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An inflammasome-driven differentiation program in intestinal stem cells protects against Salmonella infection

ABSTRACT: Intestinal stem cells (ISCs) are essential for sustaining epithelial renewal and barrier integrity, yet their role in orchestrating defense against enteric pathogens remains unclear. Here, we identify a stem cell–intrinsic immune mechanism whereby Lgr5⁺ ISCs detect intracellular Salmonella enterica and activate an inflammasome-dependent differentiation program. Using fluorescent-labeled Salmonella enterica, single-cell transcriptomics, fate mapping, organoid models, and genetic perturbations, we show that invaded ISCs undergo rapid reprogramming toward antimicrobial peptide-enriched Paneth cells via ASC (Pycard)-mediated inflammasome signaling. This fate switch enhances epithelial antimicrobial capacity and restricts pathogen persistence in the crypt. The response is Salmonella-specific and conserved in human intestinal organoids. Moreover, the invasion-associated transcriptional signature is enriched in ISCs from Crohn’s disease patients. Our findings reveal that ISCs act as active sensors of bacterial invasion and initiate epithelial remodeling through inflammasome signaling, highlighting stem cell plasticity as a frontline innate immune strategy.

INSTRUMENT(S):

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Paneth Cell Of Epithelium Of Small Intestine, Small Intestine

DISEASE(S): Bacterial Infectious Disease

SUBMITTER: Vladyslav Holiar

LAB HEAD: Moshe Biton

PROVIDER: PXD075756 | Pride | 2026-04-05

REPOSITORIES: Pride

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			Action	DRS
	MBI_24932_all_groups_3vv_in_each_group_protein_report.xlsx	Xlsx
	TTU_MB_24932_0-1_21092025_9-24-2025_6462.d.zip	Other
	TTU_MB_24932_0-2_21092025_9-24-2025_6463.d.zip	Other
	TTU_MB_24932_0-3_21092025_9-24-2025_6469.d.zip	Other
	TTU_MB_24932_0-4_21092025_9-24-2025_6472.d.zip	Other

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Project description:Purpose: We isolated Drosophila midgut cells : Delta+ intestinal stem cells (ISCs), Su(H)+enteroblasts (EBs), Esg+ cells (ISC+EB), Myo1A+Enterocytes (ECs), Pros+Enteroendocrine cells (EEs) and How+Visceral muscle cells (VM) from whole midguts to identify stem cell specific genes and study cell type specificities of midgut cells. We also isolated all the cell types from the 5 major regions (R1-R5) of the Drosophila midgut to study differences in cells in different regions. Methods: 3-7 day old female flies were dissected. Flies with GFP/YFP marking different cell types (using the GAL4-UAS system) were used to separate cells of the midgut.The midguts were dissociated with Elastase and FACS sorted using FACS AriaIII. RNA was extracted, amplified and sequenced. Whole midgut samples were sequenced on Illumina GAIIX and regional cell populations were sequenced on HiSeq2000. Methods:Raw fastqc reads were mapped to the Drosophila genome (Drosophila_melanogaster.BDGP5.70.dna.toplevel.fa) using Tophat 2.0.9 at default (using boost_1_54_0, bowtie2-2.1.0, samtools-0.1.19). Methods: For differential expression analysis, DESeq (p-value adjustment 0.05 by method Benjamini-Hochberg) was used. The reads were normalized also to Reads per kilobase of transcript per million mapped reads (RPKM). Results: More than 50% of the genome is expressed in the adult midgut (FlyAtlas- Chintapalli et al., 2007), of these genes about 50% (2457) were differentially expressed (DE) between all 4 cell types (ISCs, EBs, ECs and EEs) atleast 2 folds with 95% confidence Results: 159 genes that were specifically enriched in ISCs, 509 genes were specifically repressed in ISCs Conclusions: Our study represents the first detailed analysis of Drosophila intestinal cell transcriptomes, with biologic replicates, generated by RNA-seq technology.Our data facilitates comparative investigations of expression profiles of cells and reveals novel stem cell genes. Further region specific profiling adds precision to the analysis of variances in the midgut regions. We identify transcriptional regulators and regional transcription factors which modulate the midgut physiology. The dataset will be a great resource for hypothesis generation, tool building and fine tuned studies on the Drosophila midgut. mRNA profiles of Drosophila intestinal cells from whole midguts and midgut regions were generated by Deep Sequencing. Whole midgut profiles were generated in triplicates (Illumina GAIIx, 72 bp read length) and regional cell type profiles were genrated in duplicates (HiSeq 2000, 50bp read length).

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An inflammasome-driven differentiation program in intestinal stem cells protects against Salmonella infection

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