Exploring Metabolic and Gut Microbiome Responses to Paraquat Administration in Male Wistar Rats: Implications for Oxidative Stress

Abstract

3-hydroxibutiric acid; Gut microbiome; Oxidative stress

Àcid 3-hidroxibutíric; Microbioma intestinal; Estrès oxidatiu

Ácido 3-hidroxibutírico; Microbioma intestinal; Estrés oxidativo

In this study, we examined the metabolic and gut microbiome responses to paraquat (PQ) in male Wistar rats, focusing on oxidative stress effects. Rats received a single intraperitoneal injection of PQ at 15 and 30 mg/kg, and various oxidative stress parameters (i.e., MDA, SOD, ROS, 8-isoprostanes) were assessed after three days. To explore the omic profile, GC-qTOF and UHPLC-qTOF were performed to assess the plasma metabolome; 1H-NMR was used to assess the urine metabolome; and shotgun metagenomics sequencing was performed to study the gut microbiome. Our results revealed reductions in body weight and tissue changes, particularly in the liver, were observed, suggesting a systemic effect of PQ. Elevated lipid peroxidation and reactive oxygen species levels in the liver and plasma indicated the induction of oxidative stress. Metabolic profiling revealed changes in the tricarboxylic acid cycle, accumulation of ketone body, and altered levels of key metabolites, such as 3-hydroxybutyric acid and serine, suggesting intricate links between energy metabolism and redox reactions. Plasma metabolomic analysis revealed alterations in mitochondrial metabolism, nicotinamide metabolism, and tryptophan degradation. The gut microbiome showed shifts, with higher PQ doses influencing microbial populations (e.g., Escherichia coli and Akkermansia muciniphila) and metagenomic functions (pyruvate metabolism, fermentation, nucleotide and amino acid biosynthesis). Overall, this study provides comprehensive insights into the complex interplay between PQ exposure, metabolic responses, and gut microbiome dynamics. These findings enhance our understanding of the mechanisms behind oxidative stress-induced metabolic alterations and underscore the connections between xenobiotic exposure, gut microbiota, and host metabolism.

This research was financially supported by the Catalan Government through the funding grant ACCIÓ-Eurecat (PRIV2019-PREVENTOMICS); the Centre for the Development of Industrial Technology (CDTI) of the Spanish Ministry of Science and Innovation under grant agreement: TECNOMIFOOD project. CER-20191010; the European Union’s Horizon 2020 research and innovation program under the Marie Skłodowska-Curie grant agreement No 101034328.; the Agència de Gestió d’Ajuts Universitaris i de Recerca (AGAUR) of the Catalan Government (under agreement DOCTORAT INDUSTRIAL 2020-DI-109). J.H.-B. was supported by the Vicente Lopez fellowship (Eurecat). M.M. is a Serra Hunter research fellow.