Exogenous antibiotic resistance gene contributes to intestinal inflammation by modulating the gut microbiome and inflammatory cytokine responses in mouse

ABSTRACT

Dysregulation of the gut microbiota by environmental factors is associated with a variety of autoimmune and immune-mediated diseases. In addition, naturally-occurring extracellular antibiotic resistance genes (eARGs) might directly enter the gut via the food chain. However, following gut microbiota exposure to eARGs, the ecological processes shaping the microbiota community assembly, as well as the interplay between the microbiota composition, metabolic function, and the immune responses, are not well understood. Increasing focus on the One Health approach has led to an urgent need to investigate the direct health damage caused by eARGs. Herein, we reveal the significant influence of eARGs on microbiota communities, strongly driven by stochastic processes. How eARGs-stimulate variations in the composition and metabolomic function of the gut microbiota led to cytokine responses in mice of different age and sex were investigated. The results revealed that cytokines were significantly associated with immunomodulatory microbes, metabolites, and ARGs biomarkers. Cytokine production was associated with specific metabolic pathways (arachidonic acid and tryptophan metabolic pathways), as confirmed by ex vivo cytokine responses and recovery experiments in vivo. Furthermore, the gut microbial profile could be applied to accurately predict the degree of intestinal inflammation ascribed to the eARGs (area under the curve = 0.9616). The present study provided a comprehensive understanding of the influence of an eARGs on immune responses and intestinal barrier damage, shedding light on the interplay between eARGs, microbial, metabolites, and the gut antibiotic resistome in modulating the human immune system.

Graphical Abstract

KEYWORDS:

• eARGs
• gut microbiome assembly
• inflammatory cytokine response
• metabolic profiles
• intestinal inflammation

Disclosure statement

No potential conflict of interest was reported by the author(s).

Author contributions

DY and JL conceived and designed the study. RT, MJ, YS, LW, and JY performed the experiments. ZC, YS, and TC performed the statistical analysis. RT and DY wrote the manuscript. DY and JL reviewed and edited the manuscript.

Date availability

All data used to support the results of this study, including macrogenome data (bioproject ID: PRJNA863052) and 16S sequencing data (bioproject ID: PRJNA863739), have been uploaded to the NCBI.

Supplementary material

Supplemental data for this article can be accessed online at https://doi.org/10.1080/19490976.2022.2156764

Correction Statement

This article has been corrected with minor changes. These changes do not impact the academic content of the article.

Additional information

Funding

This work was supported by the key projects of National Natural Science Foundation of China [grant number 41831287], and the Tianjin Municipal Natural Science Foundation [grant number 19JCZDJC39900].