Omics · study · 2026
Intestinal metabolite TMAO promotes CKD progression by stimulating macrophage M2 polarization through histone H4 lysine 12 lactylation
Listed in NCBI GEO
Chronic kidney disease (CKD) progression is tightly associated with renal fibrosis, which is regulated by macrophage M2 polarization.
Description
The intestinal metabolite trimethylamine N-oxide (TMAO) has been reported to promote CKD, yet its underlying mechanism remains unclear. Here, we elucidate a mechanism wherein TMAO excreted through the kidneys alters the pyruvate metabolism of renal tubular epithelial cells, resulting in the production of lactic acid.
Local lactic acid accumulation in the kidney promotes adjacent macrophage M2 polarization, a process speculated to be mediated by specific lactylation of macrophage genes. Through lactylation omics analysis, we identified histone H4 lysine 12 (H4K12) as the most significantly up-regulated lysine residue subjected to lactylation. Subsequent chromatin immunoprecipitation sequencing (ChIP-seq) assays revealed H4K12 lactylation on several glycometabolism gene promoters and genes.
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Furthermore, we found that this lactylation-mediated epigenetic regulation requires the assistance of the p300 protein, as knockdown of p300 weakened the trend towards M2 polarization induced by lactic acid. Using an in vivo unilateral ureteral obstruction (UUO) mouse model, we verified the M2 polarization effect of TMAO and its detrimental role in CKD, as well as the protective effect of the TMAO inhibitor iodomethylcholine (IMC) on CKD.
Our findings suggest that CKD patients exhibit increased TMAO levels, which modulate the production of lactic acid by renal intrinsic cells. Epigenetic regulations mediated by lactic acid, particularly H4K12 lactylation on macrophage genes involved in glycometabolism, may contribute to M2 polarization. Targeting TMAO or its downstream pathways could have potential therapeutic benefits in CKD.
Links
Get the data
- GEO FTP directory ftp.ncbi.nlm.nih.gov/geo/series/GSE278nnn/GSE278903 ↗
download · from NCBI GEO
Where it is published
- GEO accession page ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE278903 ↗
landing page · from NCBI GEO
Documentation and papers
- PRJNA1169546 ncbi.nlm.nih.gov/bioproject/PRJNA1169546 ↗
project · from NCBI GEO
Topics
- Stated by source
- Genome binding/occupancy profiling by high throughput sequencing · Mus musculus
- From keywords
- Life Sciences
- Inferred from text
- Disease 75% · Sequencing 75%
Provenance · 1 source records, 9 field assertions
| Source | Key | Last seen | Raw |
|---|---|---|---|
| NCBI GEO | GSE278903 | 11 d ago | JSON v1 |
| Field | Assertion | Extractor | Evidence |
|---|---|---|---|
| access_level | source · NCBI GEO | connector:ncbi_geo@1.0.0 | |
| concepts[disease].local:disease:disease | enrichment · NCBI GEO | keyword-concept-rules@1.0.0 | title+description (75%) |
| concepts[field].local:field:life-sciences | mapping · NCBI GEO | connector:ncbi_geo@1.0.0 | |
| concepts[method].geo_series_type:genome-binding-occupancy-profiling-by-high-throughput-sequencing | source · NCBI GEO | connector:ncbi_geo@1.0.0 | /gdstype |
| concepts[modality].local:modality:sequencing | enrichment · NCBI GEO | keyword-concept-rules@1.0.0 | title+description (75%) |
| concepts[organism].NCBITaxon:10090 | source · NCBI GEO | connector:ncbi_geo@1.0.0 | /taxon |
| description | source · NCBI GEO | connector:ncbi_geo@1.0.0 | /summary |
| publication_date | source · NCBI GEO | connector:ncbi_geo@1.0.0 | |
| title | source · NCBI GEO | connector:ncbi_geo@1.0.0 | /title |