Dietary butyrate alleviates high-fat diet-induced colonic mucosal impairment accompanied by increased gut-derived indole-3-acetic acid and enhanced PPARγ signaling
- 1Department of Endocrinology, First Affiliated Hospital of Xi’an Jiaotong University
- 2MED-X institute, Center for Immunological and Metabolic Diseases, the First Affiliated Hospital of Xi’an Jiaotong University
- 3Department of Medicine, Division of Endocrinology, and Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center
Abstract
Introduction: High-fat diet (HFD) induces intestinal barrier impairment, associated with gut microbiota dysbiosis, endotoxin translocation and metabolic dysfunction. Dietary butyrate has been reported to improve intestinal homeostasis, but the underlying mechanism remains incompletely understood. This study aimed to investigate the effects of dietary butyrate on HFD-induced colonic mucosal dysfunction and to explore underlying mechanisms with respect to the role of gut microbiota and its metabolites.
Methods: Male APOE*3-Leiden.CETP mice, a well-established translational model for diet-induced metabolic dysfunction, were fed an HFD with or without 5% sodium butyrate. Metabolic phenotypes, plasma lipopolysaccharide (LPS), colonic histology, inflammatory responses, and tight junction-associated changes were assessed. Fecal microbiota transplantation (FMT) was performed in antibiotic-treated recipient mice to assess the contribution and transferability of butyrate-shaped gut microbiota. Cecal metagenomic sequencing and LC/MS-based colonic indole-3-acetic acid (IAA) measurement were performed. Caco-2 cells were used to assess the direct effects of sodium butyrate and IAA on enterocytes and to determine, through pioglitazone treatment and PPARγ knockdown, whether PPARγ mediates IAA-induced enterocyte responses.
Results: Dietary butyrate induced favorable changes in multiple colonic barrier-associated parameters, including improved colonic architecture, lower circulating LPS levels, decreased Tnf-a and Il-1b expression, and increased CLDN2, Reg-family, and PPARγ expression in the colon. In addition, butyrate reduced body weight gain, fat mass accumulation and improved glucose metabolism. FMT from butyrate-treated donors partially reproduced these beneficial effects in HFD-fed recipients. Metagenomic analysis showed enrichment of Bacteroidota and Bacteroides , particularly B. uniformis and B. thetaiotaomicron , accompanied by increased colonic IAA levels. In Caco-2 cells, IAA increased the expression of PPARγ, Reg4 , and CLDN2. While PPARγ agonist pioglitazone mimicked the upregulation of REG4 and CLDN2 expression by IAA, siRNA-induced PPARγ knockdown attenuated IAA-induced REG4 and CLDN2 upregulation.
Conclusion: Dietary butyrate improves colonic mucosal homeostasis under HFD feeding, accompanied by gut microbial remodeling and increased colonic IAA levels. Together with the PPARγ-dependent epithelial response to IAA observed in Caco-2 cells, these findings suggest a potential mechanistic framework linking butyrate-associated microbial changes, IAA metabolism, and epithelial PPARγ signaling.
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BibTeX
@article{li2026dietary,
title = {{Dietary butyrate alleviates high-fat diet-induced colonic mucosal impairment accompanied by increased gut-derived indole-3-acetic acid and enhanced PPARγ signaling}},
author = {Guoli Li and Sijing Dong and Chunhao Liu and Huan Yan and Jing Yang and Patrick C.N. Rensen and Bingyin Shi and Yanan Wang},
journal = {Frontiers in Endocrinology},
year = {2026},
month = oct,
doi = {10.3389/fendo.2026.1971187},
url = {https://www.frontiersin.org/articles/10.3389/fendo.2026.1971187/full},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Dietary butyrate alleviates high-fat diet-induced colonic mucosal impairment accompanied by increased gut-derived indole-3-acetic acid and enhanced PPARγ signaling
AU - Guoli Li
AU - Sijing Dong
AU - Chunhao Liu
AU - Huan Yan
AU - Jing Yang
AU - Patrick C.N. Rensen
AU - Bingyin Shi
AU - Yanan Wang
PY - 2026
DA - 2026/10/21
JO - Frontiers in Endocrinology
DO - 10.3389/fendo.2026.1971187
UR - https://www.frontiersin.org/articles/10.3389/fendo.2026.1971187/full
AB - Introduction: High-fat diet (HFD) induces intestinal barrier impairment, associated with gut microbiota dysbiosis, endotoxin translocation and metabolic dysfunction. Dietary butyrate has been reported to improve intestinal homeostasis, but the underlying mechanism remains incompletely understood. This study aimed to investigate the effects of dietary butyrate on HFD-induced colonic mucosal dysfunction and to explore underlying mechanisms with respect to the role of gut microbiota and its metabolites. Methods: Male APOE*3-Leiden.CETP mice, a well-established translational model for diet-induced metabolic dysfunction, were fed an HFD with or without 5% sodium butyrate. Metabolic phenotypes, plasma lipopolysaccharide (LPS), colonic histology, inflammatory responses, and tight junction-associated changes were assessed. Fecal microbiota transplantation (FMT) was performed in antibiotic-treated recipient mice to assess the contribution and transferability of butyrate-shaped gut microbiota. Cecal metagenomic sequencing and LC/MS-based colonic indole-3-acetic acid (IAA) measurement were performed. Caco-2 cells were used to assess the direct effects of sodium butyrate and IAA on enterocytes and to determine, through pioglitazone treatment and PPARγ knockdown, whether PPARγ mediates IAA-induced enterocyte responses. Results: Dietary butyrate induced favorable changes in multiple colonic barrier-associated parameters, including improved colonic architecture, lower circulating LPS levels, decreased Tnf-a and Il-1b expression, and increased CLDN2, Reg-family, and PPARγ expression in the colon. In addition, butyrate reduced body weight gain, fat mass accumulation and improved glucose metabolism. FMT from butyrate-treated donors partially reproduced these beneficial effects in HFD-fed recipients. Metagenomic analysis showed enrichment of Bacteroidota and Bacteroides , particularly B. uniformis and B. thetaiotaomicron , accompanied by increased colonic IAA levels. In Caco-2 cells, IAA increased the expression of PPARγ, Reg4 , and CLDN2. While PPARγ agonist pioglitazone mimicked the upregulation of REG4 and CLDN2 expression by IAA, siRNA-induced PPARγ knockdown attenuated IAA-induced REG4 and CLDN2 upregulation. Conclusion: Dietary butyrate improves colonic mucosal homeostasis under HFD feeding, accompanied by gut microbial remodeling and increased colonic IAA levels. Together with the PPARγ-dependent epithelial response to IAA observed in Caco-2 cells, these findings suggest a potential mechanistic framework linking butyrate-associated microbial changes, IAA metabolism, and epithelial PPARγ signaling.
SN - 1664-2392
ER -