High-fat diet-derived metabolite uridine diphosphate (UDP) impairs epithelial regeneration by P2Y 6 -receptor signaling.
- 1Department of General, Visceral, Transplantation, Vascular and Paediatric Surgery (Department of Surgery I), University Hospital Wuerzburg, Wuerzburg, Germany.
- 2Pharmaceutical Biology, Julius-von-Sachs-Institute, Biocenter University of Wuerzburg, Wuerzburg, Germany.
- 3Department of Biochemistry and Molecular Biology, Theodor Boveri Institute, Biocenter University of Wuerzburg, Wuerzburg, Germany.
Abstract
Obesity is associated with a chronic low-grade inflammation affecting metabolic changes and organ dysfunction. Impairment of the intestinal epithelial barrier (IEB) and alterations in gut microbiota are considered to contribute to this phenotype by largely undefined mechanisms. Here, we used a diet-induced obesity model in rats to investigate the early interplay between a high-fat diet (HFD), gut microbiota composition, metabolic stool contents and IEB regeneration. Male Wistar rats received either a high-fat diet or a low-fat diet (LFD) ad libitum. HFD feeding resulted in weight gain and impaired oral glucose tolerance. Impairment of IEB function was evident by augmented lipopolysaccharide levels in the blood and reduced expression of junctional proteins Claudin-3, 4, and Desmoglein-2 in colonic samples of HFD rats. 16S-rRNA marker-gene sequencing of colonic microbiota revealed decreased phylogenetic diversity in HFD rats and significant alterations in microbial community composition. Detailed analysis revealed that content from HFD rats impaired intestinal epithelial regeneration in organoid assays. Metabolomic profiling identified uridine monophosphate/uridine diphosphate (UMP/UDP) metabolites as strongly enriched in HFD samples. UDP emerged as a key metabolite mediating impaired epithelial regeneration through P2Y₆ receptor signaling, as pharmacological inhibition of P2Y₆ with antagonist MRS2578 attenuated both UDP- and HFD-induced loss of epithelial regeneration. In summary, these data demonstrate that the diet-dependent stool metabolite UDP compromises intestinal epithelial repair via P2Y₆ receptor signaling in early obesity. These findings link impaired epithelial regeneration to the onset of obesity-associated low-grade inflammation.
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BibTeX
@article{springer2026highfat,
title = {{High-fat diet-derived metabolite uridine diphosphate (UDP) impairs epithelial regeneration by P2Y 6 -receptor signaling.}},
author = {Rebecca Springer and Philip Claus and Marius Hörner and Christoph Otto and Natalie Burkard and Jakob Lauerer and Hanna Deinlein and Agnes Fekete and Werner Schmitz and Florian Seyfried and Nicolas Schlegel},
journal = {Gut microbes},
year = {2026},
month = oct,
doi = {10.1080/19490976.2026.2748160},
url = {https://europepmc.org/article/MED/42881530},
note = {CC BY},
}
RIS
TY - JOUR
TI - High-fat diet-derived metabolite uridine diphosphate (UDP) impairs epithelial regeneration by P2Y 6 -receptor signaling.
AU - Rebecca Springer
AU - Philip Claus
AU - Marius Hörner
AU - Christoph Otto
AU - Natalie Burkard
AU - Jakob Lauerer
AU - Hanna Deinlein
AU - Agnes Fekete
AU - Werner Schmitz
AU - Florian Seyfried
AU - Nicolas Schlegel
PY - 2026
DA - 2026/10/15
JO - Gut microbes
DO - 10.1080/19490976.2026.2748160
UR - https://europepmc.org/article/MED/42881530
AB - Obesity is associated with a chronic low-grade inflammation affecting metabolic changes and organ dysfunction. Impairment of the intestinal epithelial barrier (IEB) and alterations in gut microbiota are considered to contribute to this phenotype by largely undefined mechanisms. Here, we used a diet-induced obesity model in rats to investigate the early interplay between a high-fat diet (HFD), gut microbiota composition, metabolic stool contents and IEB regeneration. Male Wistar rats received either a high-fat diet or a low-fat diet (LFD) ad libitum. HFD feeding resulted in weight gain and impaired oral glucose tolerance. Impairment of IEB function was evident by augmented lipopolysaccharide levels in the blood and reduced expression of junctional proteins Claudin-3, 4, and Desmoglein-2 in colonic samples of HFD rats. 16S-rRNA marker-gene sequencing of colonic microbiota revealed decreased phylogenetic diversity in HFD rats and significant alterations in microbial community composition. Detailed analysis revealed that content from HFD rats impaired intestinal epithelial regeneration in organoid assays. Metabolomic profiling identified uridine monophosphate/uridine diphosphate (UMP/UDP) metabolites as strongly enriched in HFD samples. UDP emerged as a key metabolite mediating impaired epithelial regeneration through P2Y₆ receptor signaling, as pharmacological inhibition of P2Y₆ with antagonist MRS2578 attenuated both UDP- and HFD-induced loss of epithelial regeneration. In summary, these data demonstrate that the diet-dependent stool metabolite UDP compromises intestinal epithelial repair via P2Y₆ receptor signaling in early obesity. These findings link impaired epithelial regeneration to the onset of obesity-associated low-grade inflammation.
SN - 1949-0976
SN - 1949-0984
ER -