Roseburia intestinalis ameliorates adolescent depression via GPR43‑dependent Treg cell expansion and suppression of neuroinflammation

Adolescent depression has rapidly emerged as a critical public health concern, driven by its soaring prevalence, profound functional impairment, and heightened suicide risk. However, the underlying mechanisms remain poorly understood. A growing body of evidence highlights the gut microbiota-brain axis as a key modulator of host emotional function, acting through interconnected immune, metabolic, and neural pathways. In the current work, a clinical study involving first-diagnosed adolescent depression patients was conducted and significant reductions in Roseburia intestinalis (R.i.) and its metabolite butyrate were identified. Therefore, we hypothesized that alterations in R.i. and butyrate may be involved in adolescent depression and may serve as novel therapeutic strategy. Intriguingly, transplantation of R.i. obviously retarded the chronic restraint stress (CRS)-induced depression in adolescent mice. Critically, this protective effect was completely abrogated by blocking the G protein-coupled receptor 43 (GPR43). Mechanistically, we delineated a novel “peripheral-central” regulatory cascade: R.i. robustly promoted the expansion of peripheral CD25⁺Foxp3⁺ regulatory T (Treg) cells, alleviating pathological inflammation in both of the colon (peripheral) and brain (central). Reciprocally, depletion of Treg cells completely abolished not only R.i.’s antidepressant effects but also its anti-inflammatory actions in the colon and brain in vivo. The in vitro study revealed that either the R.i. conditioned or heated culture medium obviously alleviated the LPS+corticosterone induced neuroinflammation in microglial cells, shifting reactive state toward a homeostatic state. Collectively, our study for the first time reveals that R.i. ameliorates adolescent depression-like changes through a GPR43-dependent, Treg-mediated mechanism. Given the unmet clinical need for clinical diagnosis and therapy of adolescent depression, the present study provided the potential translational values for the novel treatments, such as transplantation of R.i. or butyrate supplement, which represent promising therapeutic strategies.