Statistical analysis was performed using t-tests, ANOVA, and Pearson correlation, with significance set at p < 0.05. Results: Hospitalized patients with confirmed Elizabethkingia anophelis infection exhibited significantly elevated circulating stress hormones compared to matched Gram-negative controls. Mean serum cortisol levels were markedly higher (29.4 ± 6.8 µg/dL vs. 18.1 ± 4.3 µg/dL, p < 0.001), accompanied by substantial increases in norepinephrine (812 ± 140 pg/mL vs. 492 ± 110 pg/mL, p < 0.001) and epinephrine (178 ± 36 pg/mL vs. 102 ± 29 pg/mL, p < 0.001). Ex vivo exposure of clinical E. anophelis isolates to physiologic concentrations of these hormones resulted in significant transcriptional upregulation of resistance-associated genes. Cortisol induced a 2.1-fold increase in blaB (p = 0.004), 1.9-fold in blaCME (p = 0.008), 1.6-fold in catB (p = 0.021), and 2.4-fold in vsr1 (p = 0.002). Norepinephrine exerted the strongest individual effect, producing 2.8-fold, 2.5-fold, 2.2-fold, and 3.1-fold increases in blaB, blaCME, catB, and vsr1, respectively (all p ≤ 0.003). Combined hormone exposure produced a synergistic effect, with upregulation reaching 3.9-fold for blaB, 3.5-fold for blaCME, 3.1-fold for catB, and 4.2-fold for vsr1 (all p < 0.001). Significant positive correlations were identified between patient norepinephrine levels and bacterial blaB (r = 0.71, p < 0.001) and vsr1 expression (r = 0.76, p < 0.001). Furthermore, hormone-exposed isolates demonstrated a modest but statistically significant 1.5-fold increase in meropenem MIC values (p = 0.018), supporting functional relevance of transcriptional activation. Conclusion: Medical stress hormones in hospitalized patients were significantly associated with activation of resistance genes in Elizabethkingia anophelis. These findings supported a Neuroendocrine–Resistome Axis linking host stress physiology to bacterial resistance regulation.