Cytokine and Microbiome Changes in Adolescents with Anorexia Nervosa at Admission, Discharge, and One-Year Follow-Up

Abstract

Anorexia nervosa (AN) is a severe eating disorder that predominantly affects females and typically manifests during adolescence. There is increasing evidence that serum cytokine levels are altered in individuals with AN. Previous research has largely focused on adult patients, assuming a low-grade pro-inflammatory state. The serum levels of the cytokine tumour necrosis factor-alpha (TNF-α), interleukin (IL)-1β, IL-6 and IL-15, which are pro-inflammatory, were examined in 63 female adolescents with AN and 41 age-matched healthy controls (HC). We included three time points (admission, discharge, and 1-year follow-up) and investigated the clinical data to assess whether the gut microbiota was associated with cytokine alterations. Relative to the HC group, serum levels of IL-1β and IL-6 were significantly lower during the acute phase (admission) of AN. IL-1β expression was normalised to control levels after weight recovery. TNF-α levels were not significantly different between the AN and HC groups. IL-15 levels were significantly elevated in patients with AN at all time points. We found associations between cytokines and bodyweight, illness duration, depressive symptoms, and the microbiome. In contrast to most findings for adults, we observed lower levels of the pro-inflammatory cytokines IL-1β and IL-6 in adolescent patients, whereas the level of IL-15 was consistently increased. Thus, the presence of inflammatory dysregulation suggests a varied rather than uniform pro-inflammatory state.

Keywords: IL-15; IL-1β; IL-6 (TNF-α); anorexia nervosa; cytokines; gut microbiome.

Figure 1

Concentrations–of cytokines in patients with anorexia nervosa (AN) and in healthy controls (HCs) at admission, discharge, and 1-year follow-up. Boxplots of serum cytokine levels, including mean and standard errors, comparing the AN and HC groups at admission, discharge, and 1-year follow-up for (A) IL-15, (B) IL-6, (C) Il-1β, and (D) TNF-α. Cytokine concentrations were log-transformed and batch-corrected via z-standardisation. Mann–Whitney U tests were performed to compare cytokine levels at each time point owing to their non-normal distributions. ns = not significant * p < 0.05, ** p < 0.01, *** p < 0.001.

Figure 2

Clinical associations of IL-15 and TNF-α in patients with anorexia nervosa. Correlations between IL-15 at admission and (A) body mass index standard deviation scores (BMI-SDS) at admission and (B) illness duration. Differences in IL-15 between (C) discharge and admission or (D) 1-year follow-up and admission, compared to the corresponding changes in BMI-SDS. (E) Correlation between changes in IL-15 levels and changes in BDI2 scores between discharge and admission. The dotted line represents the position of zero. The triangles show individual values of the patients. Cytokine levels were log-transformed via z-standardisation and batch-corrected. r: Spearman’s correlation coefficient.

Figure 3

Associations between cytokine levels and the abundance of microbiome genera in patients with anorexia nervosa (AN). Differences between cytokine levels and microbiome genera abundances at (A–D) discharge and admission and (E–H) follow-up and admission, for TNF- α (A,B,E), IL-15 (F), IL-1β (C,D), and IL-6 (G,H). Cytokine levels were log-transformed and batch-corrected. r: Spearman’s correlation coefficient.