Gene-environment-gut interactions in Huntington's disease mice are associated with environmental modulation of the gut microbiome.
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ABSTRACT:
SUBMITTER: Gubert C
PROVIDER: S-EPMC8760441 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Complex diseases are often caused by the function of multiple genes, gene-gene (G×G) interactions as well as gene-environment (G×E) interactions. G×G and G×E interactions are ubiquitous in nature. Empirical evidences have shown that the effect of G×G interaction on disease risk could be largely modified by environmental changes. Such a G×G×E triple interaction could be a potential contributing factor to phenotypic plasticity. Although the role of environmental factors moderating genetic influences on disease risk has been broadly recognized, no statistical method has been developed to rigorously assess how environmental changes modify G×G interactions to affect disease risk. To address this issue, we developed a G×G×E triple interaction model in this work. We modeled the environmental modification effect via a varying-coefficient model where the structure of the varying effect is determined by data. Thus the model has the flexibility to assess nonlinear environmental moderation effect on G×G interaction. Simulation and real data analysis were conducted to show the utility of the method. Our approach provides a quantitative framework to assess triple interactions hypothesized in literature.
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Project description:BackgroundHoloprosencephaly is the most common malformation of the forebrain (1 in 250 embryos) with severe consequences for fetal and child development. This study evaluates nongenetic factors associated with holoprosencephaly risk, severity, and gene-environment interactions.MethodsFor this retrospective case control study, we developed an online questionnaire focusing on exposures to common and rare toxins/toxicants before and during pregnancy, nutritional factors, maternal health history, and demographic factors. Patients with holoprosencephaly were primarily ascertained from our ongoing genetic and clinical studies of holoprosencephaly. Controls included children with Williams-Beuren syndrome (WBS) ascertained through online advertisements in a WBD support group and fliers.ResultsDifference in odds of exposures between cases and controls as well as within cases with varying holoprosencephaly severity were studied. Cases included children born with holoprosencephaly (n = 92) and the control group consisted of children with WBS (n = 56). Pregnancy associated risk associated with holoprosencephaly included maternal pregestational diabetes (9.2% of cases and 0 controls, p = .02), higher alcohol consumption (adjusted odds ratio [aOR], 1.73; 95% CI, 0.88-15.71), and exposure to consumer products such as aerosols or sprays including hair sprays (aOR, 2.46; 95% CI, 0.89-7.19). Significant gene-environment interactions were identified including for consumption of cheese (p < .05) and espresso drinks (p = .03).ConclusionThe study identifies modifiable risk factors and gene-environment interactions that should be considered in future prevention of holoprosencephaly. Studies with larger HPE cohorts will be needed to confirm these findings.
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Project description:Causes for miscarriages and congenital malformations can be genetic, environmental, or a combination of both. Genetic variants, hypoxia, malnutrition, or other factors individually may not affect embryo development, however, they may do so collectively. Biallelic loss-of-function variants in HAAO or KYNU, two genes of the nicotinamide adenine dinucleotide (NAD) synthesis pathway, are causative of congenital malformation and miscarriage in humans and mice. The variants affect normal embryonic development by disrupting the synthesis of NAD, a key factor in multiple biological processes, from its dietary precursor tryptophan, resulting in NAD deficiency. This study demonstrates that congenital malformations caused by NAD deficiency can occur independent of genetic disruption of NAD biosynthesis. C57BL/6J wild-type mice had offspring exhibiting similar malformations when their supply of the NAD precursors tryptophan and vitamin B3 in the diet was restricted during pregnancy. When the dietary undersupply was combined with a maternal heterozygous variant in Haao, which alone does not cause NAD deficiency or malformations, the incidence of embryo loss and malformations was significantly higher, suggesting a gene-environment interaction. Maternal and embryonic NAD levels were deficient. Mild hypoxia as an additional factor exacerbated the embryo outcome. Our data show that NAD deficiency as a cause of embryo loss and congenital malformation is not restricted to the rare cases of biallelic mutations in NAD synthesis pathway genes. Instead, monoallelic genetic variants and environmental factors can result in similar outcomes. The results expand our understanding of the causes of congenital malformations and the importance of sufficient NAD precursor consumption during pregnancy.
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Project description:IntroductionPsoriasis is a systemic immune-mediated disease primarily manifesting as skin redness and inflammation. Balneotherapy proved to be a successful non-pharmacological option to reduce the skin areas affected by the disease, but the specific mechanisms underlying this effect have not been elucidated yet. Here we test the hypothesis that the effect of thermal treatments on psoriatic lesions could be partially mediated by changes in the resident microbial population, i.e., the microbiome.MethodsIn this study, we enrolled patients with psoriasis and monitored changes in their skin and gut microbiome after a 12-bath balneotherapy course with a combination of 16S rRNA amplicon sequencing and metagenomics. Changes in the resident microbiome were then correlated with thermal therapy outcomes evaluated as changes in Psoriasis Area and Severity Index (PASI) and Body Surface Area index (BSA).ResultsThe amplicon sequencing analysis of the skin microbiome showed that after thermal treatment the microbiome composition of affected areas improved to approach that typical of unaffected skin. We moreover identified some low-abundance bacterial biomarkers indicative of disease status and treatment efficacy, and we showed via metagenomic sequencing that thermal treatments and thermal water drinking affect the fecal microbiome to host more species associated with favorable metabolic health.ConclusionsChanges in lower-abundance microbial taxa presence and abundance could be the basis for the positive effect of thermal water treatment and drinking on the cutaneous and systemic symptomatology of psoriasis.
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Project description:Mutation of the adenomatous polyposis coli (APC gene), an early event in the adenoma-carcinoma sequence, is present in 70-80% of sporadic human colorectal adenomas and carcinomas. To test the hypothesis that mutation of the APC gene alters microbial interactions with host intestinal mucosa prior to the development of polyposis, culture-independent methods (targeted qPCR assays and Illumina sequencing of the 16S rRNA gene V1V2 hypervariable region) were used to compare the intestinal microbial composition of 30 six-week old C57BL/6 APCMin/+ and 30 congenic wild type (WT) mice. The results demonstrate that similar to 12-14 week old APCMin/+ mice with intestinal neoplasia, 6 week old APCMin/+ mice with no detectable neoplasia, exhibit an increased relative abundance of Bacteroidetes spp in the colon. Parallel mouse RNA sequence analysis, conducted on a subset of proximal colonic RNA samples (6 APCMin/+, 6 WT) revealed 130 differentially expressed genes (DEGs, fold change ? 2, FDR <0.05). Hierarchical clustering of the DEGs was carried out by using 1-r dissimilarity measurement, where r stands for the Pearson correlation, and Ward minimum variance linkage, in order to reduce the number of input variables. When the cluster centroids (medians) were included along with APC genotype as input variables, analysis of variance and covariance (ANCOVA) with stepwise variable selection, selected two of seven mouse gene clusters, in addition to APC genotype, as significantly associated (p = 0.011 and p = 0.004) with the increased relative abundance of Bacteroidetes spp. One of the two clusters includes several downregulated genes encoding immunoglobulin variable regions and non-protein coding RNAs. These results support the concept that mutation of the APC gene alters colonic-microbial interactions prior to polyposis. It remains to be determined whether interventions directed at ameliorating dysbiosis in APCMin/+mice, such as through probiotics, prebiotics or antibiotics, could reduce tumor formation. Comparing the differential gene expressions in proximal colonic mucosal samples from 6 six-week-old female Apc Min/+ and 6 six-week-old female WT mice
2015-08-24 | E-GEOD-67634 | biostudies-arrayexpress
Project description:The transgenomic metabolic effects of exposure to either Lactobacillus paracasei or Lactobacillus rhamnosus probiotics have been measured and mapped in humanized extended genome mice (germ-free mice colonized with human baby flora). Statistical analysis of the compartmental fluctuations in diverse metabolic compartments, including biofluids, tissue and cecal short-chain fatty acids (SCFAs) in relation to microbial population modulation generated a novel top-down systems biology view of the host response to probiotic intervention. Probiotic exposure exerted microbiome modification and resulted in altered hepatic lipid metabolism coupled with lowered plasma lipoprotein levels and apparent stimulated glycolysis. Probiotic treatments also altered a diverse range of pathways outcomes, including amino-acid metabolism, methylamines and SCFAs. The novel application of hierarchical-principal component analysis allowed visualization of multicompartmental transgenomic metabolic interactions that could also be resolved at the compartment and pathway level. These integrated system investigations demonstrate the potential of metabolic profiling as a top-down systems biology driver for investigating the mechanistic basis of probiotic action and the therapeutic surveillance of the gut microbial activity related to dietary supplementation of probiotics.
| S-EPMC2238715 | biostudies-literature
Project description:Interventions: Group 1: A probiotic product OMNi-BiOTiC from the company Allergosan containing a mix of 10 probiotic bacterial strains will be administered orally in lyophilized form. Administration will be applied once daily with one dose equivalent to 5 * 109 colony forming units (cfu), in the morning over a period of 6 months.
Screening-phase will take up to two weeks and will be followed by a treatment period of 24 weeks. In Total 4 visits will be performed: Screening visit between -14 to -1 days before baseline. Treatment duration with probiotic product will be 24 weeks starting at the baseline visit. A study visit will be performed at week 8. End of treatment visit (EOT) takes place at week 24.
At each visit, physical examination takes place and vital signs, questionnaires (quality of life and dietary) as well as adverse events will be documented. At screening visit, study visit and EOT visit serum and whole blood as well as stool samples are collected for further analyses.
Primary outcome(s): Demonstrate a persistent modification of the intestinal microbiome in the feces (stool) of the participants following Bacteria administration as measured by metagenomics analysis by Shotgun Sequencing. Analyses are performed at the beginning of the study, after 8 weeks and at the end of the study after 24 weeks.
Study Design: Allocation: N/A: single arm study; Masking: Open (masking not used); Control: uncontrolled; Assignment: single; Study design purpose: other
| 72928 | ecrin-mdr-crc