The BHMT2/MAT1A/AHSG axis promotes M1 macrophage activation and exacerbates necrotizing enterocolitis

Background Necrotizing enterocolitis (NEC) is a devastating intestinal disorder in premature infants, characterized by inflammation and tissue injury. Identifying key regulatory pathways contributing to NEC pathogenesis is essential for developing targeted therapeutic strategies. Methods Transcriptomic analysis of NEC and control samples identified a core regulatory module comprising AHSG, BHMT2, and MAT1A. Their expression and functional roles were investigated in human primary intestinal epithelial cells (HPIECs), a transwell co-culture system with THP-1 macrophages, and a mouse model of NEC. Molecular techniques, including RT-qPCR, Western blotting, ELISA, chromatin immunoprecipitation, and flow cytometry were employed to decipher the functional mechanism of this regulatory module. Results AHSG, BHMT2, and MAT1A were upregulated in NEC samples and LPS-stimulated HPIECs. BHMT2 and MAT1A regulated AHSG expression through S-adenosylmethionine production and histone methylation. In the co-culture system, silencing BHMT2, MAT1A, or AHSG in LPS-stimulated HPIECs attenuated M1 macrophage polarization, inflammatory cytokine production, and invasive capacity of THP-1 cells. Conversely, overexpressing these genes in HPIECs promoted M1 macrophage activation. In the NEC mouse model, targeting BHMT2, MAT1A, or AHSG alleviated intestinal tissue damage, inflammation, and M1 macrophage polarization. Conclusion The BHMT2/MAT1A/AHSG axis in intestinal epithelial cells orchestrates M1 macrophage activation and contributes to the exacerbation of NEC. Targeting this pathway may represent a potential therapeutic strategy for NEC management.

• Publication year

  2025

• Venue

  Scientific Reports

• Publication date

  2025-11-11

• Fields of study

  Biology, Medicine

• Identifiers
  DOI 10.1038/s41598-025-22915-1PMID 41219226PMCID 12606173
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• Necrotizing enterocolitis: current understanding of the prevention and management

  2024cited by this paper
• Intestinal macrophages in pathogenesis and treatment of gut leakage: current strategies and future perspectives.

  2024cited by this paper
• M1 intestinal macrophages-derived exosomes promote colitis progression and mucosal barrier injury

  2024cited by this paper
• NLRP3 activation in macrophages promotes acute intestinal injury in neonatal necrotizing enterocolitis

  2023cited by this paper
• Macrophage polarization in inflammatory bowel disease

  2023cited by this paper
• New insights into intestinal macrophages in necrotizing enterocolitis: the multi-functional role and promising therapeutic application

  2023cited by this paper
• Current therapy option for necrotizing enterocolitis: Practicalities and challenge

  2022cited by this paper
• Models of necrotizing enterocolitis.

  2022cited by this paper
• Stem cell therapy as a promising strategy in necrotizing enterocolitis

  2022cited by this paper
• KEGG for taxonomy-based analysis of pathways and genomes

  2022cited by this paper
• Fetuin-A is an immunomodulator and a potential therapeutic option in BMP4-dependent heterotopic ossification and associated bone mass loss

  2022cited by this paper
• Fetuin-A in Activated Liver Macrophages Is a Key Feature of Non-Alcoholic Steatohepatitis

  2022cited by this paper
• The Role of Tissue-Resident Macrophages in the Development and Treatment of Inflammatory Bowel Disease

  2022cited by this paper
• Endoplasmic Reticulum Stress of Gut Enterocyte and Intestinal Diseases

  2022cited by this paper
• S-Adenosylmethionine: From the Discovery of Its Inhibition of Tumorigenesis to Its Use as a Therapeutic Agent

  2022cited by this paper
• Fetuin-A is a HIF target that safeguards tissue integrity during hypoxic stress

  2021cited by this paper
• Hydrogen Promotes the M1 Macrophage Conversion During the Polarization of Macrophages in Necrotizing Enterocolitis

  2021cited by this paper
• Fetuin-A regulates adipose tissue macrophage content and activation in insulin resistant mice through MCP-1 and iNOS: Involvement of IFNγ-JAK2-STAT1 pathway.

  2021cited by this paper
• Fetuin-A secretion from β-cell accumulates macrophages in islets, aggravates inflammation and impairs insulin secretion.

  2021cited by this paper
• The relationship between fetuin-A and coronary atherosclerotic heart disease (CHD) and CHD-related risk factors

  2021cited by this paper
• A Mouse Model of Necrotizing Enterocolitis.

  2021cited by this paper
• Activated M1 macrophages suppress c-kit expression via TNF-α-mediated upregulation of miR-222 in Neonatal Necrotizing Enterocolitis

  2021cited by this paper
• Serine, glycine and one-carbon metabolism in cancer (Review)

  2020cited by this paper
• Intestinal Barrier Dysfunction, LPS Translocation, and Disease Development

  2020cited by this paper
• At the Forefront of the Mucosal Barrier: The Role of Macrophages in the Intestine

  2020cited by this paper
• Neutrophils and Macrophages as Targets for Development of Nanotherapeutics in Inflammatory Diseases

  2020cited by this paper
• Pathophysiological Implication of Fetuin-A Glycoprotein in the Development of Metabolic Disorders: A Concise Review

  2019cited by this paper
• The Impact of One Carbon Metabolism on Histone Methylation

  2019cited by this paper
• A 30 Gb/s PAM4 underwater wireless laser transmission system with optical beam reducer/expander

  2019cited by this paper
• Necrotizing enterocolitis

  2019cited by this paper
• Methionine metabolism in health and cancer: a nexus of diet and precision medicine

  2019cited by this paper
• Partners in crime: neutrophils and monocytes/macrophages in inflammation and disease

  2018cited by this paper
• FTY720 attenuates intestinal injury and suppresses inflammation in experimental necrotizing enterocolitis via modulating CXCL5/CXCR2 axis.

  2018cited by this paper
• Methionine adenosyltransferases in cancers: Mechanisms of dysregulation and implications for therapy

  2018cited by this paper
• Fetuin-A deficiency protects mice from Experimental Autoimmune Encephalomyelitis (EAE) and correlates with altered innate immune response

  2017cited by this paper
• Methionine adenosyltransferases in liver health and diseases.

  2017cited by this paper
• A Perfect Match: Explant and Organoid Systems Help Study Cytokines in Sickness and Health

  2016cited by this paper
• Necrotizing enterocolitis: new insights into pathogenesis and mechanisms

  2016cited by this paper
• Monocyte and M1 Macrophage-induced Barrier Defect Contributes to Chronic Intestinal Inflammation in IBD

  2015cited by this paper
• Metabolic aspects of epigenome: coupling of S-adenosylmethionine synthesis and gene regulation on chromatin by SAMIT module.

  2013cited by this paper
• Fetuin-A acts as an endogenous ligand of TLR4 to promote lipid-induced insulin resistance

  2012cited by this paper
• Intestinal epithelial Toll-like receptor 4 regulates goblet cell development and is required for necrotizing enterocolitis in mice.

  2012cited by this paper
• Anti-inflammatory role of fetuin-A in injury and infection.

  2011cited by this paper
• Necrotizing enterocolitis.

  2011cited by this paper
• Fetuin/α2-HS Glycoprotein Is a Transforming Growth Factor-β Type II Receptor Mimic and Cytokine Antagonist*

  1996cited by this paper

• No citing papers are available for this paper.