Sexual Dimorphism of Atherosclerosis by Gut Microbiome in a Hyperlipidemic Diversity Outbred F1 Mouse Population

Abstract Objectives Atherosclerosis is a complex multifactorial disease that develops through the interaction of various genetic and environmental factors. The environmental factors affecting atherosclerosis susceptibility include gender differences and the gut microbiota. However, the association between sex, microbiota, and atherosclerosis remains unclear. We hypothesized that the association between gut microbial profiles and atherosclerosis demonstrates sexual dimorphism. In order to test this hypothesis, we examined atherosclerosis and microbiota in a population of hyperlipidemic outbred mice. Methods We collected offspring (262 female and 269 male mice) from a cross between hyperlipidemic male C57BL/6J mice, transgenic for both human apolipoprotein E-Leiden and cholesterol ester transfer protein genes, and ∼200 female Diversity Outbred (DO) mice, a population derived from 8 inbred strains. We fed the offspring a high fat/cholesterol diet for 12 weeks. We then examined over 20 cardio-metabolic traits and their fecal microbiota compositions using 16S rRNA sequencing. Results Female mice were significantly more susceptible to atherosclerosis with higher lesion area (P < 0.0001) and plasma cholesterol (P < 0.0001) than males. For gut microbiota analysis, females had higher microbial α-diversity (Shannon diversity, P < 0.0001) than males and their β-diversity (Unweighted UniFrac, R2 = 0.01, PERMANOVA < 0.001) showed that the overall community is significantly different. We also examined the association between sexually-dimorphic gut phylotypes and cardiometabolic phenotypes and identified a negative correlation between atherosclerosis and the abundance of the genus Bifidobacterium, while abundances of genus Lactococcus were positively associated with atherosclerosis. Upcoming studies will be designed to identify host genes affecting microbiota abundance and functional characterization of specific microbiota-atherosclerosis traits. Conclusions To the best of our knowledge, this study suggests the first example of complex interactions between sexually dimorphic traits and gut microbiota associated with atherosclerosis using DO-F1 mice. Funding Sources This work was supported by the National Heart, Lung, and Blood Institute.

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Sexual dimorphism in species of Schistura (Teleostei: Nemacheilidae) from the Mae Khlong basin and peninsular Thailand

Zootaxa ◽

10.11646/zootaxa.3586.1.33 ◽

2012 ◽

Vol 3586 (1) ◽

pp. 353 ◽

Cited By ~ 1

Author(s):

RUNGTHIP PLONGSESTHEE ◽

F. WILLIAM H. BEAMISH ◽

LAWRENCE M. PAGE

Keyword(s):

Sexual Dimorphism ◽

Environmental Factors ◽

The Other ◽

Sexually Dimorphic ◽

Morphometric Characteristics ◽

Pectoral Fin ◽

Caudal Fin

Sexually dimorphic characteristics are described for four species of Schistura from the Mae Khlong basin and peninsularThailand. Males of S. mahnerti have a suborbital flap and rows of unculi on the upper surfaces of the pectoral-fin rays.Females of S. mahnerti have a suborbital groove. None of the morphological measurements differ significantly betweenmales and females of S. mahnerti. In the other three species, S. aurantiaca, S. cf. aurantiaca, and S. sexcauda, all indi-viduals lack the flap or groove, but most males have a conspicuous black botch on the procurrent rays of the upper lobeof the caudal fin, a feature absent in most females. Some morphometric characteristics vary between sexes of these spe-cies. Sexually dimorphic traits presumably have a function related to reproduction; however, little is known about reproduction in Schistura, and variation in morphology in relation to habitat or other environmental factors has not been studied.

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GENETIC HETEROGENEITY OF RABBIT ALPHA-1-ANTITRYPSIN

Genetics ◽

10.1093/genetics/106.4.695 ◽

1984 ◽

Vol 106 (4) ◽

pp. 695-703

Author(s):

F Kueppers ◽

C C Lee ◽

R R Fox ◽

J K Mills

Keyword(s):

Sexual Dimorphism ◽

Genetic Heterogeneity ◽

Inbred Strains ◽

Quantitative Variation ◽

Moderate Degree ◽

Inhibiting Activity ◽

Interindividual Differences ◽

Alpha 1 Antitrypsin ◽

Serum Trypsin

ABSTRACT Sixteen inbred or partially inbred strains of rabbits were investigated for electrophoretic and quantitative variations of alpha-1-antitrypsin (A-1-AT). We found interindividual differences in the electrophoretic A-1-AT patterns as well as quantitative differences in the concentrations of A-1-AT and the serum trypsin-inhibiting activity. Three electrophoretic phenotypes were distinguished: M, P and MP. M was characterized by a predominant anodal A-1-AT band, and P had a major cathodal component. The MP pattern can be explained by the occurrence of the M and P components in the same serum due to heterozygosity. The P pattern was associated with an A-1-AT concentration of approximately 56% of that in sera with the M phenotype. The levels of A-1-AT in sera with the MP phenotype were intermediate between those in M and P types. In addition to the type-specific quantitative variation, we found a quantitative sexual dimorphism of a moderate degree: Female rabbits had A-1-AT concentrations 16% less than males.

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A Combined Analysis of Gut and Skin Microbiota in Infants with Food Allergy and Atopic Dermatitis: A Pilot Study

Nutrients ◽

10.3390/nu13051682 ◽

2021 ◽

Vol 13 (5) ◽

pp. 1682

Author(s):

Ewa Łoś-Rycharska ◽

Marcin Gołębiewski ◽

Marcin Sikora ◽

Tomasz Grzybowski ◽

Marta Gorzkiewicz ◽

...

Keyword(s):

Atopic Dermatitis ◽

Food Allergy ◽

Gut Microbiota ◽

Bacterial Species ◽

Rrna Gene ◽

Healthy Children ◽

Skin Microbiota ◽

Fecal Samples ◽

Healthy Infants ◽

Α Diversity

The gut microbiota in patients with food allergy, and the skin microbiota in atopic dermatitis patients differ from those of healthy people. We hypothesize that relationships may exist between gut and skin microbiota in patients with allergies. The aim of this study was to determine the possible relationship between gut and skin microbiota in patients with allergies, hence simultaneous analysis of the two compartments of microbiota was performed in infants with and without allergic symptoms. Fifty-nine infants with food allergy and/or atopic dermatitis and 28 healthy children were enrolled in the study. The skin and gut microbiota were evaluated using 16S rRNA gene amplicon sequencing. No significant differences in the α-diversity of dermal or fecal microbiota were observed between allergic and non-allergic infants; however, a significant relationship was found between bacterial community structure and allergy phenotypes, especially in the fecal samples. Certain clinical conditions were associated with characteristic bacterial taxa in the skin and gut microbiota. Positive correlations were found between skin and fecal samples in the abundance of Gemella among allergic infants, and Lactobacillus and Bacteroides among healthy infants. Although infants with allergies and healthy infants demonstrate microbiota with similar α-diversity, some differences in β-diversity and bacterial species abundance can be seen, which may depend on the phenotype of the allergy. For some organisms, their abundance in skin and feces samples may be correlated, and these correlations might serve as indicators of the host’s allergic state.

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Relationship between Nutrient Intake and Human Gut Microbiota in Monozygotic Twins

Medicina ◽

10.3390/medicina57030275 ◽

2021 ◽

Vol 57 (3) ◽

pp. 275

Author(s):

Natsuko Matsumoto ◽

Jonguk Park ◽

Rie Tomizawa ◽

Hitoshi Kawashima ◽

Koji Hosomi ◽

...

Keyword(s):

Individual Differences ◽

Environmental Factors ◽

Gut Microbiota ◽

Human Health ◽

Negative Correlation ◽

Nutrient Intake ◽

Monozygotic Twins ◽

Human Gut ◽

Positive Correlation ◽

Human Gut Microbiota

Background and Objectives: The gut microbiota is associated with human health and dietary nutrition. Various studies have been reported in this regard, but it is difficult to clearly analyze human gut microbiota as individual differences are significant. The causes of these individual differences in intestinal microflora are genetic and/or environmental. In this study, we focused on differences between identical twins in Japan to clarify the effects of nutrients consumed on the entire gut microbiome, while excluding genetic differences. Materials and Methods: We selected healthy Japanese monozygotic twins for the study and confirmed their zygosity by matching 15 short tandem repeat loci. Their fecal samples were subjected to 16S rRNA sequencing and bioinformatics analyses to identify and compare the fluctuations in intestinal bacteria. Results: We identified 12 genera sensitive to environmental factors, and found that Lactobacillus was relatively unaffected by environmental factors. Moreover, we identified protein, fat, and some nutrient intake that can affect 12 genera, which have been identified to be more sensitive to environmental factors. Among the 12 genera, Bacteroides had a positive correlation with retinol equivalent intake (rs = 0.38), Lachnospira had a significantly negative correlation with protein, sodium, iron, vitamin D, vitamin B6, and vitamin B12 intake (rs = −0.38, −0.41, −0.39, −0.63, −0.42, −0.49, respectively), Lachnospiraceae ND3007 group had a positive correlation with fat intake (rs = 0.39), and Lachnospiraceae UCG-008 group had a negative correlation with the saturated fatty acid intake (rs = −0.45). Conclusions: Our study is the first to focus on the relationship between human gut microbiota and nutrient intake using samples from Japanese twins to exclude the effects of genetic factors. These findings will broaden our understanding of the more intuitive relationship between nutrient intake and the gut microbiota and can be a useful basis for finding useful biomarkers that contribute to human health.

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X chromosome escapee genes are involved in ischemic sexual dimorphism through epigenetic modification of inflammatory signals

Journal of Neuroinflammation ◽

10.1186/s12974-021-02120-3 ◽

2021 ◽

Vol 18 (1) ◽

Author(s):

Shaohua Qi ◽

Abdullah Al Mamun ◽

Conelius Ngwa ◽

Sharmeen Romana ◽

Rodney Ritzel ◽

...

Keyword(s):

Sexual Dimorphism ◽

X Chromosome ◽

Epigenetic Modification ◽

Artery Occlusion ◽

Sexually Dimorphic ◽

Mrna Levels ◽

Young Females ◽

Human Stroke ◽

Histone H3k4 ◽

Cerebral Artery Occlusion

Abstract Background Stroke is a sexually dimorphic disease. Previous studies have found that young females are protected against ischemia compared to males, partially due to the protective effect of ovarian hormones, particularly estrogen (E2). However, there are also genetic and epigenetic effects of X chromosome dosage that contribute to stroke sensitivity and neuroinflammation after injury, especially in the aged. Genes that escape from X chromosome inactivation (XCI) contribute to sex-specific phenotypes in many disorders. Kdm5c and kdm6a are X escapee genes that demethylate H3K4me3 and H3K27me3, respectively. We hypothesized that the two demethylases play critical roles in mediating the stroke sensitivity. Methods To identify the X escapee genes involved in stroke, we performed RNA-seq in flow-sorted microglia from aged male and female wild type (WT) mice subjected to middle cerebral artery occlusion (MCAO). The expression of these genes (kdm5c/kdm6a) were confirmed in four core genotypes (FCG) mice and in post-mortem human stroke brains by immunohistochemistry (IHC), Western blot, and RT-PCR. Chromatin immunoprecipitation (ChIP) assays were conducted to detect DNA levels of inflammatory interferon regulatory factor (IRF) 4/5 precipitated by histone H3K4 and H3K27 antibodies. Manipulation of kdm5c/kdm6a expression with siRNA or lentivirus was performed in microglial culture, to determine downstream pathways and examine the regulatory roles in inflammatory cytokine production. Results Kdm5c and kdm6a mRNA levels were significantly higher in aged WT female vs. male microglia, and the sex difference also existed in ischemic brains from FCG mice and human stroke patients. The ChIP assay showed the IRF 4/5 had higher binding levels to demethylated H3K4 or H3K27, respectively, in female vs. male ischemic microglia. Knockdown or over expression of kdm5c/kdm6a with siRNA or lentivirus altered the methylation of H3K4 or H3K27 at the IRF4/5 genes, which in turn, impacted the production of inflammatory cytokines. Conclusions The KDM-Histone-IRF pathways are suggested to mediate sex differences in cerebral ischemia. Epigenetic modification of stroke-related genes constitutes an important mechanism underlying the ischemic sexual dimorphism.

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The melanocortin-3 receptor is a pharmacological target for the regulation of anorexia

Science Translational Medicine ◽

10.1126/scitranslmed.abd6434 ◽

2021 ◽

Vol 13 (590) ◽

pp. eabd6434

Author(s):

Patrick Sweeney ◽

Michelle N. Bedenbaugh ◽

Jose Maldonado ◽

Pauline Pan ◽

Katelyn Fowler ◽

...

Keyword(s):

Sexual Dimorphism ◽

Feeding Behavior ◽

Critical Role ◽

Brain Regions ◽

Sexually Dimorphic ◽

Male And Female ◽

Female Mice ◽

Bidirectional Regulation ◽

Fear And Anxiety ◽

Agouti Related Protein

Ablation of hypothalamic AgRP (Agouti-related protein) neurons is known to lead to fatal anorexia, whereas their activation stimulates voracious feeding and suppresses other motivational states including fear and anxiety. Despite the critical role of AgRP neurons in bidirectionally controlling feeding, there are currently no therapeutics available specifically targeting this circuitry. The melanocortin-3 receptor (MC3R) is expressed in multiple brain regions and exhibits sexual dimorphism of expression in some of those regions in both mice and humans. MC3R deletion produced multiple forms of sexually dimorphic anorexia that resembled aspects of human anorexia nervosa. However, there was no sexual dimorphism in the expression of MC3R in AgRP neurons, 97% of which expressed MC3R. Chemogenetic manipulation of arcuate MC3R neurons and pharmacologic manipulation of MC3R each exerted potent bidirectional regulation over feeding behavior in male and female mice, whereas global ablation of MC3R-expressing cells produced fatal anorexia. Pharmacological effects of MC3R compounds on feeding were dependent on intact AgRP circuitry in the mice. Thus, the dominant effect of MC3R appears to be the regulation of the AgRP circuitry in both male and female mice, with sexually dimorphic sites playing specialized and subordinate roles in feeding behavior. Therefore, MC3R is a potential therapeutic target for disorders characterized by anorexia, as well as a potential target for weight loss therapeutics.

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Population parameters and the relationships between environmental factors and abundance of the Acetes americanus shrimp (Dendrobranchiata: Sergestidae) near a coastal upwelling region of Brazil

Brazilian Journal of Oceanography ◽

10.1590/s1679-87592015086206303 ◽

2015 ◽

Vol 63 (3) ◽

pp. 229-238

Author(s):

Ana Paula Freitas dos Santos ◽

Sabrina Morilhas Simões ◽

Gabriel Lucas Bochini ◽

Cinthia Helena Costa ◽

Rogerio Caetano da Costa

Keyword(s):

Population Dynamics ◽

Sexual Dimorphism ◽

Environmental Factors ◽

Primary Productivity ◽

Low Temperatures ◽

Coastal Upwelling ◽

Statistical Correlation ◽

Individual Growth ◽

Otter Trawl ◽

Population Parameters

AbstractThe population dynamics of Acetes americanus was investigated, focusing on the sex ratio, individual growth, longevity, recruitment and relationship between abundance and environmental factors in the region of Macaé, strongly influenced by coastal upwelling. Otter trawl net samplings were performed from July 2010 to June 2011 at two points (5 m and 15 m). Nearly 19,500 specimens, predominantly females (77.15%), were captured. Their sizes, larger than that of males, indicated sexual dimorphism. Shrimps at lower latitudes present larger sizes and longer longevity than those from higher latitudes. This difference is probably due to low temperatures and high primary productivity. Though no statistical correlation was found between abundance and environmental factors, the species was more abundant in temperatures closer to 20.0º C and in months with high chlorophyll-a levels. Due to the peculiar characteristics of this region, A. americanusshowed greater differences in size and longevity than individuals sampled in other studies undertaken in the continental shelf of Southeast Brazil.

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Gut Microbiome in BALB/c and C57BL/6J Mice Undergoing Experimental Thyroid Autoimmunity Associate with Differences in Immunological Responses and Thyroid Function

Hormone and Metabolic Research ◽

10.1055/a-0653-3766 ◽

2018 ◽

Vol 50 (12) ◽

pp. 932-941 ◽

Cited By ~ 11

Author(s):

Sajad Moshkelgosha ◽

Giulia Masetti ◽

Utta Berchner-Pfannschmidt ◽

Hedda Verhasselt ◽

Mareike Horstmann ◽

...

Keyword(s):

Gut Microbiota ◽

Thyroid Function ◽

Thyroid Autoimmunity ◽

Low Frequency ◽

Inbred Strains ◽

Experimental Models ◽

Immune Response Gene ◽

Knock Out ◽

Immunological Responses ◽

Thyroid Stimulating Antibodies

AbstractExperimental models of hyperthyroid Graves’ disease (GD) and Graves’ orbitopathy (GO) are efficiently developed by genetic immunisation by electroporation with human thyrotropin hormone receptor (hTSHR) A-subunit plasmid in female BALB/c (H-2d) mice. We investigated susceptibility in C57BL/6 J (H-2b) animals to allow studies on disease mechanisms in transgenic and immune response gene knock-out mice. Higher numbers of female C57BL/6 J were positive for pathogenic thyroid stimulating antibodies, but induced hyperthyroidism remained at a low frequency compared to BALB/c animals. Assessment of hTSHR specific T cells showed reduced proliferation in C57BL/6 J animals accompanied with anti-inflammatory IL-10, with less pro-inflammatory IFN-γ compared to BALB/c. Whilst the orbital tissue from immune BALB/c mice showed inflammation and adipogenesis, in contrast C57BL/6 J animals showed normal pathology. We characterised the gut microbiota using 16 S ribosomal RNA gene sequencing to explore its possible pathogenic role in the model. Despite being housed under identical conditions, we observed significantly different organisation of the microbiota (beta-diversity) in the two strains. Taxonomic differences were also noted, with C57BL/6 J showing an enrichment of Operational Taxonomic Units (OTUs) belonging to the Paludibacter and Allobaculum, followed by Limibacter, Anaerophaga and Ureaplasma genera. A higher number of genera significantly correlating with clinical features was observed in C57BL/6 J compared to BALB/c; for example, Limibacter OTUs correlated negatively with thyroid-stimulating antibodies in C57BL/6 J mice. Thus, our data suggest gut microbiota may play a pivotal immunomodulatory role that differentiates the thyroid function and orbital pathology outcome in these two inbred strains undergoing experimental GO.

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Sexual dimorphism in the antennae of terrestrial isopods: a result of male contests or scramble competition?

Canadian Journal of Zoology ◽

10.1139/z00-128 ◽

2000 ◽

Vol 78 (11) ◽

pp. 1987-1993 ◽

Cited By ~ 18

Author(s):

F Lefebvre ◽

M Limousin ◽

Y Caubet

Keyword(s):

Sexual Dimorphism ◽

Negative Correlation ◽

Morphological Analysis ◽

Scramble Competition ◽

Behavioral Analysis ◽

Sexually Dimorphic ◽

Selection Pressures ◽

Terrestrial Isopods ◽

Male Contests

In Oniscidea (terrestrial crustaceans), males are known to have longer antennae than females. This sexual dimorphism may result from a variety of selection pressures. However, some species are well known for their highly aggressive males, which use their antennae as weapons. We tested the hypothesis that longer antennae in males have been selected for by means of antennal contests. Morphological analysis of the antennae and behavioral analysis of male dyads were performed in parallel on 7 species. We demonstrate significant sexual dimorphism of the antennae in 6 of the 7 species, and various forms of male aggressiveness depending on the species. Our hypothesis was rejected because we found a negative correlation between the use of the antennae in contests and the magnitude of sexual dimorphism. Furthermore, some species are sexually dimorphic but the males never compete using their antennae. We propose and argue that scramble competition to be the first to find receptive females could explain why males have longer chemoreceptive antennae.

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Sexual dimorphism in a top predator ( Notophthalmus viridescens ) drives aquatic prey community assembly

Proceedings of The Royal Society B Biological Sciences ◽

10.1098/rspb.2018.1717 ◽

2018 ◽

Vol 285 (1890) ◽

pp. 20181717 ◽

Cited By ~ 7

Author(s):

Denon Start ◽

Stephen De Lisle

Keyword(s):

Sexual Dimorphism ◽

Sex Ratio ◽

Intraspecific Variation ◽

Structure And Function ◽

Sexually Dimorphic ◽

Ecological Communities ◽

Top Predator ◽

Aquatic Mesocosms ◽

And Function ◽

The Impact

Intraspecific variation can have important consequences for the structure and function of ecological communities, and serves to link community ecology to evolutionary processes. Differences between the sexes are an overwhelmingly common form of intraspecific variation, but its community-level consequences have never been experimentally investigated. Here, we manipulate the sex ratio of a sexually dimorphic predacious newt in aquatic mesocosms, then track their impact on prey communities. Female and male newts preferentially forage in the benthic and pelagic zones, respectively, causing corresponding reductions in prey abundances in those habitats. Sex ratio differences also explained a large proportion (33%) of differences in the composition of entire pond communities. Ultimately, we demonstrate the impact of known patterns of sexual dimorphism in a predator on its prey, uncovering overlooked links between evolutionary adaptation and the structure of contemporary communities. Given the extreme prevalence of sexual dimorphism, we argue that the independent evolution of the sexes will often have important consequences for ecological communities.

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