Insights into inflammatory depression: investigating the relationship between plasma short-chain fatty acids, inflammatory markers, and depressive symptoms

Background: Research in recent years has shown that inflammation, characterized by increased levels of inflammatory markers such as C-reactive protein (CRP) or Interleukin (IL)-6 is present in a substantial subgroup of individuals with Major Depressive Disorder (MDD). Animal models suggest that short-chain fatty acids (SCFAs) such as butyrate, acetate, and propionate, which are strongly associated with immune system regulation, may play an important role in mediating anti-inflammatory effects in depression [1]. However, the relationship between circulating SCFAs, inflammation, and depressive symptoms has barely been studied in larger human cohorts to date.

Aim: To gain a better understanding of the role of SCFAs in inflammatory depression, we systematically investigated the relationship between circulating SCFAs, inflammatory markers, and depressive symptoms in a well-characterized human cohort.

Methods: For the present analysis, data from baseline time points of five studies (PRIME, ENFORCE, PRIME-REWARD, MODULATE, and DeFLAME) conducted at Goethe university hospital Frankfurt were pooled, including 156 participants with MDD and 156 age-, sex-, and body mass index (BMI)-matched HCs. CRP was measured in the Central Laboratory, peripheral inflammatory markers, IL-6, tumour necrosis factor (TNF)-α, and IL-10, were measured using a proximity extension assay (OLINK) performed by the Fraunhofer Institute for Translational Medicine and Pharmacology, and SCFA levels were determined via gas chromatography-mass spectrometry, using fasted plasma samples. The Beck Depression Inventory (BDI) was used to assess depression severity. Statistical analyses were conducted in R and included spearman correlation and linear models, using age, sex, and BMI as covariates.

Results: Peripheral CRP levels did not differ between subjects with MDD and HCs (β = -0.03, t = -0.31, p = 0.76), but IL-6 levels were significantly increased in individuals with MDD (β = 0.37, t = 3.92, p < 0.001). There were no significant differences in plasma SCFA levels between the two groups for butyrate (β = 0.06, t = 0.53, p = 0.59), acetate (β = -0.01, t = -0.09, p = 0.93), and propionate (β = 0.16, t = 1.46, p = 0.15), and these findings remained unchanged after stratification by CRP levels (< 1 mg/L versus ≥ 1 mg/L), indicating no vs. mild inflammation. Further, none of the inflammatory markers (CRP, IL-6, TNF-α, and IL-10) were predictive for butyrate, acetate or propionate levels (all p > 0.11). Correlation analyses revealed no association between BDI scores and butyrate (ρ = 0.02, p = 0.70) and acetate (ρ = -0.06, p = 0.27). There was a weak positive correlation between BDI score and propionate (ρ = 0.12, p = 0.04).

Conclusion: Although IL-6 was significantly increased in subjects with MDD, indicating the presence of inflammatory processes in depression, there was no relationship between inflammatory markers and circulating SCFAs. Furthermore, peripheral SCFA levels were not altered in depressed patients and showed only a weak association with depression severity. Together, this suggests a limited relationship of circulating SCFAs with inflammatory processes and symptom severity in depression in this cohort. Future studies may account for additional covariates such as dietary fibre intake, which may influence observed associations.

References

1. Liu, P., Liu, Z., Wang, J., Wang, J., Gao, M., Zhang, Y., Yang, C., Zhang, A., Li, G., Li, X., Liu, S., Liu, L., Sun, N., & Zhang, K. (2024). Immunoregulatory role of the gut microbiota in inflammatory depression. Nature communications, 15(1), 3003. https://doi.org/10.1038/s41467-024-47273-w.