Weaning-Driven Gut Microbiome Shapes Intestinal Stem Cell Epigenetics to Train Immunological Memory (RNA-seq)
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE275418 | GEO | 2026/02/06
REPOSITORIES: GEO
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Project description:During weaning, the transition from milk to solid food rapidly expands and diversifies the gut microbiome, triggering the weaning reaction, a programmed immune response critical for long-lasting mucosal immunity. We characterized how these microbiome changes from weaning through young adulthood in mice shape the DNA methylome and transcriptome of intestinal stem cells (ISCs). We identified a weaning-induced IFN-g–TET3 axis as a key driver of MHC class II enhancer-linked epigenetic reprogramming, creating a transcriptional memory that persists through differentiation into adulthood. Early-life disruption of this axis, via IFN-g blockade or low-dose penicillin, impaired microbiota-mediated epigenetic control and mucosal immunity. Weaning-associated microbiome shifts enriched metabolites such as α-ketoglutarate, Fe2+, and methionine g-lyase, promoting TET-dependent DNA demethylation. These findings reveal how early-life events imprint lifelong epigenetic regulation of mucosal immunity, highlighting epithelial cells as innate immune sentinels that acquire trained transcriptional memory in response to microbial cues.
2026-02-06 | GSE275219 | GEO
Project description:During weaning, the shift from milk to solid food is accompanied by a rapid expansion and diversification of the gut microbiome. This triggers the weaning reaction, a programmed immune response important for long-lasting mucosal immunity that is poorly understood. Here, we characterize the impact of the gut microbiome on the DNA methylome and transcriptome of intestinal stem cells (ISCs) from weaning to young adulthood in mice. We identify a weaning- IFN-g-TET3 axis that reprograms epithelial MHC-II signaling via enhancer demethylation in ISCs, establishing a lasting transcriptional memory into adulthood. Disruption of this axis by IFN-g blockade or low-dose penicillin attenuates the microbiota-mediated epigenetic control of epithelial MHC-II signaling, leading to impaired mucosal immunity. By engaging immune crosstalk and metabolite production, the weaning microbiome drives epigenetic reprogramming, thereby establishing a microbiome-induced regulatory pathway that couples developmental cues to lifelong epithelial immune resilience.
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Project description:Leber2015 - Mucosal immunity and gut
microbiome interaction during C. difficile infection
This model is described in the article:
Systems Modeling of
Interactions between Mucosal Immunity and the Gut Microbiome
during Clostridium difficile Infection.
Leber A, Viladomiu M, Hontecillas R,
Abedi V, Philipson C, Hoops S, Howard B, Bassaganya-Riera
J.
PLoS ONE 2015; 10(7): e0134849
Abstract:
Clostridium difficile infections are associated with the use
of broad-spectrum antibiotics and result in an exuberant
inflammatory response, leading to nosocomial diarrhea, colitis
and even death. To better understand the dynamics of mucosal
immunity during C. difficile infection from initiation through
expansion to resolution, we built a computational model of the
mucosal immune response to the bacterium. The model was
calibrated using data from a mouse model of C. difficile
infection. The model demonstrates a crucial role of T helper 17
(Th17) effector responses in the colonic lamina propria and
luminal commensal bacteria populations in the clearance of C.
difficile and colonic pathology, whereas regulatory T (Treg)
cells responses are associated with the recovery phase. In
addition, the production of anti-microbial peptides by inflamed
epithelial cells and activated neutrophils in response to C.
difficile infection inhibit the re-growth of beneficial
commensal bacterial species. Computational simulations suggest
that the removal of neutrophil and epithelial cell derived
anti-microbial inhibitions, separately and together, on
commensal bacterial regrowth promote recovery and minimize
colonic inflammatory pathology. Simulation results predict a
decrease in colonic inflammatory markers, such as neutrophilic
influx and Th17 cells in the colonic lamina propria, and length
of infection with accelerated commensal bacteria re-growth
through altered anti-microbial inhibition. Computational
modeling provides novel insights on the therapeutic value of
repopulating the colonic microbiome and inducing regulatory
mucosal immune responses during C. difficile infection. Thus,
modeling mucosal immunity-gut microbiota interactions has the
potential to guide the development of targeted fecal
transplantation therapies in the context of precision medicine
interventions.
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2024-09-02 | BIOMD0000000583 | BioModels
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Project description:On going efforts are directed at understanding the mutualism between the gut microbiota and the host in breast-fed versus formula-fed infants. Due to the lack of tissue biopsies, no investigators have performed a global transcriptional (gene expression) analysis of the developing human intestine in healthy infants. As a result, the crosstalk between the microbiome and the host transcriptome in the developing mucosal-commensal environment has not been determined. In this study, we examined the host intestinal mRNA gene expression and microbial DNA profiles in full term 3 month-old infants exclusively formula fed (FF) (n=6) or breast fed (BF) (n=6) from birth to 3 months. Host mRNA microarray measurements were performed using isolated intact sloughed epithelial cells in stool samples collected at 3 months. Microbial composition from the same stool samples was assessed by metagenomic pyrosequencing. Both the host mRNA expression and bacterial microbiome phylogenetic profiles provided strong feature sets that clearly classified the two groups of babies (FF and BF). To determine the relationship between host epithelial cell gene expression and the bacterial colony profiles, the host transcriptome and functionally profiled microbiome data were analyzed in a multivariate manner. From a functional perspective, analysis of the gut microbiota's metagenome revealed that characteristics associated with virulence differed between the FF and BF babies. Using canonical correlation analysis, evidence of multivariate structure relating eleven host immunity / mucosal defense-related genes and microbiome virulence characteristics was observed. These results, for the first time, provide insight into the integrated responses of the host and microbiome to dietary substrates in the early neonatal period. Our data suggest that systems biology and computational modeling approaches that integrate “-omic” information from the host and the microbiome can identify important mechanistic pathways of intestinal development affecting the gut microbiome in the first few months of life. KEYWORDS: infant, breast-feeding, infant formula, exfoliated cells, transcriptome, metagenome, multivariate analysis, canonical correlation analysis 12 samples, 2 groups
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