Biology subjects

Zwick, R.

Publications and source records attributed to Zwick, R..

3 recordsLinked to original sources

bioRxiv2026

Intestinal fructose metabolism drives unsaturated fat absorption and synergizes with GLP-1 receptor agonism to promote weight loss

High-fat, high-sucrose (HFHS) diets are established risk factors for obesity. In the intestine, sucrose is hydrolyzed into glucose and fructose, with fructose being taken up by epithelial cells and phosphorylated by ketohexokinase (KHK). We hypothesized that KHK is required for the obesogenic effects of HFHS diets and performed genetic and pharmacologic experiments in mice using diet-induced obesity (DIO) models. We show that genetic loss of KHK prevents HFHS-induced weight gain and intestinal villus elongation. Moreover, pharmacologic inhibition of KHK (KHKi) promotes weight and fat loss during continued HFHS feeding in DIO mice and enhances weight loss and weight maintenance during and after incretin-mimetic therapy. The anti-obesogenic effects of KHKi were associated with delayed intestinal lipid absorption, reprogramming of lipid metabolism in the distal intestinal epithelium, and reduced absorption of unsaturated dietary fats. Together, these findings identify fructose metabolism as a key regulator of intestinal lipid handling and suggest that fructose promotes obesity, in part, by enhancing intestinal lipid absorption and metabolism.

cell biology↗

bioRxiv2025

Mapping mesenchymal diversity in the developing human intestine and organoids

The organization of diverse mesenchymal populations during human intestinal development is critical for tissue architecture and function yet remains poorly defined. To construct a comprehensive, tissue-scale map of the developing human small intestine, we leveraged single-cell RNA-sequencing data to build a custom Xenium spatial transcriptomics gene panel covering the diversity of cell types in the human intestine. Analysis was focused on the developing mesenchyme populations (also referred to as fibroblasts or stroma) given the lack of spatiotemporal information about these cell populations. We defined 5 broad mesenchymal populations occupying discrete anatomical locations within the lamina propria and submucosa - the subepithelial cells (SEC), lamina propria fibroblasts (LPF), submucosal fibroblasts (SMF), smooth muscle cells (SMC), and CXCL13+ fibroblasts. Our data reveal dynamic spatial remodeling of fibroblast communities during development and establish molecular markers to distinguish these populations. We leverage this high-resolution atlas to benchmark pluripotent stem cell-derived human intestinal organoids and to demonstrate how this foundational resource can be used to dissect intestinal stromal signaling in a spatial manner, with broad implications for modeling development, regeneration, and disease. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=177 SRC="FIGDIR/small/665939v1_ufig1.gif" ALT="Figure 1"> View larger version (69K): org.highwire.dtl.DTLVardef@46299borg.highwire.dtl.DTLVardef@55a014org.highwire.dtl.DTLVardef@180a104org.highwire.dtl.DTLVardef@1cb42b2_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LIA spatial atlas of fibroblast heterogeneity in the human intestine C_LIO_LIPopulations include subepithelial, submucosal, lamina propria, and CXCL13+ fibroblasts C_LIO_LIFibroblast position in the developing intestine is maintained into adulthood C_LIO_LIOrganoids largely recreate the spatial organization of the human intestine C_LI

developmental biology↗

bioRxiv2022

A Development-Inspired Niche for Homeostatic Human Mini-Intestines

Epithelial organoids derived from intestinal tissue, also referred to as mini-intestines or mini-guts, recapitulate many aspects of the organ in vitro and can be used for biological discovery, personalized medicine, and drug development. Murine intestinal organoids represent a homeostatic system that balances stem cell maintenance within a crypt-like compartment and differentiation within a villus-like compartment1-3. However, this homeostatic balance and spatial organization has not been achieved with human intestinal organoids4. Here, we leverage single cell RNA-seq data (scRNA-seq) and high-resolution imaging to interrogate the developing human intestinal stem cell niche. We identified an EGF-family member, EPIREGULIN (EREG), as uniquely expressed in the developing crypt, and found that EREG can take the place of EGF as an in vitro niche factor. Unlike EGF, which leads to growth of thin-walled cystic organoids, EREG-organoids are spatially resolved into budded and proliferative crypt domains and a differentiated villus-like central lumen. Transcriptomics and epigenomics showed that EREG-organoids are globally similar to the native intestine while EGF-organoids have an altered chromatin landscape, downregulate the master intestinal transcription factor CDX25,6, and ectopically express stomach genes.

developmental biology↗