Angptl4 integrates dietary and microbial signals to disrupt gut barrier function in MASH

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a major contributor to liver morbidity, yet mechanisms linking gut barrier dysfunction to early progression remains poorly defined. We identify intestinal angiopoietin-like 4 (Angptl4) as a central integrator of dietary and microbial signals that governs barrier integrity and hepatic oxidative stress, key early MASLD features. Using intestinal-specific Angptl4 knockout mice, mechanistic in vitro systems, humanized microbiota models, and multi-cohort human studies, we show that intestinal Angptl4 expression is regulated by dietary fatty acids via PPARα signaling and microbiota-derived pattern-recognition pathways, including flagellin-activated-TLR5-EGR1 activation, alongside diet-associated shifts in TLR signaling. These signals destabilize epithelial barriers, amplifying gut-to-liver metabolic and microbial flux. In human cohorts, fecal Angptl4 increases with dysbiosis and metabolic dysfunction, capturing a gut barrier-related dimension distinct from endotoxemia or acute injury. Thus, intestinal Angptl4 emerges as a mechanistic hub linking diet, microbiota, and gut-liver dysfunction, supporting precision barrier-targeted strategies in MASLD.

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Publication Details

Journal
Nature Communications
Published
2026-05-22
DOI
https://doi.org/10.1038/s41467-026-72575-6
Primary Topic
Lipid metabolism and disorders
Type
article
Field-Weighted Citation Impact
0.00
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article

Angptl4 integrates dietary and microbial signals to disrupt gut barrier function in MASH

Marcus Ivan Gerard Vos, Mintu Pal, Walter Wahli, Sunny H. Wong et al.
Nature Communications
Lipid metabolism and disorders
article

Angptl4 integrates dietary and microbial signals to disrupt gut barrier function in MASH

Marcus Ivan Gerard Vos, Mintu Pal, Walter Wahli, Sunny H. Wong, Rattanaporn Kiatbumrung, Kazuyuki Kasahara, Damien Chua, Gourav Kaushal, Nguan Soon Tan, Pornjira Somnark, Natthaya Chuaypen, Zun Siong Low, Kuo Chao Yew, Hong Sheng Cheng, Beiming Cui, Natalie Hooi, Christine Cheung, Min Xu, Mathan Raj, Shaun Tan, Ekaterina Sviriaeva, Chun Loong Ho, Aparna Mahadevan, Joseph Han Sol Kim, Liang Li, Pisit Tangkijvanich, Yue Shi, Yin Hao Lee, Ru Zhang
article en

Abstract

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a major contributor to liver morbidity, yet mechanisms linking gut barrier dysfunction to early progression remains poorly defined. We identify intestinal angiopoietin-like 4 (Angptl4) as a central integrator of dietary and microbial signals that governs barrier integrity and hepatic oxidative stress, key early MASLD features. Using intestinal-specific Angptl4 knockout mice, mechanistic in vitro systems, humanized microbiota models, and multi-cohort human studies, we show that intestinal Angptl4 expression is regulated by dietary fatty acids via PPARα signaling and microbiota-derived pattern-recognition pathways, including flagellin-activated-TLR5-EGR1 activation, alongside diet-associated shifts in TLR signaling. These signals destabilize epithelial barriers, amplifying gut-to-liver metabolic and microbial flux. In human cohorts, fecal Angptl4 increases with dysbiosis and metabolic dysfunction, capturing a gut barrier-related dimension distinct from endotoxemia or acute injury. Thus, intestinal Angptl4 emerges as a mechanistic hub linking diet, microbiota, and gut-liver dysfunction, supporting precision barrier-targeted strategies in MASLD.

Nature Communications
Agency for Science, Technology and Research (SG), Chulalongkorn University (TH), Nanyang Technological University (SG), École Nationale Vétérinaire de Toulouse (FR), Chinese University of Hong Kong (HK), King Chulalongkorn Memorial Hospital (TH), Tan Tock Seng Hospital (SG), Southern University of Science and Technology (CN), Institut National de Recherche pour l'Agriculture, l'Alimentation et l'Environnement (FR), Toxicologie Alimentaire (FR), Shenzhen Institutes of Advanced Technology (CN), All India Institute of Medical Sciences (IN), Institute of Molecular and Cell Biology (SG), University of Lausanne (CH)
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Lipid metabolism and disorders
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