Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Maternal indole supplementation protects offspring from NAFLD through altered microbiota- and AHR-mediated ceramide metabolism

ABSTRACT: MaternalWestern-style diet (WD) disrupts early life gut microbiota in the offspring and is associated with pediatric nonalcoholic fatty liver disease (NAFLD). Here, we report that oral supplementation with gut-derived tryptophan metabolites indole (Ind) or indole-3-acetate (I3A) during pregnancy and lactation in WD-fed dams had persistent effects in offspring liver, acting on key upstream regulators in WD-challenged offspring that suppress pathways for steatosis, fibrosis, and oxidative stress. Maternal Ind or I3A activated aryl hydrocarbon receptor (AHR) signaling, leading to increases in long-chain and very long-chain (VLC) ceramides in offspring liver and small intestine. These effects were evident as early as postnatal day 14. The tryptophan metabolite 5-hydroxyindoleacetate (5-HIAA), an AHR ligand, was depleted in offspring by maternal WD and restored by maternal I3A treatment. Fecal transplantation studies demonstrated that VLC ceramides and liver fibrosis remodeling were mediated by maternal indoles altering the gut microbiota, with strong associations with Lactobacillaceae. Collectively, these findings define a novel and persistent protective effect of maternal Ind and I3A to prevent NAFLD, acting both directly on the liver and through the microbiota. These tryptophan metabolites may serve as therapeutic targets for future interventional studies aimed at prevention of pediatric NAFLD.

ORGANISM(S): Mus musculus

PROVIDER: GSE247323 | GEO | 2026/01/21

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Liver proteiomic analysis on westeren diet fed mice under oral supplementation of indole-3-acetate

Project description:Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in Western countries. There is growing evidence that dysbiosis of the intestinal microbiota and disruption of microbiota-host interactions contribute to the pathology of NAFLD. We previously demonstrated that gut microbiota derived tryptophan metabolite indole-3-acetate (I3A) was decreased in both cecum and liver of high-fat diet-fed mice and attenuated the expression of inflammatory cytokines in macrophages and TNF-a and fatty acid induced inflammatory responses in an aryl-hydrocarbon receptor (AhR) dependent manner in hepatocytes. In this study, we investigated the effect of orally administered I3A in a mouse model of diet induced NAFLD. Western diet (WD)-fed mice given sugar water (SW) with I3A showed dramatically decreased serum ALT, hepatic TG, liver steatosis, hepatocyte ballooning, lobular inflammation, and hepatic production of inflammatory cytokines, compared to WD-fed mice given only SW. Metagenomic analysis show that I3A administration did not significantly modify the intestinal microbiome, suggesting that I3A’s beneficial effects likely reflect the metabolite’s direct actions on the liver. Administration of I3A partially reversed WD induced alterations of liver metabolome and proteome, notably, decreasing expression of several enzymes in hepatic lipogenesis and β- oxidation. Mechanistically, we also show that AMP-activated protein kinase (AMPK) mediates the anti-inflammatory effects of I3A in macrophages. The potency of I3A in alleviating liver steatosis and inflammation clearly demonstrates its potential as a therapeutic modality for preventing the progression of steatosis to NASH.

2024-02-23 | PXD046255 | Pride

Mitochondrial dysfunction charachterizes the multigenerational effects of maternal obesity on MASLD

Project description:Although maternal obesity is an independent risk factor for metabolic dysfunction-associated steatotic liver disease (MASLD), the pathogenesis remains unclear. We aimed to evaluate the effect and mechanisms of multigenerational maternal western diet (WD) on MASLD progression, and test drug candidates in a preclinical model. Female mice were fed WD from 8 weeks before breeding initiation with a normal chow (NC)-fed male, throughout pregnancy and lactation. Male offspring were weaned onto NC or WD and assessed at the age of 16 weeks. Maternal WD feeding aggravated body weight gain, insulin resistance, steatosis and inflammation. Fibrosis was only observed in offspring exposed to maternal WD. Mechanistically, the latter exhibited reduced OXPHOS activity. Maternal WD aggravates MASLD in male offspring, with mitochondrial dysfunction contributing to disease severity.

2025-06-18 | GSE291363 | GEO

Dietary amino acid source elicits sex-specific metabolic response to diet-induced NAFLD in murine model.

Project description:Non-alcoholic fatty liver disease (NAFLD) is a sexually dimorphic disease influenced by dietary factors. Here, we assess the metabolic and hepatic effects of dietary amino acid (AA) source in Western diet (WD)-induced NAFLD in male and female mice. The AA source was either casein or a free AA mixture mimicking the composition of casein. As expected, males fed a casein-based WD displayed glucose intolerance, fasting hyperglycemia, and insulin-resistance and developed NAFLD associated with changes in hepatic gene expression and dysbiosis. In contrast, males fed the AA-based WD showed no steatosis, a similar gene expression profile as males fed a control diet, and a distinct microbiota composition compared to males fed a casein-based WD. Females were protected against WD-induced liver damage, hepatic gene expression, and gut microbiota changes regardless of the AA source. Thus, free dietary AA intake prevents the unhealthy metabolic outcomes of a WD in a sex-specific manner.

2024-01-01 | GSE234591 | GEO

Maternal Western-Style Diet alters Kupffer Cell proportion leading to Metabolic Dysfunction-Associated Steatotic Liver Disease when challenged with western diet in adulthood

Project description:Exposure to maternal western-style diet (mWD) is associated with early development of metabolic dysfunction-associated fatty liver disease (MAFLD) in offspring. Kupffer cells (KCs), the main resident macrophage population in the liver, are known to promote MAFLD progression, however, the effects of mWD on KC subtypes, ontogeny, and gene expression in offspring are not fully understood. In this manuscript, we used two different models of mWD exposure and challenge in adulthood to understand the impact of mWD on KC proportion, ontogeny, and gene expression in adult offspring. Our data indicate that in the absence of challenge in adulthood, mWD results in increased KC proportion in offspring, with limited changes in KC ontogeny or liver phenotype. In contrast, mWD mice challenged with WD in adulthood had increased expression of inflammatory (Nlrp3) and fibrosis (Tgfb1) related genes compared to chow (CH)-WD fed mice. Although KC proportion and ontogeny were similar when comparing CH-WD and WD-WD fed mice, we found that WD-WD mice had a greater reduction in KC proportion and TdT labelling than CH-WD fed mice when normalized to their respective maternal diet controls. Similar results were found when mice were weaned onto normal chow and re-challenged with WD later on in adulthood. Bulk RNA sequencing data indicate that KCs from mWD mice re-challenged with WD in adulthood had increased expression of inflammatory and antigen presenting genes compared to KCs isolated from WD fed mice lacking mWD exposure. These findings highlight the intergenerational repercussions of mWD on liver phenotype as well as KC proportion and ontogeny and provide novel insight into the mechanisms dictating MAFLD.

2025-12-05 | GSE312316 | GEO

Maternal high-fat diet aggravates the development of atherosclerosis in offspring via epigenetic memory (ATAC-Seq CUT&Tag)

Project description:Maternal exposure to a western-type diet (WD) increases the susceptibility of adult offspring to atherosclerosis. Lining the inner layer of blood vessels, fetus endothelial cells (ECs) become dysfunctional and inflamed in response to risk factors from mother through maternal and fetal blood exchange. However, the mechanism by which maternal WD promotes vascular endothelial dysfunction and atherosclerosis in offspring after adulthood has not been fully clarified. Here, we found that maternal WD exposure sensitized offspring to WD exposure in adulthood of Ldlr-/- mice, significantly increasing atherosclerotic lesions in the aorta and aortic roots, endowed inflammatory memory at the chromatin level and regulated chromatin dynamics by transcription factor AP-1 in mouse aortic ECs. Plasma 27-hydroxycholesterol (27-HC) was significantly increased in maternal blood and transferred into the offspring. Additionally, 27-HC played a crucial role in memory establishment and also acted as a secondary stimulator, amplifying the expression of inflammatory memory factors and enhancing the enrichment of AP-1/p300 and H3K27ac in the binding domain in human ECs. Inhibiting AP-1 binding to chromatin reduced the inflammatory response in human umbilical vein ECs from mother with maternal hypercholesterolemia and the occurrence and development of atherosclerosis in the offspring with maternal WD exposure. Our findings demonstrate that maternal WD aggravating EC dysfunction and atherosclerosis in offspring after adulthood acquires AP-1-associated epigenetic memory to increase chromatin accessibility of inflammatory genes.

2025-01-23 | GSE276350 | GEO

Maternal high-fat diet aggravates the development of atherosclerosis in offspring via epigenetic memory (SMART-Seq)

2025-01-22 | GSE276351 | GEO

Gut microbiota promote immune tolerance at the maternal-fetal interface

Project description:Immune tolerance at the maternal-fetal interface is required for fetal development. Excessive maternal interferon gamma (IFNγ) and interleukin-17 (IL-17) is linked to pregnancy complications, but the regulation of maternal IFNγ and IL-17 at the maternal-fetal interface (MFI) is poorly understood. Here we demonstrate a gut-placenta immune axis in pregnant mice in which the absence or perturbation of gut microbiota dysregulates maternal IFNγ and IL-17 responses at the MFI, resulting in fetal resorption. Microbiota-dependent tryptophan derivatives suppress IFNγ+ and IL-17+ T cells at the MFI by priming myeloid-derived suppressor cells (MDSCs) and gut-derived RORγt+ Tregs, respectively. The tryptophan derivative indole-3-carbinol, or tryptophan-metabolizing Lactobacillus murinus, rebalances the T cell response at the MFI and reduces fetal resorption in germ-free mice. Furthermore, MDSCs, RORγt+ Tregs, and microbiota-dependent tryptophan derivatives are dysregulated at the MFI in human recurrent miscarriage cases. Together, our findings identify microbiota-dependent immune tolerance mechanisms that promote fetal development.

2025-12-17 | GSE310031 | GEO

Sub-optimal paternal diet at the time of mating perturbs maternal adaptations in the late gestation mouse

Project description:Pregnancy represents a stage during which maternal physiology and homeostatic regulation undergo dramatic change and adaptation. The fundamental purpose of these adaptations is to ensure the survival of her offspring through adequate nutrient provision and an environment that is tolerant to the semi-allogenic fetus. While poor maternal diet during pregnancy is associated with perturbed maternal adaptations during pregnancy, the influence of paternal diet on maternal well-being is less clearly-defined. We fed male mice either a control (CD), low protein diet (LPD), a high fat/sugar Western diet (WD) or the LPD or WD supplemented with methyl donors (MD-LPD and MD-WD respectively) for a minimum of 8 weeks prior to mating. Females were culled at day 17 of gestation for the analysis of maternal metabolic, gut, cardiac and bone health. Paternal diet had minimal influences on maternal metabolic status or gut microbiota diversity. However, analysis of the maternal hepatic transcriptome revealed distinct profiles of differential gene expression in response to the diet of the father. Paternal LPD and MD-LPD resulted in differential expression of genes associated with lipid metabolism, transcription, ubiquitin conjugation and immunity in dams, while paternal WD and MD-WD modified the expression of genes associated with ubiquitin conjugation and cardiac morphology. Finally, we observed changes in maternal femur length, volume of trabecular bone, trabecular connectivity, volume of the cortical medullar cavity and thickness of the cortical bone in response to the father’s diets. Our current study demonstrates that poor paternal diet at the time of mating can influence the patterns of maternal metabolism and gestation-associated adaptations to her physiology. Such changes could have significant consequences for the long-term health of his offspring and the mother.

2024-07-18 | GSE265783 | GEO

Maternal high fat diet induces circadian clock-independent endocrine alterations impacting metabolism of the offspring

Project description:Maternal obesity has long-term effects on offspring metabolic health. Among the potential mechanisms, prior research has indicated potential disruptions in circadian rhythms and gut microbiota in the offspring. To challenge this hypothesis, we implemented a maternal high fat diet regimen before and during pregnancy, followed by a standard diet after birth. Our findings confirm that maternal obesity impacts offspring birth weight and glucose and lipid metabolisms. However, we found minimal impact on circadian rhythms and microbiota that are predominantly driven by the feeding/fasting cycle. Notably, maternal obesity altered rhythmic liver gene expression, affecting mitochondrial function and inflammatory response without disrupting the hepatic circadian clock. These changes could be explained by a masculinisation of liver gene expression similar to the changes observed in polycystic ovarian syndrome. Intriguingly, such alterations seem to provide the first-generation offspring with a degree of protection against obesity when exposed to a high fat diet.

2024-06-09 | GSE240147 | GEO

Proteome Dynamics Reveals Pro-inflammatory Remodeling of Plasma Proteome in a Mouse Model of NAFLD

Project description:Nonalcoholic fatty liver disease (NAFLD) is associated with an increased risk of cardiovascular disease (CVD). Liver is the major source of the circulatory proteins and alterations in plasma proteome have been implicated in atherosclerosis. We used a recently developed 2H2O-metabolic labeling method in combination with the label-free quantification to evaluate the effect of a Western diet (WD) on the dynamics of plasma proteins in LDL receptor-deficient (LDLR-/-) mice, a model of NAFLD and atherosclerosis. There were no significant changes in the expression level of total proteins due to the WD with a bulk protein mean half-life of 18.0±15.1 hours in control and 16.7±11.1 hours in WD groups. WD led to pro-inflammatory distribution of circulatory proteins analyzed in apoB-depleted plasma attributed to their increased production. The fractional catabolic rates of fast-turnover proteins with stress-response, lipid metabolism and transport functions were significantly increased with WD (P<0.05). The pathway analyses revealed that alterations in plasma proteome dynamics were related to the suppression of hepatic PPARα, which was confirmed based on reduced gene and protein expression of PPARα on WD. These changes were associated with ~4 fold increase (P<0.0001) in pro-inflammatory property of apoB-depleted plasma. In conclusion, the proteome dynamics method reveals pro-inflammatory remodeling of plasma proteome relevant to liver disease. As in vivo metrics of liver function, this approach can be used to test therapies in NAFLD and other diseases

2016-06-06 | PXD004270 | Pride

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data