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Fructose malabsorption in ChREBP-deficient mice disrupts the small intestine immune microenvironment and leads to diarrhea-dominant bowel habit changes

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A Correction to this article was published on 19 May 2023

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Abstract

Background

The mechanism by which incompletely absorbed fructose causes gastrointestinal symptoms is not fully understood. In this study, we investigated the immunological mechanisms of bowel habit changes associated with fructose malabsorption by examining Chrebp-knockout mice exhibiting defective fructose absorption.

Methods

Mice were fed a high-fructose diet (HFrD), and stool parameters were monitored. The gene expression in the small intestine was analyzed by RNA sequencing. Intestinal immune responses were assessed. The microbiota composition was determined by 16S rRNA profiling. Antibiotics were used to assess the relevance of microbes for HFrD-induced bowel habit changes.

Results

Chrebp-knockout (KO) mice fed HFrD showed diarrhea. Small-intestine samples from HFrD-fed Chrebp-KO mice revealed differentially expressed genes involved in the immune pathways, including IgA production. The number of IgA-producing cells in the small intestine decreased in HFrD-fed Chrebp-KO mice. These mice showed signs of increased intestinal permeability. Chrebp-KO mice fed a control diet showed intestinal bacterial imbalance, which the HFrD exaggerated. Bacterial reduction improved diarrhea-associated stool parameters and restored the decreased IgA synthesis induced in HFrD-fed Chrebp-KO mice.

Conclusions

The collective data indicate that gut microbiome imbalance and disrupting homeostatic intestinal immune responses account for the development of gastrointestinal symptoms induced by fructose malabsorption.

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Data availability

The datasets generated or analyzed during the current study are available from the corresponding author on reasonable request.

Change history

Abbreviations

APRIL:

A proliferation-inducing ligand

BAFF:

B cell-activating factor of the tumor necrosis factor family

ChREBP:

Carbohydrate-responsive element-binding protein

DEGs:

Differentially expressed genes

FPKM:

Fragments per kilobase of exon per million fragments mapped

GI:

Gastrointestinal

GSEA:

Gene set enrichment analysis

HFrD:

High-fructose diet

KEGG:

Kyoto encyclopedia of genes and genomes

KO:

Knockout

LP:

Lamina propria

LTs:

Lymphotoxins

SCFA:

Short-chain fatty acids

TGF-β:

Transforming growth factor β

WT:

Wild-type

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Acknowledgments

We thank the Gachon University Core-facility for Cell to In-vivo imaging for flow cytometer analysis.

Funding

A-RO is a recipient of a Global Ph.D. fellowship from the National Research Foundation of Korea (NRF) Grant funded by the Ministry of Education (NRF-2018H1A2A1062963). This study was supported by a National Research Foundation of Korea (NRF) Grant funded by the Korean Government (MSIT) (No. NRF-2020R1A2C1003351 and NRF-2021R1A5A2030333 to YJ, and NRF-2022R1A2C1012833 to J-YC), the Korea Mouse Phenotyping Project (2013M3A9D5072550) to J-YC, and the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI) funded by the Ministry of Health & Welfare (Grant number HI14C1135) to J-YC.

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Author notes

  1. Ah-Reum Oh

    Present address: Department of Biomedical Sciences, College of Medicine, Inha University, Incheon, 22212, Korea

  2. Jinsun Jang, Soonjae Hwang, Ah-Reum Oh, YunJae Jung, Ji-Young Cha contributed equally to this work.

Authors and Affiliations

  1. Department of Health Science and Technology, Gachon Advanced Institute for Health Science and Technology, Gachon University, Inchon, Korea

    Jinsun Jang, Ah-Reum Oh, Sohyeon Park, Uzma Yaseen, Sangbin Park, YunJae Jung & Ji-Young Cha

  2. Department of Biochemistry, Lee Gil Ya Cancer and Diabetes Institute, College of Medicine, Gachon University, 155 Gaetbeol-ro, Yeonsu-gu, Inchon, 21999, Korea

    Soonjae Hwang & Ji-Young Cha

  3. Department of Microbiology, Lee Gil Ya Cancer and Diabetes Institute, College of Medicine, Gachon University, 155 Gaetbeol-ro, Yeonsu-gu, Inchon, 21999, Korea

    Jae Gon Kim & YunJae Jung

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Contributions

Conceptualization: YJ and J-YC; methodology: JJ, SH, A-RO, YJ and J-YC; formal analysis and investigation: JJ, SH, A-RO, SP, UY, JGK, SP; writing—original draft preparation: JJ, SH, A-RO; writing—review and editing: YJ and J-YC; funding acquisition: A-RO, YJ and J-YC; resources: YJ and J-YC; supervision: YJ and J-YC. All authors reviewed the manuscript.

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Correspondence to YunJae Jung or Ji-Young Cha.

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Jang, J., Hwang, S., Oh, AR. et al. Fructose malabsorption in ChREBP-deficient mice disrupts the small intestine immune microenvironment and leads to diarrhea-dominant bowel habit changes. Inflamm. Res. 72, 769–782 (2023). https://doi.org/10.1007/s00011-023-01707-1

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