Lycopene ameliorates Di-(2-ethylhexyl) phthalate-induced neurotoxicity in mice via the gut-brain axis

Abstract

Background

Di(2-ethylhexyl) phthalate (DEHP), a ubiquitous plasticizer present in numerous consumer products, poses a substantial neurotoxic risk through environmental and dietary exposure. Growing evidence highlights a critical association between DEHP-induced neurotoxicity and gut microbiota dysbiosis. Renowned for its potent antioxidant and anti-inflammatory capabilities, the natural carotenoid lycopene (Lyc) demonstrates therapeutic promise in treating various neurological disorders.

Purpose

The potential neuroprotective mechanisms of Lyc against DEHP-induced neurotoxicity in mice were investigated in this study, with a specific focus on its interaction with the gut-brain axis.

Methods

For 35 consecutive days, mice received daily intragastric administrations of DEHP or Lyc. A comprehensive approach involving integrated transcriptome, microbiome, and molecular biology analyses, in conjunction with bacteriotherapy, was utilized to thoroughly investigate the underlying mechanisms.

Results

Our findings demonstrated that Lyc administration or fecal microbiota transplantation (FMT) from Lyc-treated mice effectively ameliorated DEHP-induced anxiety- and depression-like behaviors. At the molecular level, Lyc mitigated neuroinflammation in the hippocampus, potentially through modulation of the NOD-like receptor signaling pathway. Furthermore, Lyc treatment improved gut microbiota composition by promoting the growth of beneficial bacteria, such as Akkermansiaceae, and enhanced intestinal barrier integrity via increased expression of tight junction proteins. Lyc also regulated the LPS-TLR4/MyD88 signaling pathway in the colon, thereby reducing local inflammation.

Conclusion

These results provide compelling evidence that Lyc confers protection against DEHP-induced neurotoxicity through a multifaceted strategy involving modulation of gut-brain axis, suppression of neuroinflammation, and restoration of gut homeostasis. We propose a novel therapeutic strategy to alleviate the risks posed by DEHP to both neurological and intestinal health. This approach involves either supplementation with Lyc or the application of bacteriotherapy.