A defective interleukin-17 receptor A1 causes weight loss and intestinal metabolism-related gene downregulation in Japanese medaka, Oryzias latipes

Yo Okamura,Masahiro Sakai,Masato Kinoshita,Jun-Ichi Hikima,Tomoya Kono,Hiroshi Miyanishi

doi:10.1038/s41598-021-91534-3

Yo Okamura, Masahiro Sakai + Show 4 more

Open Access

https://doi.org/10.1038/s41598-021-91534-3

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Journal: Scientific Reports	Publication Date: Jun 8, 2021
Citations: 5	License type: open-access

Affiliation: University of Miyazaki, Kyoto University

Abstract

In the intestine, the host must be able to control the gut microbiota and efficiently absorb transiently supplied metabolites, at the risk of enormous infection. In mammals, the inflammatory cytokine interleukin (IL)-17A/F is one of the key mediators in the intestinal immune system. However, many functions of IL-17 in vertebrate intestines remain unclarified. In this study, we established a gene-knockout (KO) model of IL-17 receptor A1 (IL-17RA1, an IL-17A/F receptor) in Japanese medaka (Oryzias latipes) using genome editing technique, and the phenotypes were compared to wild type (WT) based on transcriptome analyses. Upon hatching, homozygous IL-17RA1-KO medaka mutants showed no significant morphological abnormality. However, after 4 months, significant weight decreases and reduced survival rates were observed in IL-17RA1-KO medaka. Comparison of gene-expression patterns in WT and IL-17RA1-KO medaka revealed that various metabolism- and immune-related genes were significantly down-regulated in IL-17RA1-KO medaka intestine, particularly genes related to mevalonate metabolism (mvda, acat2, hmgcs1, and hmgcra) and genes related to IL-17 signaling (such as il17c, il17a/f1, and rorc) were found to be decreased. Conversely, expression of genes related to cardiovascular system development, including fli1a, sox7, and notch1b in the anterior intestine, and that of genes related to oxidation–reduction processes including ugp2a, aoc1, and nos1 in posterior intestine was up-regulated in IL-17RA1-KO medaka. These findings show that IL-17RA regulated immune- and various metabolism-related genes in the intestine for maintaining the health of Japanese medaka.

Highlights

In the intestine, the host must be able to control the gut microbiota and efficiently absorb transiently supplied metabolites, at the risk of enormous infection
Among the genes known to encode antibacterial molecules that were downregulated in IL-17A/F1 KO medaka, expression of Elastase encoding genes listed in Table 2 was downregulated in IL-17RA1 KO medaka
Expression of tfa, lyz, and pla2g1b was significantly downregulated in IL-17A/F1 KO medaka, but no significant decrease was observed in IL-17RA1 KO medaka

Summary

Introduction

The host must be able to control the gut microbiota and efficiently absorb transiently supplied metabolites, at the risk of enormous infection. Expression of genes related to cardiovascular system development, including fli1a, sox[7], and notch1b in the anterior intestine, and that of genes related to oxidation–reduction processes including ugp2a, aoc[1], and nos[1] in posterior intestine was up-regulated in IL-17RA1-KO medaka. These findings show that IL-17RA regulated immune- and various metabolism-related genes in the intestine for maintaining the health of Japanese medaka. IL-17A/F signaling is important for the host’s metabolic activity in the intestinal tract, in regulating gut microbiota, and in the direct induction of metabolism-related genes

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Conclusion