Inhibition of IRAK4 by microbial trimethylamine blunts metabolic inflammation and ameliorates glycemic control
File(s)
Published version
OA Location
Author(s)
Type
Journal Article
Abstract
The global type 2 diabetes epidemic is a major health crisis. Although the microbiome has roles in the onset of insulin resistance (IR), low-grade inflammation and diabetes, the microbial compounds controlling these processes remain to be discovered. Here, we show that the microbial metabolite trimethylamine (TMA) decouples inflammation and IR from diet-induced obesity by inhibiting interleukin-1 receptor-associated kinase 4 (IRAK4), a central kinase in the Toll-like receptor pathway sensing danger signals. TMA blunts TLR4 signalling in primary human hepatocytes and peripheral blood monocytic cells and rescues mouse survival after lipopolysaccharide-induced septic shock. Genetic deletion and chemical inhibition of IRAK4 result in metabolic and immune improvements in high-fat diets. Remarkably, our results suggest that TMA—unlike its liver co-metabolite trimethylamine N-oxide, which is associated with cardiovascular disease—improves immune tone and glycemic control in diet-induced obesity. Altogether, this study supports the emerging role of the kinome in the microbial–mammalian chemical crosstalk.
Date Issued
2025-12-01
Date Acceptance
2025-10-22
Citation
Nature Metabolism, 2025, 7 (12), pp.2531-2547
ISSN
2522-5812
Publisher
Nature Research
Start Page
2531
End Page
2547
Journal / Book Title
Nature Metabolism
Volume
7
Issue
12
Copyright Statement
© The Author(s) 2025. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
License URL
Identifier
https://www.ncbi.nlm.nih.gov/pubmed/41361024
PII: 10.1038/s42255-025-01413-8
Subjects
BACTERIAL-INFECTIONS
CHOLINE
Endocrinology & Metabolism
GLUCOSE
GUT MICROBIOTA
INSULIN-RESISTANCE
INTERLEUKIN-1
Life Sciences & Biomedicine
LIPID-METABOLISM
MONOOXYGENASE 3
N-OXIDE
OBESITY
Science & Technology
Publication Status
Published
Coverage Spatial
Germany
Date Publish Online
2025-12-08