scholarly journals Sex-specific effects of microbiome perturbations on cerebral Aβ amyloidosis and microglia phenotypes

2019 ◽  
Vol 216 (7) ◽  
pp. 1542-1560 ◽  
Author(s):  
Hemraj B. Dodiya ◽  
Thomas Kuntz ◽  
Shabana M. Shaik ◽  
Caroline Baufeld ◽  
Jeffrey Leibowitz ◽  
...  
Keyword(s):  
Gut Microbiome ◽  
Amyloid Β ◽  
Fecal Microbiota ◽  
Male Mice ◽  
Female Mice ◽  
Antibiotic Cocktail ◽  
Specific Effects ◽  
Plaque Pathology ◽  
Microglial Morphology

We demonstrated that an antibiotic cocktail (ABX)-perturbed gut microbiome is associated with reduced amyloid-β (Aβ) plaque pathology and astrogliosis in the male amyloid precursor protein (APP)SWE/presenilin 1 (PS1)ΔE9 transgenic model of Aβ amyloidosis. We now show that in an independent, aggressive APPSWE/PS1L166P (APPPS1-21) mouse model of Aβ amyloidosis, an ABX-perturbed gut microbiome is associated with a reduction in Aβ pathology and alterations in microglial morphology, thus establishing the generality of the phenomenon. Most importantly, these latter alterations occur only in brains of male mice, not in the brains of female mice. Furthermore, ABX treatment lead to alterations in levels of selected microglial expressed transcripts indicative of the “M0” homeostatic state in male but not in female mice. Finally, we found that transplants of fecal microbiota from age-matched APPPS1-21 male mice into ABX-treated APPPS1-21 male restores the gut microbiome and partially restores Aβ pathology and microglial morphology, thus demonstrating a causal role of the microbiome in the modulation of Aβ amyloidosis and microglial physiology in mouse models of Aβ amyloidosis.

Gut microbiota–driven brain Aβ amyloidosis in mice requires microglia

2021 ◽  
Vol 219 (1) ◽  
Author(s):  
Hemraj B. Dodiya ◽  
Holly L. Lutz ◽  
Ian Q. Weigle ◽  
Priyam Patel ◽  
Julia Michalkiewicz ◽  
...  
Keyword(s):  
Gut Microbiome ◽  
Fecal Microbiota Transplantation ◽  
Critical Role ◽  
Amyloid Β ◽  
Fecal Microbiota ◽  
Degenerative Changes ◽  
High Dose ◽  
Male Mice ◽  
Treated Male ◽  
Plaque Pathology

We previously demonstrated that lifelong antibiotic (ABX) perturbations of the gut microbiome in male APPPS1-21 mice lead to reductions in amyloid β (Aβ) plaque pathology and altered phenotypes of plaque-associated microglia. Here, we show that a short, 7-d treatment of preweaned male mice with high-dose ABX is associated with reductions of Aβ amyloidosis, plaque-localized microglia morphologies, and Aβ-associated degenerative changes at 9 wk of age in male mice only. More importantly, fecal microbiota transplantation (FMT) from transgenic (Tg) or WT male donors into ABX-treated male mice completely restored Aβ amyloidosis, plaque-localized microglia morphologies, and Aβ-associated degenerative changes. Transcriptomic studies revealed significant differences between vehicle versus ABX-treated male mice and FMT from Tg mice into ABX-treated mice largely restored the transcriptome profiles to that of the Tg donor animals. Finally, colony-stimulating factor 1 receptor (CSF1R) inhibitor-mediated depletion of microglia in ABX-treated male mice failed to reduce cerebral Aβ amyloidosis. Thus, microglia play a critical role in driving gut microbiome–mediated alterations of cerebral Aβ deposition.

Role of the ovary in sexual differentiation of lactotrophs and somatotrophs in the mouse adenohypophysis: a stereological morphometric study by electron microscopy

1983 ◽  
Vol 99 (3) ◽  
pp. 355-NP ◽  
Author(s):  
F. Sasaki ◽  
M. Sano
Keyword(s):  
Adult Male ◽  
Sexual Differentiation ◽  
Morphometric Study ◽  
Normal Male ◽  
Corpora Lutea ◽  
Male Mice ◽  
Female Mice ◽  
Pituitary Glands ◽  
Normal Males

To study the effect of the ovary on sexual differentiation of somatotrophs and lactotrophs, the anterior pituitary glands of castrated adult male mice which had received an ovarian transplant during postnatal development were studied using a stereological morphometric technique with an electron microscope. In adult male mice which were castrated neonatally and given ovarian transplants at the age of puberty (NCT-males), the ovaries contained follicles and corpora lutea. The percentages (∼40) and numbers (∼2 × 105) of lactotrophs were similar in normal dioestrous females and NCT-males, but were higher than the percentage (9·3) and number (4·6 × 104) in normal males. Ovarian grafts in adult male mice which were simultaneously castrated and given an ovarian transplant just before puberty (PCT-males) contained numerous follicles of various sizes but no corpora lutea. The percentage (46·8) and number (3·9 × 105) of lactotrophs were greater in these mice than in dioestrous females. The percentage of somatotrophs in NCT-males (34·7) was less than in normal males (52·6), but was similar to that in dioestrous female mice (37·4). The percentage of somatotrophs in PCT-males (27·4) was less than in normal male and dioestrous female mice. These data indicate that lactotrophs and somatotrophs differentiate to the female phenotype when a cyclically functional ovary is present after puberty.

scholarly journals Chronic rapamycin treatment causes diabetes in male mice

2014 ◽  
Vol 307 (4) ◽  
pp. R434-R443 ◽  
Author(s):  
Christine E. Schindler ◽  
Uttara Partap ◽  
Bonnie K. Patchen ◽  
Steven J. Swoap
Keyword(s):  
Glucose Intolerance ◽  
Mammalian Target Of Rapamycin ◽  
Protective Role ◽  
Metabolic Effects ◽  
Current Evidence ◽  
Male Mice ◽  
Rapamycin Treatment ◽  
Female Mice ◽  
Glucose Levels

Current evidence indicates that the mammalian target of rapamycin inhibitor rapamycin both increases longevity and, seemingly contradictorily, impairs glucose homeostasis. Most studies exploring the dimensions of this paradox have been based on rapamycin treatment in mice for up to 20 wk. We sought to better understand the metabolic effects of oral rapamycin over a substantially longer period of time in HET3 mice. We observed that treatment with rapamycin for 52 wk induced diabetes in male mice, characterized by hyperglycemia, significant urine glucose levels, and severe glucose and pyruvate intolerance. Glucose intolerance occurred in male mice by 4 wk on rapamycin and could be only partially reversed with cessation of rapamycin treatment. Female mice developed moderate glucose intolerance over 1 yr of rapamycin treatment, but not diabetes. The role of sex hormones in the differential development of diabetic symptoms in male and female mice was further explored. HET3 mice treated with rapamycin for 52 wk were gonadectomized and monitored over 10 wk. Castrated male mice remained glucose intolerant, while ovariectomized females developed significant glucose intolerance over the same time period. Subsequent replacement of 17β-estradiol (E2) in ovariectomized females promoted a recovery of glucose tolerance over a 4-wk period, suggesting the protective role of E2against rapamycin-induced diabetes. These results indicate that 1) oral rapamycin treatment causes diabetes in male mice, 2) the diabetes is partially reversible with cessation of treatment, and 3) E2plays a protective role against the development of rapamycin-induced diabetes.

scholarly journals Ornithine decarboxylase antizyme in kidneys of male and female mice

1988 ◽  
Vol 254 (2) ◽  
pp. 367-372 ◽  
Author(s):  
Y Murakami ◽  
M Marumo ◽  
S I Hayashi
Keyword(s):  
Ornithine Decarboxylase ◽  
Half Life ◽  
Mouse Kidney ◽  
Repeated Injection ◽  
Male Mice ◽  
Protein Inhibitor ◽  
Male And Female ◽  
Female Mice ◽  
Htc Cells

Antizyme, a protein inhibitor of ornithine decarboxylase (ODC), was shown to be induced in mouse kidney by repeated injection of putrescine. Antizyme was also present as a complex with ODC in the kidney of untreated mouse. The amount of the renal ODC-antizyme complex was 3-fold higher in male mice than in female mice. On the contrary, the proportion of ODC present as a complex with antizyme was 24-fold higher in females than in males, and the decay of renal ODC activity after cycloheximide treatment was about 5-fold more rapid in females than in males. Administration of testosterone to female mice, a procedure known to prolong the half-life of renal ODC, increased both ODC activity and the content of ODC-antizyme complex, but decreased the antizyme/ODC ratio in the kidney. These results are consistent with the previous observation in HTC cells that the decay rate of ODC activity in the presence of cycloheximide correlated well with the proportion of ODC present as a complex with antizyme, suggesting the ubiquitous role of antizyme in ODC degradation.

scholarly journals Recent advances in modulating the microbiome

F1000Research ◽  
2020 ◽  
Vol 9 ◽  
pp. 46 ◽  
Author(s):  
Eamonn M.M Quigley ◽  
Prianka Gajula
Keyword(s):  
Gut Microbiome ◽  
Fecal Microbiota Transplantation ◽  
Fecal Microbiota ◽  
Human Phenotype ◽  
Host Interactions ◽  
Healthy Humans ◽  
Probiotic Strains ◽  
The Many ◽  
Definition Of

We are in the midst of “the microbiome revolution”—not a day goes by without some new revelation on the potential role of the gut microbiome in some disease or disorder. From an ever-increasing recognition of the many roles of the gut microbiome in health and disease comes the expectation that its modulation could treat or prevent these very same diseases. A variety of interventions could, at least in theory, be employed to alter the composition or functional capacity of the microbiome, ranging from diet to fecal microbiota transplantation (FMT). For some, such as antibiotics, prebiotics, and probiotics, an extensive, albeit far from consistent, literature already exists; for others, such as other dietary supplements and FMT, high-quality clinical studies are still relatively few in number. Not surprisingly, researchers have turned to the microbiome itself as a source for new entities that could be used therapeutically to manipulate the microbiome; for example, some probiotic strains currently in use were sourced from the gastrointestinal tract of healthy humans. From all of the extant studies of interventions targeted at the gut microbiome, a number of important themes have emerged. First, with relatively few exceptions, we are still a long way from a precise definition of the role of the gut microbiome in many of the diseases where a disturbed microbiome has been described—association does not prove causation. Second, while animal models can provide fascinating insights into microbiota–host interactions, they rarely recapitulate the complete human phenotype. Third, studies of several interventions have been difficult to interpret because of variations in study population, test product, and outcome measures, not to mention limitations in study design. The goal of microbiome modulation is a laudable one, but we need to define our targets, refine our interventions, and agree on outcomes.

Sex-specific effects of neonatal oral sucrose treatment on growth and liver choline and glucocorticoid metabolism in adulthood

2021 ◽  
Author(s):  
Cynthia Yamilka Ramírez-Contreras ◽  
Arya E Mehran ◽  
Melody Salehzadeh ◽  
Ei-Xia Mussai ◽  
Joshua W Miller ◽  
...  
Keyword(s):  
Body Weight ◽  
Preterm Infants ◽  
Serum Insulin ◽  
Control Diet ◽  
Male Mice ◽  
Long Term Effects ◽  
Female Mice ◽  
Specific Effects ◽  
Oral Sucrose

Hospitalized preterm infants experience painful medical procedures. Oral sucrose is the non‑pharmacological standard of care for minor procedural pain relief. Infants are treated with numerous doses of sucrose, raising concerns about potential long-term effects. The objective of this study was to determine the long‑term effects of neonatal oral sucrose treatment on growth and liver metabolism in a mouse model. Neonatal female and male mice were randomly assigned to one of two oral treatments (n=7‑10 mice/group/sex): sterile water or sucrose. Pups were treated 10 times/day for the first six days of life with 0.2mg/g body weight of respective treatments (24% solution; 1‑4μl/dose) to mimic what is given to preterm infants. Mice were weaned at age 3 weeks onto a control diet and fed until age 16 weeks. Sucrose-treated female and male mice gained less weight during the treatment period and were smaller at weaning than water-treated mice (p≤0.05); no effect of sucrose treatment on body weight was observed at adulthood. However, adult sucrose-treated female mice had smaller tibias and lower serum insulin-like growth factor-1 than adult water-treated female mice (p≤0.05); these effects were not observed in males. Lower liver S-adenosylmethionine, phosphocholine, and glycerophosphocholine were observed in adult sucrose-treated compared to water-treated female and male mice (p≤0.05). Sucrose-treated female, but not male, mice had lower liver free choline and higher liver betaine compared to water-treated female mice (p<0.01). Our findings suggest that repeated neonatal sucrose treatment has long-term sex-specific effects on growth and liver methionine and choline metabolism.

scholarly journals Antibiotic Exposure Has Sex-Dependent Effects on the Gut Microbiota and Metabolism of Short-Chain Fatty Acids and Amino Acids in Mice

mSystems ◽  
2019 ◽  
Vol 4 (4) ◽  
Author(s):  
Hongchang Gao ◽  
Qi Shu ◽  
Jiuxia Chen ◽  
Kai Fan ◽  
Pengtao Xu ◽  
...  
Keyword(s):  
Amino Acids ◽  
Fatty Acids ◽  
Gut Microbiota ◽  
Gut Microbiome ◽  
Short Chain Fatty Acids ◽  
Antibiotic Exposure ◽  
Male Mice ◽  
Female Mice ◽  
Structural Composition ◽  
Host Metabolism

ABSTRACT The gut microbiota has the capability to regulate homeostasis of the host metabolism. Since antibiotic exposure can adversely affect the microbiome, we hypothesized that antibiotic effects on the gut microbiota and host metabolism are sex dependent. In this study, we examined the effects of antibiotic treatments, including vancomycin (Vanc) and ciprofloxacin-metronidazole (CiMe), on the gut microbiome and metabolome in colonic contents and tissues in both male and female mice. We found that the relative abundances and structural composition of Firmicutes were significantly reduced in female mice after both Vanc and CiMe treatments but in male mice only after treatment with Vanc. However, Vanc exposure considerably altered the relative abundances and structural composition of representatives of the Proteobacteria especially in male mice. The levels of short-chain fatty acids (SCFAs; acetate, butyrate, and propionate) in colonic contents and tissues were significantly decreased in female mice after both antibiotic treatments, while these reductions were detected in male mice only after Vanc treatment. However, another SCFA, formate, exhibited the opposite tendency in colonic tissues. Both antibiotic exposures significantly decreased the levels of alanine, branched-chain amino acids (BCAAs; leucine, isoleucine, and valine) and aromatic amino acids (AAAs; phenylalanine and tyrosine) in colonic contents of female mice but not in male mice. Additionally, female mice had much greater correlations between microbe and metabolite than male mice. These findings suggest that sex-dependent effects should be considered for antibiotic-induced modifications of the gut microbiota and host metabolism. IMPORTANCE Accumulating evidence shows that the gut microbiota regulates host metabolism by producing a series of metabolites, such as amino acids, bile acids, fatty acids, and others. These metabolites have a positive or negative effect on host health. Antibiotic exposure can disrupt the gut microbiota and thereby affect host metabolism and physiology. However, there are a limited number of studies addressing whether antibiotic effects on the gut microbiota and host metabolism are sex dependent. In this study, we uncovered a sex-dependent difference in antibiotic effects on the gut microbiota and metabolome in colonic contents and tissues in mice. These findings reveal that sex-dependent effects need to be considered for antibiotic use in scientific research or clinical practice. Moreover, this study will also give an important direction for future use of antibiotics to modify the gut microbiome and host metabolism in a sex-specific manner.

Extragonadal effects of luteinizing hormone in mice

1989 ◽  
Vol 121 (4) ◽  
pp. 587-594 ◽  
Author(s):  
Kaoru Nomura ◽  
David W. Puett ◽  
David Puett ◽  
Kazuo Shizume ◽  
Grant W. Liddle
Keyword(s):  
Physiological Role ◽  
Male Mice ◽  
Intact Female ◽  
Intact Male ◽  
Kidney Weight ◽  
Kidney Size ◽  
Female Mice ◽  
Cellular Hypertrophy ◽  
Kidney Growth

Abstract. LH is composed of isoforms which exhibit microheterogeneity. We recently demonstrated that a particular ovine or porcine LH preparation (G100-fr.3) stimulates kidney growth. This study was conducted to clarify the physiological role of this renotropic activity and other extragonadal effects of the ovine LH preparation in CD-1 mice. Hypophysectomy caused a significantly greater reduction in relative dry kidney weight (i.e. g/100 g body weight) when compared to adrenalectomy, castration, thyroidectomy, and castration plus thyroidectomy. Supplementation with G100-fr.3 in these animals partially restored not only kidney size but also DNA, RNA and protein content. Treatment with standard LH preparations (NIDDKoLH24 and G3-268DA), as well as PRL, GH, FSH and TSH, failed to reverse the renal atrophy induced by hypophysectomy and castration. Administration of testosterone to castrated hypophysectomized mice increased kidney weight and RNA content, but not renal DNA. The relative dry kidney weight increased significantly at the onset of puberty in intact male mice, but not in castrated males or intact female mice. In addition, human CG increased kidney size in hypophysectomized male mice, but not in castrated hypophysectomized animals. These findings indicate that LH isoforms may regulate kidney growth in the male mouse both directly as a renotropin stimulating hyperplasia and indirectly as a gonadotropin via testicular androgen, producing cellular hypertrophy. It was also noted that G100-fr.3 decreased hepatic weight, DNA, RNA and protein, but produced no significant change in the spleen, heart or adrenal glands in castrated-hypophysectomized mice. Such extragonadal effects of G100-fr.3 were also observed in intact female mice. These results suggest that certain LH isoforms may have extragonadal actions involving the kidney and liver.

scholarly journals Sex-Dependent Effects of 7,8-Dihydroxyflavone on Metabolic Health Are Associated with Alterations in the Host Gut Microbiome

Nutrients ◽  
2021 ◽  
Vol 13 (2) ◽  
pp. 637
Author(s):  
Priyanka Sharma ◽  
Guojun Wu ◽  
Deeptha Kumaraswamy ◽  
Natalie Burchat ◽  
Hong Ye ◽  
...  
Keyword(s):  
Body Weight ◽  
Adipose Tissue ◽  
Gut Microbiome ◽  
Lipid Accumulation ◽  
Intestinal Microbiome ◽  
Sexually Dimorphic ◽  
Adipose Tissue Inflammation ◽  
Male Mice ◽  
Female Mice ◽  
Hepatic Lipid Accumulation

7,8-Dihydroxyflavone (DHF) is a naturally occurring flavonoid that has been reported to protect against a variety of pathologies. Chronic administration of DHF prevents high-fat diet (HFD)-induced obesity in female, but not male, mice. However, the mechanisms underlying this sexual dimorphism have not been elucidated. We have discovered that oral DHF supplementation significantly attenuates fat mass, hepatic lipid accumulation, and adipose tissue inflammation in female mice. In contrast, male mice were not protected from adiposity, and had a paradoxical worsening of hepatic lipid accumulation and adipose tissue inflammation upon DHF supplementation. Consistent with these sexually dimorphic effects on body weight and metabolic health, 7,8-DHF induced early and stable remodeling of the female intestinal microbiome. DHF supplementation significantly increased gut microbial diversity, and suppressed potentially detrimental bacteria, particularly Desulfovibrionaceae, which are pro-inflammatory and positively associated with obesity and inflammation. Changes in the female gut microbiome preceded alterations in body weights, and in silico analyses indicated that these early microbial changes were highly predictive of subsequent weight gain in female mice. While some alterations in the intestinal microbiome were also observed in male DHF-supplemented mice, these changes were distinct from those in females and, importantly, were not predictive of subsequent body weight changes in male animals. The temporality of microbial changes preceding alterations in body weight in female mice suggests a role for the gut microbiome in mediating the sexually dimorphic effects of DHF on body weight. Given the significant clinical interest in this flavonoid across a wide range of pathologies, further elucidation of these sexually dimorphic effects will aid the development of effective clinical therapies.

scholarly journals SUN-253 PROKR2 Neurons of the Amygdalohippocampal Area in Reproductive Function

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Brenda Cisneros Larios ◽  
Carol F Elias
Keyword(s):  
Steroid Receptors ◽  
Reproductive Function ◽  
Sexually Dimorphic ◽  
Male Mice ◽  
Loss Of Function ◽  
Exposure Test ◽  
Male And Female ◽  
Female Mice ◽  
Reproductive Control

Abstract Kallmann Syndrome (KS) is characterized by infertility and anosmia due to deficiency in gonadotropin releasing hormone (GnRH) neuronal migration and olfactory bulb dysgenesis. Genetic studies have revealed that KS is caused by loss-of-function mutations in several genes including the prokineticin receptor 2 (PROKR2) gene (Abreu et al., 2008, Hardelin & Dode 2008). Mice with global deletion of Prokr2 replicate the phenotype of KS patients (Ng et al., 2005, Matsumoto et al., 2006). Whereas the role of PROKR2 during development is defined, little is known about PROKR2 neurons in adult reproduction. PROKR2 mRNA are highly expressed in reproductive control sites of the adult mouse brain (Cheng et al., 2006). Previous studies in our lab found PROKR2 mRNA and Prokr2-Cre GFP+ cells highly expressed in the amygdalohippocampal area (AHi, also called posterior nucleus of the amygdala) in a sexually-dimorphic pattern. Male mice have higher PROKR2 expression in the AHi compared to female mice (Mohsen et al., 2017). The amygdala is an important site of socio-sexual inputs and reproductive neuroendocrine responses in rodents and primates, including humans. We hypothesize Prokr2-Cre neurons in the AHi have a role in both male and female reproductive function. Using genetic tracing techniques, we mapped AHi Prokr2-Cre neuronal projections in both male and female mice and found dense innervation to reproductive control sites such as the medial preoptic area and the ventral premammillary nucleus in a sexually dimorphic pattern. A soiled bedding exposure test in sexually experienced male mice showed that an estimated 45% of cFos + cells in the AHi express Prokr2-Cre GFP. Dense sex steroid receptors expression was observed in AHi Prokr2-Cre GFP neurons of both male and female mice. Our preliminary data suggests AHi Prokr2-Cre neurons have a reproductive function in male and potentially also in female mice. Future studies will focus on selective activation and inhibition of these neurons using chemogenetic technology to determine putative inputs to brain sites that control the hypothalamo-pituitary-gonadal axis. We expect our studies will contribute to the understanding of the role of PROKR2 neurons in adult reproduction and reproductive deficits associated with PROKR2 mutations.

Sign in / Sign up

Export Citation Format

Share Document