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The tumor suppressor Tip60 inhibits TOR signaling in response to the microbiota to promote autophagy and enterocyte differentiation

ABSTRACT: The differentiation of enterocyte precursors into mature enterocytes is a complex process that is essential for intestinal homeostasis, and the accumulation of undifferentiated precursors is a harbinger of malignant transformation and metastasis. Here, using a Drosophila model, we elucidate the connection between microbial fermentation product acetate, the tumor suppressor and lysine acetylase Tip60, and normal differentiation of enterocytes. Acetate activates Tip60 in enterocytes. Tip60 was previously found to acetylate mTOR. Here we report that Tip60 diminishes signaling through the PI3K/AKT/mTOR pathway, which activates autophagy. Blocking Tip60 in enterocytes results in microbial penetration of the intestinal barrier, accumulation of undifferentiated enterocytes, and a failure of the acidic region of the MMG to develop. We previously showed that Tip60 controls innate immune signaling in enteroendocrine cells in response to microbial acetate. This assigns two additional innate immune functions to Tip60, namely destruction of intracellular bacteria via xenophagy and differentiation of the acid-producing cells of the MMG. Because the fermentation pathways of microbiota are highly conserved as is the Tip60 lysine acetyltransferase and AKT/PI3K/mTOR signaling, we propose that a similar process may tie the intestinal microbiota, Tip60, and mTOR to each other and to the intestinal innate immune response and oncogenesis.

ORGANISM(S): Drosophila melanogaster

PROVIDER: GSE325455 | GEO | 2026/05/08

REPOSITORIES: GEO

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The tumor suppressor Tip60 inhibits TOR signaling in response to the microbiota to promote autophagy and enterocyte differentiation [RNAseq_Tip60]

Project description:The differentiation of enterocyte precursors into mature enterocytes is a complex process that is essential for intestinal homeostasis, and the accumulation of undifferentiated precursors is a harbinger of malignant transformation and metastasis. Here, using a Drosophila model, we elucidate the connection between microbial fermentation product acetate, the tumor suppressor and lysine acetylase Tip60, and normal differentiation of enterocytes. Acetate activates Tip60 in enterocytes. Tip60 was previously found to acetylate mTOR. Here we report that Tip60 diminishes signaling through the PI3K/AKT/mTOR pathway, which activates autophagy. Blocking Tip60 in enterocytes results in microbial penetration of the intestinal barrier, accumulation of undifferentiated enterocytes, and a failure of the acidic region of the MMG to develop. We previously showed that Tip60 controls innate immune signaling in enteroendocrine cells in response to microbial acetate. This assigns two additional innate immune functions to Tip60, namely destruction of intracellular bacteria via xenophagy and differentiation of the acid-producing cells of the MMG. Because the fermentation pathways of microbiota are highly conserved as is the Tip60 lysine acetyltransferase and AKT/PI3K/mTOR signaling, we propose that a similar process may tie the intestinal microbiota, Tip60, and mTOR to each other and to the intestinal innate immune response and oncogenesis.

2026-05-08 | GSE330182 | GEO

Human Caco-2 proteome and N-glycome during differentiation

Project description:Park, D, Brune, KA, Mitra, A, Marusina, AI, Maverakis, E, Lebrilla, CB. Characteristic Changes in Cell Surface Glycosylation Accompany Intestinal Epithelial Cell Differentiation: High Mannose Structures Dominate the Cell Surface Glycome of Undifferentiated Enterocytes, Molecular and Cellular Proteomics: submitted.

2015-08-21 | MSV000079264 | MassIVE

Single-cell transcriptome analysis reveals the association between ketone body synthesis and morphogenic profile of intestinal epithelia in neonatal mice II

Project description:The intestinal epithelium undergoes robust maturation postnatally, yet its early-life characteristics remain poorly understood. Using single-cell RNA sequencing, we analyzed intestinal epithelial cells from neonatal and juvenile mice reared under both specific pathogen-free and germ-free conditions. Among the various cell types comprising the intestinal epithelia, we found that enterocytes, in particular, exhibit markedly different features between these stages. Enterocytes of neonatal mice show reduced expression of secretory host defense-related genes independently of microbial colonization. Conversely, neonatal enterocytes display upregulation of ketogenesis-related genes, which correlates with high expression of genes contributing to cell morphogenesis rather than serving primarily as an energy source. These findings provide novel insights into early-life maturation of intestinal epithelia offering implications for understanding neonatal intestinal pathologies.

2026-01-05 | GSE311168 | GEO

Single-cell transcriptome analysis reveals the association between ketone body synthesis and morphogenic profile of intestinal epithelia in neonatal mice

Project description:The intestinal epithelium undergoes robust maturation postnatally, yet its early-life characteristics remain poorly understood. Using single-cell RNA sequencing, we analyzed intestinal epithelial cells from neonatal (10-day-old) and juvenile (21-day-old) mice reared under both specific pathogen-free and germ-free conditions. Among the various cell types comprising the intestinal epithelia, we found that enterocytes, in particular, exhibit markedly different features between these stages. Enterocytes of neonatal mice show reduced expression of secretory host defense-related genes independently of microbial colonization. These genes are upregulated in juvenile enterocytes in a microbiota-dependent manner. Conversely, neonatal enterocytes display upregulation of ketogenesis-related genes, which correlates with high expression of genes contributing to cell morphogenesis rather than serving primarily as an energy source. These findings provide novel insights into early-life maturation of intestinal epithelia offering implications for understanding neonatal intestinal pathologies.

2026-01-05 | GSE296272 | GEO

Stool-derived 16s rRNA V4 sequencing from intestinal-epithelium-LSD1-cKO mice against WT controls (both at 2-month-old and P14 timepoints)

Project description:Villin-Cre+ Lsd1fl/fl (cKO) mice display an immature intestinal epithelium characterized by an incomplete differentiation of enterocytes and secretory lineages, reduced number of goblet cells and a complete loss of Paneth cells. This experiment aims to elucidate the differences in stool microbial composition derived from WT (Villin-Cre- Lsd1fl/fl) and cKO mice both in adult (2-month-old) and neonatal (14 days postpartum P14) stages. Different timepoints are crucial to understand the role of intestinal maturation in microbiome composition since said maturation is dependent on time-dependent external cues happening at P14-21 (weaning and transition from milk to solid foods).

2023-10-31 | E-MTAB-12489 | biostudies-arrayexpress

Mitochondria regulate dietary lipid processing in enterocytes

Project description:Digested dietary fats are taken up, processed and transported by enterocytes to supply the body with lipids. Most absorbed lipids are assembled into pre-chylomicrons in the endoplasmic reticulum (ER) of enterocytes, which are then transported to the Golgi for maturation and subsequent secretion to the circulation. The role of mitochondria in regulating intestinal lipid transport remains unknown. Here we show that mitochondrial dysfunction in enterocytes inhibits chylomicron production and the transport of dietary lipids to peripheral organs. Mice with intestinal epithelial cell (IEC)-specific ablation of the mitochondrial-specific aspartyl - tRNA synthetase DARS2, as well as of the respiratory chain subunit SDHA or the assembly factor COX10 failed to thrive and showed massive accumulation of lipids within large lipid droplets (LDs) in enterocytes of the proximal small intestine (SI). Feeding a fat-free diet inhibited the formation of LDs in DARS2-deficient enterocytes, showing that accumulating lipids derive mostly from digested fat. Furthermore, metabolic tracing studies revealed impaired transport of dietary lipids to peripheral organs in mice lacking DARS2 in IECs. Moreover, DARS2-deficient enterocytes showed a distinct lack of mature chylomicrons concomitant with a disorganisation of the Golgi apparatus, suggesting that impaired ER to Golgi trafficking underlies impaired chylomicron production and secretion. Taken together, these results revealed a vital role of mitochondria in regulating dietary lipid transport in enterocytes, which is relevant for understanding the intestinal and nutritional defects observed in patients with mitochondrial defects.

2023-12-21 | PXD026934 | Pride

Dissecting the in vivo metabolic potential of two human gut acetogens.

Project description:Fermenting microbial communities generate hydrogen: its removal through production of acetate, methane, or hydrogen sulfide modulates the efficiency of energy extraction from available nutrients in many ecosystems. We noted that pathway components for acetogenesis are more abundantly and consistently represented in the gut microbiomes of monozygotic twins and their mothers than components for methanogenesis or sulfate reduction, and subsequently analyzed the metabolic potential of two sequenced human gut acetogens, Blautia hydrogenotrophica and Marvinbryantia formatexigens in vitro and in the intestines of gnotobiotic mice harboring a prominent saccharolytic bacterium. To do so, we developed a generally applicable method for multiplex sequencing of expressed microbial mRNAs, and together with mass spectrometry of metabolites, show that these organisms have distinct patterns of substrate utilization. B. hydrogenotrophica targets aliphatic and aromatic amino acids. It increases the efficiency of fermentation by consuming reducing equivalents, thereby maintaining a high NAD+/NADH ratio and boosting acetate production. In contrast, M. formatexigens consumes oligosaccharides, does not impact the redox state of the gut, and boosts the yield of succinate. These findings have strategic implications for those who wish to manipulate the hydrogen economy of gut microbial communities in ways that modulate energy harvest.

2010-05-22 | GSE21906 | GEO

Transcriptional analysis of the response of Caldicellulosiruptor saccharolyticus to different H2 partial pressures

Project description:Caldicellulosiruptor saccharolyticus is an extremely thermophilic, gram-positive anaerobe which ferments a broad range of substrates to mainly acetate, CO2, and hydrogen gas (H2). Its high hydrogen-producing capacity make this bacterium an attractive candidate for microbial biohydrogen production. However, increased H2 levels tend to inhibit hydrogen formation and leads to the formation of other reduced end products like lactate and ethanol. To investigate the organism’s strategy for dealing with elevated H2 levels and to identify alternative pathways involved in the disposal of the reducing equivalents, the effect of the hydrogen partial pressure (PH2) on fermentation performance was studied. For this purpose cultures were grown under high and low PH2 in a glucose limited chemostat setup. Transcriptome analysis revealed the up-regulation of genes involved in the disposal of reducing equivalents under high PH2, like lactate dehydrogenase and alcohol dehydrogenase as well as the NADH-dependent and ferredoxin-dependent hydrogenases. These findings were in line with the observed shift in fermentation profiles from acetate production under low PH2 to a mixed production of acetate, lactate and ethanol under high PH2. In addition, differential transcription was observed for genes involved in carbon metabolism, fatty acid biosynthesis and several transport systems. The presented transcription data provides experimental evidence for the involvement of the redox sensing Rex protein in gene regulation under high PH2 cultivation conditions. Overall, these findings indicate that the PH2 dependent changes in the fermentation pattern of C. saccharolyticus are, in addition to the known regulation at the enzyme/metabolite level, also regulated at the transcription level.

2013-08-28 | GSE40430 | GEO

Deletion of intestinal Hdac3 remodels the lipidome of enterocytes and protects mice from diet-induced obesity

Project description:Deletion of intestinal Hdac3 remodels the lipidome of enterocytes and protects mice from diet-induced obesity

2020-01-13 | PXD015738 | Pride

An early endosomal network participates to enterocyte functions and intestinal homeostasis

Project description:Membrane trafficking is defined as the vesicular transport of molecules throughout the cell. In intestinal enterocytes, defects in endocytic/recycling pathways impair their function and are linked to genetic diseases. How does trafficking regulate intestinal tissue homeostasis is poorly understood. Using the Drosophila intestine as an in vivo model system, we investigated enterocyte-specific functions for early endosomal trafficking in gut homeostasis. We focused on the small GTPase Rab21 that regulates specific early endosomal trafficking steps. Rab21-depleted guts showed severe intestinal morphology abnormalities, with deregulated homeostasis associated with a gain in mitotic cells and increased cell death. Increased in both apoptosis and Yki signaling were responsible for compensatory proliferation and tissue inflammation. Using a RNAi screen, we identified autophagy and specific membrane trafficking regulators phenocopying Rab21 loss. We further showed that Rab21-induced hyperplasia was rescued by inhibition of Egfr signaling, and we identified improperly trafficked cargoes in enterocytes depleted of Rab21. Our data shed light on an important role for the early endosomal protein Rab21, and early endosomal trafficking in enterocytes-mediated intestinal homeostasis.

2022-08-12 | PXD022413 | Pride

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