Abstract
The intestine interacts with many factors, including dietary components and ethanol (EtOH), which can impact intestinal health. Previous studies showed that different types of dietary fats can modulate EtOH-induced changes in the intestine; however, mechanisms underlying these effects are not completely understood. Here, we examined intestinal transcriptional responses to EtOH in WT and transgenic fat-1 mice (which endogenously convert n6 to n3 polyunsaturated fatty acids [PUFAs]) to identify novel genes and pathways involved in EtOH-associated gut pathology and discern the impact of n3 PUFA enrichment. WT and fat-1 mice were chronically fed EtOH, and ileum RNA-seq and bioinformatic analyses were performed. EtOH consumption led to a marked down-regulation of genes encoding digestive and xenobiotic-metabolizing enzymes, and transcription factors involved in developmental processes and tissue regeneration. Compared to WT, fat-1 mice exhibited a markedly plastic transcriptome response to EtOH. Cell death, inflammation, and tuft cell markers were downregulated in fat-1 mice in response to EtOH, while defense responses and PPAR signaling were upregulated. This transcriptional reprogramming may contribute to the beneficial effects of n3 PUFAs on EtOH-induced intestinal pathology. In summary, our study provides a reference dataset of the intestinal mucosa transcriptional responses to chronic EtOH exposure for future hypothesis-driven mechanistic studies.
Highlights
The intestine interacts with many factors, including dietary components and ethanol (EtOH), which can impact intestinal health
The current study is an extension of our previous work analyzing the intestinal transcriptional responses to chronic EtOH administration that addresses the following goals: (1) to identify novel genes and pathways of intestinal dysregulation that contribute to alcohol-associated gut pathology; and (2) to examine gene expression signatures underlying the beneficial effects of n3 polyunsaturated fatty acid (PUFA)-mediated intestinal protection against EtOH-induced damage
To examine the impact of chronic EtOH administration and elevated levels of endogenous n3 PUFAs on the intestinal transcriptome, we performed RNAseq analysis and compared the transcriptomes of intestinal epithelial tissue obtained from wild type (WT) and fat-1 mice subjected to control or EtOH-containing diets (EtOH-fed mice, see Supplemental Fig. S1a for study design)
Summary
The intestine interacts with many factors, including dietary components and ethanol (EtOH), which can impact intestinal health. Inflammation, and tuft cell markers were downregulated in fat-1 mice in response to EtOH, while defense responses and PPAR signaling were upregulated This transcriptional reprogramming may contribute to the beneficial effects of n3 PUFAs on EtOH-induced intestinal pathology. The GI tract causing damaging effects on intestinal health in experimental animals and in humans These effects include pathological changes in numerous metabolic pathways and functions such as loss of gut barrier integrity, increased inflammation, and microbial dysbiosis, among o thers[7,8,9]. The current study is an extension of our previous work analyzing the intestinal transcriptional responses to chronic EtOH administration that addresses the following goals: (1) to identify novel genes and pathways of intestinal dysregulation that contribute to alcohol-associated gut pathology; and (2) to examine gene expression signatures underlying the beneficial effects of n3 PUFA-mediated intestinal protection against EtOH-induced damage. Understanding changes in the intestinal transcriptome and how these changes influence host metabolism/health in vivo may identify novel therapeutic targets for the treatment of alcohol-induced intestinal pathology
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