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Loss of sex and age driven differences in the gut microbiome characterize arthritis-susceptible 0401 mice but not arthritis-resistant 0402 mice.

ABSTRACT: BACKGROUND: HLA-DRB1 0401 is associated with susceptibility, while HLA-DRB1 0402 is associated with resistance to developing rheumatoid arthritis (RA) and collagen-induced arthritis in humans and transgenic mice respectively. The influence of gut-joint axis has been suggested in RA, though not yet proven. METHODOLOGY/PRINCIPAL FINDINGS: We have used HLA transgenic mice carrying arthritis susceptible and -resistant HLA-DR genes to explore if genetic factors and their interaction with gut flora gut can be used to predict susceptibility to develop arthritis. Pyrosequencing of the 16S rRNA gene from the fecal microbiomes of DRB1 0401 and DRB1 0402 transgenic mice revealed that the guts of 0401 mice is dominated by a Clostridium-like bacterium, whereas the guts of 0402 mice are enriched for members of the Porphyromonadaceae family and Bifidobacteria. DRB1 0402 mice harbor a dynamic sex and age-influenced gut microbiome while DRB1 0401 mice did not show age and sex differences in gut microbiome even though they had altered gut permeability. Cytokine transcripts, measured by rtPCR, in jejuna showed differential TH17 regulatory network gene transcripts in 0401 and 0402 mice. CONCLUSIONS/SIGNIFICANCE: We have demonstrated for the first time that HLA genes in association with the gut microbiome may determine the immune environment and that the gut microbiome might be a potential biomarker as well as contributor for susceptibility to arthritis. Identification of pathogenic commensal bacteria would provide new understanding of disease pathogenesis, thereby leading to novel approaches for therapy.

SUBMITTER: Gomez A

PROVIDER: S-EPMC3338357 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature

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Loss of sex and age driven differences in the gut microbiome characterize arthritis-susceptible 0401 mice but not arthritis-resistant 0402 mice.

Gomez Andres A Luckey David D Yeoman Carl J CJ Marietta Eric V EV Berg Miller Margret E ME Murray Joseph A JA White Bryan A BA Taneja Veena V

PloS one 20120424 4

<h4>Background</h4>HLA-DRB1 0401 is associated with susceptibility, while HLA-DRB1 0402 is associated with resistance to developing rheumatoid arthritis (RA) and collagen-induced arthritis in humans and transgenic mice respectively. The influence of gut-joint axis has been suggested in RA, though not yet proven.<h4>Methodology/principal findings</h4>We have used HLA transgenic mice carrying arthritis susceptible and -resistant HLA-DR genes to explore if genetic factors and their interaction with ...[more]

PMID: 22553482

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Project description:IntroductionRecent evidence has demonstrated that the microbiome is a driver of the underlying pathophysiological mechanisms of respiratory disease. Studies have indicated that bacterial metabolites produced in the gut and lung can impact lung inflammation and immune cell activity, affecting disease pathology. Despite asthma being a disease with marked sex differences, experimental work linking microbiomes and asthma has not considered the sex variable.MethodsTo test the hypothesis that the lung and gut microbial composition impacts allergic lung inflammation in a sex-specific manner, we evaluated lung and gut microbiome alterations in a mouse model of allergic inflammation and assessed their association with lung function and inflammation phenotypes. For this, we exposed male and female adult C57BL/6J mice intranasally to 25 µg of a house dust mite extract mix (HDM) daily, or phosphate-buffered saline (PBS) as control, for 5 weeks (n = 4-6/group). DNA from fecal pellets collected before and after the 5-week treatment, and from lung tissue collected at endpoint, was extracted using the ZymoBIOMICS®-96 MagBead DNA Kit and analyzed to determine the 16S microbiome via Targeted Metagenomic Sequencing.ResultsThe HDM treatment induced a sex-specific allergic inflammation phenotype with significantly higher neutrophilia, lymphocytosis, inflammatory gene expression, and histopathological changes in females than males following exposure to HDM, but higher airway hyperresponsiveness (AHR) in males than females. In addition, sex-specific lung gene expression and associated pathways were identified HDM mix after challenge. These changes corresponded to sex-specific alterations in the gut microbiome, where the Firmicutes to Bacteroidetes ratio (F:B) was significantly reduced in fecal samples from only male mice after HDM challenge, and alpha diversity was increased in males, but decreased in females, after 5-weeks of HDM treatment.DiscussionOverall, our findings indicate that intranasal allergen challenge triggers sex-specific changes in both gut and lung microbiomes, and induces sex-specific lung inflammation, AHR, and lung inflammatory gene expression pathways, suggesting a contribution of the lung-gut axis in allergic airway disease.

Project description:Food allergy is a potentially fatal disease affecting 8% of children and has become increasingly common in the past two decades. Despite the prevalence and severe nature of the disease, the mechanisms underlying sensitization remain to be further elucidated. The Collaborative Cross is a genetically diverse panel of inbred mice that were specifically developed to study the influence of genetics on complex diseases. Using this panel of mouse strains, we previously demonstrated CC027/GeniUnc mice, but not C3H/HeJ mice, develop peanut allergy after oral exposure to peanut in the absence of a Th2-skewing adjuvant. Here, we investigated factors associated with sensitization in CC027/GeniUnc mice following oral exposure to peanut, walnut, milk, or egg. CC027/GeniUnc mice mounted antigen-specific IgE responses to peanut, walnut and egg, but not milk, while C3H/HeJ mice were not sensitized to any antigen. Naïve CC027/GeniUnc mice had markedly lower total fecal IgA compared to C3H/HeJ, which was accompanied by stark differences in gut microbiome composition. Sensitized CC027/GeniUnc mice had significantly fewer CD3+ T cells but higher numbers of CXCR5+ B cells and T follicular helper cells in the mesenteric lymph nodes compared to C3H/HeJ mice, which is consistent with their relative immunoglobulin production. After oral challenge to the corresponding food, peanut- and walnut-sensitized CC027/GeniUnc mice experienced anaphylaxis, whereas mice exposed to milk and egg did not. Ara h 2 was detected in serum collected post-challenge from peanut-sensitized mice, indicating increased absorption of this allergen, while Bos d 5 and Gal d 2 were not detected in mice exposed to milk and egg, respectively. Machine learning on the change in gut microbiome composition as a result of food protein exposure identified a unique signature in CC027/GeniUnc mice that experienced anaphylaxis, including the depletion of Akkermansia. Overall, these results demonstrate several factors associated with enteral sensitization in CC027/GeniUnc mice, including diminished total fecal IgA, increased allergen absorption and altered gut microbiome composition. Furthermore, peanuts and tree nuts may have inherent properties distinct from milk and eggs that contribute to allergy.

Project description:BackgroundAlzheimer's disease (AD) is a fatal neurodegenerative disease. APOE4 is the greatest genetic risk factor for AD, increasing risk up to 15-fold compared to the common APOE3. Importantly, female (♀) APOE4 carriers have a greater risk for developing AD and an increased rate of cognitive decline compared to male (♂) APOE4 carriers. While recent evidence demonstrates that AD, APOE genotype, and sex affect the gut microbiome (GM), how APOE genotype and sex interact to affect the GM in AD remains unknown.MethodsThis study analyzes the GM of 4-month (4 M) ♂ and ♀ E3FAD and E4FAD mice, transgenic mice that overproduce amyloid-β 42 (Aβ42) and express human APOE3+/+ or APOE4+/+. Fecal microbiotas were analyzed using high-throughput sequencing of 16S ribosomal RNA gene amplicons and clustered into operational taxonomic units (OTU). Microbial diversity of the EFAD GM was compared across APOE, sex and stratified by APOE + sex, resulting in 4-cohorts (♂E3FAD, ♀E3FAD, ♂E4FAD and ♀E4FAD). Permutational multivariate analysis of variance (PERMANOVA) evaluated differences in bacterial communities between cohorts and the effects of APOE + sex. Mann-Whitney tests and machine-learning algorithms identified differentially abundant taxa associated with APOE + sex.ResultsSignificant differences in the EFAD GM were associated with APOE genotype and sex. Stratification by APOE + sex revealed that APOE-associated differences were exhibited in ♂EFAD and ♀EFAD mice, and sex-associated differences were exhibited in E3FAD and E4FAD mice. Specifically, the relative abundance of bacteria from the genera Prevotella and Ruminococcus was significantly higher in ♀E4FAD compared to ♀E3FAD, while the relative abundance of Sutterella was significantly higher in ♂E4FAD compared to ♂E3FAD. Based on 29 OTUs identified by the machine-learning algorithms, heatmap analysis revealed significant clustering of ♀E4FAD separate from other cohorts.ConclusionsThe results demonstrate that the 4 M EFAD GM is modulated by APOE + sex. Importantly, the effect of APOE4 on the EFAD GM is modulated by sex, a pattern similar to the greater AD pathology associated with ♀E4FAD. While this study demonstrates the importance of interactive effects of APOE + sex on the GM in young AD transgenic mice, changes associated with the development of pathology remain to be defined.

Project description:BACKGROUND:Accumulating evidence indicates that high-fat diet (HFD)-induced metabolic disorders are associated with dysbiosis of the gut microbiota. However, the sex-specific characteristics of the gut microbiota and its association with a sexually dimorphic response to a HFD remain unclear. METHODS:Male and female mice were randomly assigned to receive a chow diet (CD) or HFD for 12 weeks. A group of HFD mice were pretreated with antibiotic cocktails for 4 weeks. Body weight, insulin sensitivity and the levels of serum metabolic parameters (blood glucose and insulin) were evaluated. 16S rRNA gene sequencing was performed to analyze the composition of the gut microbiota. RESULTS:HFD-induced body weight gain (BWG) was higher in male mice than in female mice. While insulin resistance was increased in the HFD group compared to CD group in male mice, there was no difference in insulin resistance among female mice. Antibiotic-pretreatment alleviated HFD-induced insulin resistance in male mice and elevated fasting blood glucose in female mice. The composition of the gut microbiota in male mice was remarkably different from that in female mice independent of diet. A higher abundance of the genera Parabacteroides, Lactobacillus, Bacteroides, and Bifidobacterium was observed in females than inmales. HFD feeding also influenced the structure of the gut microbiota, as it decreased the abundance of short-chain fatty acids-producing bacteria including Roseburia and Lachnospiraceae_NK4A136_group. Alterations in the gut microbiota in response to antibiotics followed by HFD were different between males and females, indicating sex-dependent sensitivity to antibiotics. CONCLUSIONS:We identified that sex had a greater impact on the composition of gut microbiota than environmental factors (HFD and antibiotics). The enrichment of beneficial microbes in female mice may be associated with the resistance of female mice to HFD-induced metabolic disorders, which was weakened by antibiotic pretreatment.

Dataset Information

Loss of sex and age driven differences in the gut microbiome characterize arthritis-susceptible 0401 mice but not arthritis-resistant 0402 mice.

Publications

Loss of sex and age driven differences in the gut microbiome characterize arthritis-susceptible 0401 mice but not arthritis-resistant 0402 mice.

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