Tryptophan-rich diet and its effects on brain Tregs in alleviating neuroinflammation and cognitive impairment

Abstract

Abstract Background: Perioperative neurocognitive disorders (PND) present a common challenge for elderly people and contribute to increased postoperative dementia rates and mortality. Notably, neuroinflammation serves as a pivotal pathogenic mechanism for PND. Regulatory T cells (Tregs) exhibit potent anti-inflammatory properties and can modulate neurodegenerative diseases arising from central nervous system inflammatory responses. However, the role of Tregs in neuroinflammation-related PND remains unclear. It is highly plausible that brain Tregs expressing unique genes associated with the nervous system, including the Htr7 gene encoding the serotonin receptor 5-HT7, play a pivotal role. Methods: A model of neuroinflammation-mediated cognitive dysfunction was established via intracerebroventricular injection of lipopolysaccharide (LPS). The activation and infiltration of Tregs were measured using flow cytometry. Metagenomic sequencing of fecal samples was employed to investigate alterations in gut bacterial abundance following LPS administration. TMT-based quantitative proteomics analysis was employed to detect the proteomes of hippocampal tissue following LPS treatment. Primary Tregs were cocultured separately with primary CD8+ T cells and primary microglia for in vitro validation of the impact of 5-HT and Htr7 on Tregs. Prior to their transfer into recombination activating gene 1 (Rag1−/−) mice, Tregs were ex vivo transfected with lentivirus to knock down the expression of Htr7. Results: In this study, the tryptophan-rich diet was found to reverse LPS-induced cognitive impairment and reduce the levels of 5-HT in peripheral blood. Following intracerebroventricular microinjection of LPS, there was a decrease in the abundance of 5-HT-related gut microbiota. The tryptophan-rich diet led to increased levels of 5-HT in peripheral blood, which in turn promoted the proliferation and activation of brain Tregs. Additionally, proteomic alterations were observed in the hippocampus of the mice following LPS treatment. The tryptophan-rich diet was also shown to attenuate LPS-mediated neuroinflammation by activating brain Tregs. Furthermore, 5-HT and Htr7 were found to enhance the immunosuppressive effect of Tregs on CD8+ T cells and microglia. In Rag1-/- mice, brain Tregs were shown to alleviate LPS-induced neuroinflammation and cognitive impairment. Conclusions: Our research revealed the ability of brain Tregs to mitigate neuroinflammation and prevent neuronal damage by suppressing the infiltration of CD8+ T cells into the brain and excessive activation of microglia, thereby ameliorating LPS-induced cognitive impairment. These insights may offer novel therapeutic targets involving Tregs for PND.