Lauer, F. T. | Search bioRxiv

bioRxiv2025

Metabolomic, Lipidomic, and Enterohormone Changes in the Progression from MASLD to MASH

Background & AimsMetabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) and Metabolic Dysfunction-Associated Steatohepatitis (MASH) represent progressive stages of liver disease, with distinct metabolic and cellular alterations. This study investigates the progression from MASLD to MASH through metabolomics, lipidomics, and assessment of hormones. MethodsMale C57BL/6NTac mice were fed a high-fat diet for 16 weeks to induce MASLD and for 29 weeks to develop MASH. Aged-matched controls on a normal diet were used for comparison. Histology confirmed the progression of MASLD to MASH. We performed metabolomic and lipidomic profiling of liver, colon, and stool samples to identify metabolic and lipid alterations. Plasma enteroendocrine hormones and cytokines were quantified. Immunofluorescence was performed to assess enteroendocrine cells changes in the colon and the association of serotonin (5-HT) with fibronectin in the liver. ResultsMetabolomic and lipidomic analysis revealed significant alterations at different stages of the disease. Specifically, cholic acid was increased across the liver, colon, and stool in both MASLD and MASH mice compared to controls. Compared to the control group, MASLD mice exhibited an increase in enteroendocrine hormones, GLP-1, GIP, and PYY, whereas no changes were observed in MASH mice. Comparing MASLD to MASH livers, we found hepatic 5-HT levels were increased in MASH mice compared to MASLD mice. The MASH liver also exhibited a colocalization between fibronectin and 5-HT, suggesting a potential role of 5-HT in liver fibrosis. ConclusionsOur study provides novel insights into the progressive metabolic and hormonal changes from MASLD to MASH. The increase in cholic acid and differential enteroendocrine hormone responses highlight the complex interactions between the gut and liver in metabolic liver diseases. These findings suggest that enteroendocrine hormones may play a role in the progression of MASLD to MASH as well as liver fibrosis, offering potential therapeutic avenues for targeting the gut-liver axis in metabolic liver diseases.

cell biology↗

bioRxiv2023

Uranium-bearing dust induces differentiation and expansion of enteroendocrine cells in human colonoids

Chronic exposure to environmental toxins and heavy metals has been associated with intestinal inflammation, increased susceptibility to pathogen-induced diseases, and higher incidences of colorectal cancer, all of which have been steadily increasing in prevalence for the past 40 years. The negative effects of heavy metals on barrier permeability and inhibition of intestinal epithelial healing have been described; however, transcriptomic changes within the intestinal epithelial cells and impacts on lineage differentiation are largely unknown. Uranium exposure remains an important environmental legacy and physiological health concern, with hundreds of abandoned uranium mines located in the Southwestern United States largely impacting underserved indigenous communities. Herein, using human colonoids, we defined the molecular and cellular changes that occur in response to uranium bearing dust (UBD) exposure. We used single cell RNA sequencing to define the molecular changes that occur to specific identities of colonic epithelial cells. We demonstrate that this environmental toxicant disrupts proliferation and induces hyperplastic differentiation of secretory lineage cells, particularly enteroendocrine cells (EEC). EECs respond to UBD exposure with increased differentiation into de novo EEC sub-types not found in control colonoids. This UBD-induced EEC differentiation does not occur via canonical transcription factors NEUROG3 or NEUROD1. These findings highlight the significance of crypts-based proliferative cells and secretory cell differentiation as major colonic responses to heavy metal-induced injury.

cell biology↗