Abstract
A high-fat diet (HFD) alters the gut microbiota (GM), impairs metabolic efficiency, and increases gut permeability and inflammation. Obesity and insulin resistance are associated with GM dysbiosis. The GM is strongly associated with metabolic disorders and fatty liver disease. The co-chaperone protein FK506-binding protein-5 (FKBP5) regulates several vital cellular processes. Although FKBP5 has been implicated in stress-related disorders, it has not been directly linked to HFD-induced metabolic fatty liver disease. This study aimed to elucidate how FK506 binding protein 5 impairment affects the GM in HFD-induced metabolic dysfunction–associated fatty liver disease and metabolic dysfunction-associated steatotic liver disease (MASLD). Wild-type and FKBP5-knockout (FKKO) mice were fed a normal chow diet or a high-fat diet for 16 weeks. Mouse GM was examined using 16 S rRNA metagenomic analysis. The number of gut-liver immune cells was measured using flow cytometry. HFD-induced hepatic steatosis and inflammation were prevented in FKBP5-deficient mice. FKKO animals showed higher butyric acid levels and GM resistance to diet-induced obesity alterations according to 16 S ribosomal rRNA gene analysis and displayed an HFD-specific gut-liver immunological response that maintained gut barrier failure and mucosal immunity, which are important for GM homeostasis. FKBP5 helps the GM address inadequate immunological responses, including lower gut and liver CD11b+Ly6C+ monocytes and neutrophils, and protects against obesity by improving the GM response to HFD-induced MASLD. FKBP5 protects against HFD-induced MASLD through metabolic coordination between the gut barrier and intrahepatic immunity.
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Data availability
The data supporting the findings of this study are available from the corresponding author upon request. The sequencing data were deposited in the DNA Data Bank of Japan under accession number PRJNA610239 for 16 S rRNA sequencing.
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Acknowledgements
We would like to express our gratitude to Dr. Yu-Lun Kuo of BIOTOOLS Co., Ltd., Taiwan, for assisting us with the NGS data analysis. We would also like to express our gratitude for the technical help offered by the flow cytometric analysis, sorting, and imaging cores of the First Core Laboratory at the National Taiwan and Yang Ming University College of Medicine. We thank the NYCU Microbiota Research Center and the Taiwan Mouse Clinical National Comprehensive Mouse Phenotyping and Drug Testing Center. We thank National Center for Biomodels (NCB), NIAR, Taiwan, for technical support in service of isolator. We thank the Taiwan Mouse Clinic, Academia Sinica, and the Taiwan Animal Consortium for their technical support. NLAC (NARLabs, Taiwan) provided technical assistance to isolators. The authors acknowledge the research collaboration and technical service supported by National Human Microbiome Core Facility, Taiwan. We acknowledge the research collaboration and technical service supported by National Human Microbiome Core Facility. FKBP5 KO mice were obtained from Dr. Yi Hsuan Lee. We are grateful to the summer student Zi-Yun Wang (Department of Pharmacology & Toxicology, University of Toronto, Toronto, ON M5S 1A8, Canada) for assistance with data analysis. All authors discussed the results and approved the manuscript.
Funding
Ministry of Science and Technology (MOST) of Taiwan, Grant Number: 108-2320-B-010-045-MY3, 110-2320-B-002-080-MY3, MOST 111-2314-B-A49-072, NSTC 112-2314-B-A49-028-MY3, NSTC 112-2740-B-A49-002, NSTC 113-2740-B-A49-003, NSTC 113-2321-B-A49-014-, NSTC 114-2321-B-A49-004 -, NSTC 114-2740-B-A49-003- (to LLW), and MOST 106-2320-B-010-009-MY3 (to CCJ); Yen Tjing Ling Medical Foundation, Grant Number: CI-110-22,CI-111-24 and CI-115-33 (to LLW).
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Li-Ling Wu conceived and designed the experiments; Yu-Jen Liao, Luen-Kui Chen, Yi-Chen Huang, Chia-Yen Chen, Wei-Hao Peng Performed the experiments; Li-Ling Wu and Yu-Jen Liao conducted the data analysis; Li-Ling Wu and Chi-Chang Juan revised the manuscript; Li-Ling Wu Wrote the manuscript. All authors have read and agreed to the published version of the manuscript.
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Wu, LL., Liao, YJ., Peng, WH. et al. FK506-binding protein-5 in high-fat diet-induced metabolic dysfunction-associated steatotic liver disease. Sci Rep (2026). https://doi.org/10.1038/s41598-026-38549-w
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DOI: https://doi.org/10.1038/s41598-026-38549-w
