Association between environmental phthalates exposure and gut microbiota and metabolome in dementia with Lewy bodies

Background: Emerging evidence has shown the potential involvement of phthalates (PAEs) exposure in the development of dementia with Lewy bodies (DLB). Metabolomics can reflect endogenous metabolites variation in the progress of disease after chemicals exposure. However, little is known about the association between PAEs, gut microbiota and metabolome in DLB. Objective: We aim to explore the intricate relationship among urinary PAEs metabolites (mPAEs), dysbiosis of gut bacteria, and metabolite profiles in DLB. Methods: A total of 43 DLB patients and 45 normal subjects were included in this study. Liquid chromatography was used to analyze the levels of mPAEs in the urine of the two populations. High-throughput sequencing and liquid chromatography-mass spectrometry were used to analyze gut microbiota and the profile of gut metabolome, respectively. The fecal microbiota transplantation (FMT) experiment was performed to verify the potential role of mPAEs on gut dysbiosis contribute to aggravating cognitive dysfunction in α-synuclein tg DLB/PD mice. Results: The DLB patients had higher DEHP metabolites (MEOHP, MEHHP and MEHP), MMP and MnBP, lower MBP and MBzP than the control group and different microbiota. A significantly higher abundance of Ruminococcus gnavus and lower Prevotella copri, Prevotella stercorea and Bifidobacterium were observed in DLB. Higher 3 DEHP metabolites, MMP, MnBP and lower MBP and MBzP were significantly negatively associated with Prevotella copri, Prevotella stercorea and Bifidobacterium. Additionally, using metabolomics, we found that altered bile acids, short-chain fatty acids and amino acids metabolism are linked to these mPAEs. We further found that FMT of fecal microbiota from highest DEHP metabolites donors significantly impaired cognitive function in the germ-free DLB/PD mice. Conclusion: Our study suggested that PAEs exposure may alter the microbiota-gut-brain axis and providing novel insights into the interactions among environmental perturbations and microbiome-host in pathogenesis of DLB.