High-fat diet-mediated dysbiosis exacerbates NSAID-induced small intestinal damage through the induction of interleukin-17A

Naoki Sugimura,Koichi Taira,Shuhei Hosomi,Kosuke Fujimoto,Tetsuya Tanigawa,Toshio Watanabe,Yasuaki Nagami,Yasuhiro Fujiwara,Satoshi Uematsu,Sunao Shimada,Koji Otani,Yuji Nadatani,Noriko Kamata,Geicho Nakatsu,Fumio Tanaka

doi:10.1038/s41598-019-52980-2

Naoki Sugimura, Koichi Taira + Show 13 more

Open Access

https://doi.org/10.1038/s41598-019-52980-2

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Abstract

Non-steroidal anti-inflammatory drugs (NSAIDs) cause damage in the small intestine in a bacteria-dependent manner. As high-fat diet (HFD) is a potent inducer of gut dysbiosis, we investigated the effects of HFD on bacterial flora in the small intestine and NSAID-induced enteropathy. 16S rRNA gene analysis revealed that the population of Bifidobacterium spp. significantly decreased by fold change of individual operational taxonomic units in the small intestine of mice fed HFD for 8 weeks. HFD increased intestinal permeability, as indicated by fluorescein isothiocyanate-dextran absorption and serum lipopolysaccharide levels, accompanied by a decrease in the protein expressions of ZO-1 and occludin and elevated mRNA expression of interleukin (IL)-17A in the small intestine. HFD-fed mice exhibited increased susceptibility to indomethacin-induced damage in the small intestine; this phenotype was observed in normal diet-fed mice that received small intestinal microbiota from HFD-fed mice. Administration of neutralizing antibodies against IL-17A to HFD-fed mice reduced intestinal permeability and prevented exacerbation of indomethacin-induced damage. Thus, HFD-induced microbial dysbiosis in small intestine caused microinflammation through the induction of IL-17A and increase in intestinal permeability, resulting in the aggravation of NSAID-induced small intestinal damage.

Highlights

Non-steroidal anti-inflammatory drugs (NSAIDs) cause damage in the small intestine in a bacteriadependent manner
We demonstrated that high-fat diet (HFD) treatment changed the gut microbiota in the small intestine and exacerbated NSAID-induced small intestinal damage
Microbiota analysis showed that the proportion of gram-positive anaerobic bacilli, Bifidobacterium spp., was significantly reduced in HFD-fed mice

Summary

Introduction

Non-steroidal anti-inflammatory drugs (NSAIDs) cause damage in the small intestine in a bacteriadependent manner. As high-fat diet (HFD) is a potent inducer of gut dysbiosis, we investigated the effects of HFD on bacterial flora in the small intestine and NSAID-induced enteropathy. Administration of neutralizing antibodies against IL-17A to HFD-fed mice reduced intestinal permeability and prevented exacerbation of indomethacin-induced damage. HFD-induced microbial dysbiosis in small intestine caused microinflammation through the induction of IL-17A and increase in intestinal permeability, resulting in the aggravation of NSAID-induced small intestinal damage. HFD-induced dysbiosis attenuates intestinal barrier function[9], resulting in leaky gut that causes metabolic endotoxemia, inflammation, and associated disorders due to increased intestinal permeability[10]. We investigated changes in bacterial flora and permeability within the small intestine after HFD intake and their influence on NSAID-induced small intestinal damage in mice

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