Moshe Biton Lab

Little is known about how interactions of diet, intestinal stem cells (ISCs), and immune cells affect early-stage intestinal tumorigenesis. We show that a high-fat diet (HFD) reduces the expression of the major histocompatibility complex class II (MHC class II) genes in intestinal epithelial cells, including ISCs. This decline in epithelial MHC class II expression in a HFD correlates with reduced intestinal microbiome diversity. Microbial community transfer experiments suggest that epithelial MHC class II expression is regulated by intestinal flora. Mechanistically, pattern recognition receptor (PRR) and interferon-gamma (IFNγ) signaling regulates epithelial MHC class II expression. MHC class II-negative (MHC-II−) ISCs exhibit greater tumor-initiating capacity than their MHC class II-positive (MHC-II+) counterparts upon loss of the tumor suppressor Apc coupled with a HFD, suggesting a role for epithelial MHC class II-mediated immune surveillance in suppressing tumorigenesis. ISC-specific genetic ablation of MHC class II increases tumor burden cell autonomously. Thus, HFD perturbs a microbiome-stem cell-immune cell interaction that contributes to tumor initiation in the intestine.

Genome-wide association studies (GWAS) have revealed risk alleles for ulcerative colitis (UC). To understand their cell type specificities and pathways of action, we generate an atlas of 366,650 cells from the colon mucosa of 18 UC patients and 12 healthy individuals, revealing 51 epithelial, stromal, and immune cell subsets, including BEST4(+) enterocytes, microfold-like cells, and IL13RA2(+)IL11(+) inflammatory fibroblasts, which we associate with resistance to anti-TNF treatment. Inflammatory fibroblasts, inflammatory monocytes, microfold-like cells, and T cells that co-express CD8 and IL-17 expand with disease, forming intercellular interaction hubs. Many UC risk genes are cell type specific and coregulated within relatively few gene modules, suggesting convergence onto limited sets of cell types and pathways. Using this observation, we nominate and infer functions for specific risk genes across GWAS loci. Our work provides a framework for interrogating complex human diseases and mapping risk variants to cell types and pathways.

Intestinal regeneration and host defense require adaptation to environmental cues, but the mechanisms underlying this coordination remain unclear. We show that intestinal Lgr5\u207a stem cells act as luminal sensors via apically localized Toll-like receptor 2 (TLR2), enabling direct detection of microbiota-derived signals. We identify apical TLR2 activation as a mechanism of luminal sensing in adult stem cells and show that it controls epithelial differentiation, antimicrobial peptide production, and crypt organization, with a particularly strong influence on Paneth cell maturation. Genetic ablation of constitutive, epithelial, or stem cell-specific TLR2 disrupts these processes, leading to impaired antimicrobial defense and altered epithelial composition. Using germ-free mice and human intestinal organoids, we demonstrate that this pathway is microbiota-dependent and evolutionarily conserved, respectively. These findings support a model in which stem cells act as active integrators of environmental information and suggest a broader principle by which barrier tissues couple microbial sensing to regeneration and host protection.Competing Interest StatementThe authors have declared no competing interest.Center for New Scientists at the Weizmann Institute of ScienceIsrael Science Foundation, 1587/20, 3775/25Helen and Martin Kimmel Institute for Stem Cell Research at The Weizmann Institute of ScienceMinerva FoundationFederal German Ministry for Education and ResearchMoross Integrated Cancer CenterIsrael Ministry of ScienceDr. Gilbert S. Omenn and Martha A. Darling Weizmann Institute - Schneider Hospital Fund for Clinical Breakthroughs through Scientific CollaborationsSnider FoundationAbisch-Frenkel RNA Therapeutics CenterShimon and Golde PickerHerbert K. Bennett Charitable FundDwek Institute for Cancer Therapy Research