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Maternal Western-style Diet Promotes Immune Tolerance and Liver Sinusoidal Endothelial Cell Dysfunction in Nonhuman

Michael J Nash, Benjamin N Nelson, Molly McGuckin

    Biorxiv : the Preprint Server for Biology
    |January 16, 2026
    PubMed

    Insights

    Maternal Western diet during pregnancy programs offspring liver for metabolic dysfunction-associated steatotic liver disease (MASLD). This diet creates a durable, immune-tolerant, pro-fibrotic liver environment resistant to later dietary changes.

    Area of Science:

    • Hepatology
    • Immunology
    • Developmental Programming

    Background:

    • Maternal Western-style diet (mWSD) consumption during gestation and lactation is linked to metabolic dysfunction-associated steatotic liver disease (MASLD) in offspring.
    • Understanding the cellular mechanisms, particularly immune and endothelial cell roles, is crucial for addressing this developmental programming.

    Purpose of the Study:

    • To investigate the impact of maternal Western diet exposure on liver non-parenchymal cells in juvenile nonhuman primates.
    • To characterize the cellular and molecular changes in immune and endothelial cells contributing to MASLD development.

    Main Methods:

    • Single-cell RNA-sequencing of liver non-parenchymal cells from juvenile nonhuman primates exposed to mWSD.
    • Analysis of macrophage, dendritic cell, B cell, T cell, and liver sinusoidal endothelial cell (LSEC) phenotypes and functions.
    • Immunocytochemistry and RNAscope for spatial analysis of cell-cell interactions.

    Main Results:

    • mWSD exposure induced unique pro-fibrotic macrophage phenotypes with impaired reparative functions.
    • Decreased Kupffer and dendritic cell numbers, with impaired inflammatory and antigen presentation pathways in DCs, indicating immaturity.
    • Increased B cells with reduced inflammation and impaired differentiation, alongside T cells showing apoptosis and reduced inflammatory function.
    • Expanded LSEC populations with activated inflammation/proliferation but reduced immune cell communication, and increased periportal LSEC-immune cell associations.

    Conclusions:

    • Maternal Western diet establishes a persistent immune-tolerant liver microenvironment in offspring.
    • This environment is characterized by fibrogenic pathways, decreased pro-resolving macrophages, and altered immune cell profiles, promoting MASLD.
    • The programmed liver microenvironment resists postnatal dietary correction, highlighting the long-term consequences of in utero dietary exposure.

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