Disruption of Intestinal Homeostasis Through Altered Responses of the Microbial Community, Energy Metabolites, and Immune System in Zebrafish After Chronic Exposure to DEHP

Abstract

Di-(2-ethylhexyl) phthalate (DEHP) is ubiquitously reported in global water bodies and exhibits various environmental and human health risks. However, the effects of DEHP chronic exposure on the intestinal microbiota and associated host health concerns in aquatic species are still largely unexplored. In this study, chronic exposure to DEHP at environmental levels significantly increased the body weight, length, and body mass index (BMI), especially in male fish. The microbial community was disrupted with the relative abundance of phylum Firmicutes and genera diversity for Prevotella-7, Deefgea, PeM15, Halomonas, Akkermansia, Chitinibacter, and Roseomonas, which are significantly activated in zebrafish after exposure to DEHP. The height of the gut villus, the thickness of muscularis layer, and the number of goblet cells per villus were significantly decreased, as well as showed differences between female and male zebrafish. Further, the levels of energy-related metabolites in gut tissues were increased, compared to the control group. The expression levels of immune-related genes (interleukin 8, il-8, also referred to as cxcl8a), microbial defense-related genes (lysozyme, lyz, interleukin 10, and il-10), and obesity-related genes (aquaporin 8a, aqp8, mucin 2.1, muc2.1, fibroblast growth factor 2, fgf2, and proopiomelanocortin a, pomca) were significantly up-regulated in zebrafish, except the down-regulated expressions of toll-like receptor-5 (tlr-5) and interleukin 1β (il-1β) in the females and pomca in the males, respectively. Importantly, Spearman’s correlation analyses revealed that the levels of metabolites and gene expressions in the gut were closely related to the dominant microbial genera, such as Aeromonas, Deefgea, Akkermansia, PeM15, Mycobacterium, and Rhodobacter. Taken together, chronic exposure to DEHP at environmental levels disturbed bacterial composition accompanied by the altered expressions of intestinal metabolites and the critical immune and intestinal function-related genes, which provided novel insights into DEHP effects on perturbation of gut microbiota and metabolic homeostasis in zebrafish.

Characterization of Gut Microbiome in the Mud Snail Cipangopaludina cathayensis in Response to High-Temperature Stress

“…Halomonas strains are also considered to be pathogenic in fish [ 80 , 81 ]. Indeed, Halomonas are found to be elevated in the intestine of zebrafish ( Danio rerio ) after pathogen invasion [ 80 ] or exposure to environmental stress (e.g., Microcystis aeruginosa and phthalate esters), inducing intestinal innate immune responses [ 80 ], which results in intestinal injury [ 82 ]. These findings illustrate that the health of C. cathayensis exposed to thermal stress may be impaired.…”

“…Therefore, we speculate that increasing temperatures disrupt Firmicutes homeostasis and inhibit carbohydrate metabolism pathways, thus, inhibiting the growth of C. cathayensis . Gut microbiota homeostasis also plays an important role in host health [ 80 , 82 ]. Under thermal stress, one disease-related pathway was found to be enriched in T1, whereas more disease-related pathways were detected in T2.…”

Di‐(2‐ethylhexyl) phthalate exposure links to inflammation and low bone mass in premenopausal and postmenopausal females: Evidence from ovariectomized mice and humans

“…Moreover, DEHP not only increases the secretion of IL‐8 and monocyte chemoattractant protein‐1 by a human adipocyte model during induction of adipogenesis, 29 but it also facilitates the production of IL‐1β, IL‐8, IL‐6, and TNF‐α by human macrophage‐like THP‐1 cells 30 . DEHP exposure also upregulates the gene expressions of IL‐8 and IL‐10 by zebrafish intestines 31 . Furthermore, a variety of inflammatory cytokines, including plasma IL‐6, IL‐17A, and tissue TNF‐α have been shown to be upregulated by DEHP stimulation during the juvenile period in a mouse model through epigenetic regulation 32 .…”

“…15,22,26 30 DEHP exposure also upregulates the gene expressions of IL-8 and IL-10 by zebrafish intestines. 31 Furthermore, a variety of inflammatory cytokines, including plasma IL-6, IL-17A, and tissue TNFα have been shown to be upregulated by DEHP stimulation during the juvenile period in a mouse model through epigenetic regulation. 32 DEHP is also capable of inducing macrophage infiltration in adipose tissue and promoting the production of serum and tissue IL-1β and TNFα in a Wistar rat model.…”

Epigenetics and mitochondrial dysfunction insights into the impact of the progression of non‐alcoholic fatty liver disease

“…JAK and STAT 5, which transactivates PPARγ for adipogenesis, have previously been discovered to be important in adipocytes. DEHP allows them to express at a higher level in an attempt to uphold liver homeostasis and lipid composition 31 . Other components of NAFLD are being revealed in a new analysis.…”