Manipulations of the gut microbiome alter chemotherapy-induced inflammation and behavioral side effects in female mice

Abstract Objectives Blackcurrant, an anthocyanin-rich berry, has multiple health benefits. The purpose of this study was to examine the impacts of blackcurrant supplementation and aging on gut bacterial communities in female mice. Methods Three-month and 18-month old female mice were provided standard chow diets with or without anthocyanin-rich blackcurrant extract (BC) (1% w/w) for four months. Upon study completion, fecal samples were collected directly from the animals’ colons. Microbiome DNA was extracted from the fecal samples and the V3-V4 regions of their 16S rRNA gene were amplified and sequenced using Results Taxonomic analysis showed a significantly decrease in alpha diversity in aged female mice, compared to young counterparts. BC consumption did not alter the alpha diversity in either young or aged mice compared to control diets. For beta diversity, we observed the clustering was associated with age but not diet. The phylogenic abundance analysis showed that the relative abundance of several phyla, including Firmicutes, Bacteroidetes, Cyanobacteria, Proteobacteria, and Tenericutes was higher in aged compared to young mice. Among them, the abundance of Firmicutes was downregulated by BC in the young but not the aged mice. The abundance of Bacteroidetes was increased by BC in both the young and the aged groups. Noticeably, Verrucomicrobia was the only phylum whose relative abundance was upregulated in the aged female mice compared to the young mice. Meanwhile, its relative abundance in the aged group was suppressed by BC. Interestingly, Desulfovibrio, which is the most representative sulfate-reducing genus, was detectable only in young female mice, and BC increased its relative abundance. Conclusions Our results characterized the gut microbiome compositions in young and aged female mice, and indicated that the gut microbiome of young and aged female mice responded differently to four month BC administration. Through additional research, the microbial alterations observed in this study should be further investigated to inform our understanding of the effect of BC on the gut microbiome, the possible health benefits related to these changes, and the differing effects of BC supplementation across populations. Funding Sources This study was supported by the USDA NIFA Seed Grant (#2016-67018-24492) and the University of Connecticut Foundation Esperance Funds to Dr. Ock K. Chun. We thank the National Institute on Aging for providing aged mice for the project and Just the Berries Ltd. for providing the blackcurrant extract.

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

Journal of Experimental Medicine ◽

10.1084/jem.20182386 ◽

2019 ◽

Vol 216 (7) ◽

pp. 1542-1560 ◽

Cited By ~ 40

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.

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The Microbiota-Gut-Brain Axis in Mental Health and Medication Response: Parsing Directionality and Causality

The International Journal of Neuropsychopharmacology ◽

10.1093/ijnp/pyaa088 ◽

2021 ◽

Vol 24 (3) ◽

pp. 216-220

Author(s):

Thomaz F S Bastiaanssen ◽

John F Cryan

Keyword(s):

Mental Health ◽

Side Effects ◽

Anxiety Disorders ◽

Psychotropic Drugs ◽

Gut Microbiome ◽

Alpha Diversity ◽

Mental Health Disorders ◽

Longitudinal Cohort ◽

Health Disorders

Abstract There is increasing evidence for the role of the microbiome in various mental health disorders. Moreover, there has been a growing understanding of the importance of the microbiome in mediating both the efficacy and side effects of various medications, including psychotropics. In this issue, Tomizawa and colleagues report on the effect of psychotropic drugs on the gut microbiome of 40 patients with depression and/or anxiety disorders. In their longitudinal cohort, the authors find that antipsychotics, but not anxiolytics, decrease microbiome alpha diversity. They further find that antipsychotics dosage was negatively correlated with alpha diversity in these patients. The health consequences of these microbiome alterations remain to be fully understood. In this commentary, we will discuss such findings through the lens of several recent studies on the microbiota-gut-brain axis. We also use the paper as a backdrop to discuss directionality and, by extension, causality in relation to microbiota-gut-brain-brain signaling.

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APOE Genetics Influence Murine Gut Microbiome

10.21203/rs.3.rs-746611/v1 ◽

2021 ◽

Author(s):

Diana J. Zajac ◽

Stefan J. Green ◽

Lance A. Johnson ◽

Steven Estus

Keyword(s):

Gut Microbiome ◽

Beta Diversity ◽

Univariate Analysis ◽

Microbial Community Composition ◽

Alpha Diversity ◽

Amplicon Sequencing ◽

Linear Discriminant ◽

Fecal Microbiome ◽

Female Mice ◽

The Impact

Abstract Background: Apolipoprotein E (APOE) alleles impact pathogenesis and risk for multiple human diseases, making them primary targets for disease treatment and prevention. Previously, we and others reported an association between APOE alleles and the gut microbiome. Here, we tested whether these results are confirmed by using mice that were maintained under ideal conditions for microbiome analyses. Methods: To model human APOE alleles, this study used APOE targeted replacement (TR) mice on a C57Bl/6 background. To minimize genetic drift, APOE3 mice were crossed to APOE2 or APOE4 mice prior to the study, and the resulting heterozygous progeny crossed further to generate the study mice. To maximize environmental homogeneity, mice with mixed genotypes were housed together and used bedding from the cages was mixed and added back as a portion of new bedding. Fecal samples were obtained from mice at three-, five- and seven-months of age, and microbiota analyzed by 16S ribosomal RNA gene amplicon sequencing. APOE2/E2 and APOE2/E3 mice were categorized as APOE2, APOE3/E4 and APOE4/E4 mice were categorized as APOE4, and APOE3/E3 mice were categorized as APOE3. Linear discriminant analysis of Effect Size (LefSe) identified taxa associated with APOE status, depicted as cladograms to show phylogenetic relatedness. The influence of APOE status was tested onalpha-diversity (Shannon H index) and beta-diversity (principal coordinate analyses and PERMANOVA). Individual taxa associated with APOE status were identified by classical univariate analysis. Whether findings in the APOE mice were replicated in humans was evaluated by using published microbiome genome wide association data. Results: Cladograms revealed robust differences with APOE in male mice and limited differences in female mice. The richness and evenness (alpha-diversity) and microbial community composition (beta-diversity) of the fecal microbiome was robustly associated with APOE status in male but not female mice. Classical univariate analysis revealed individual taxa that were significantly increased or decreased with APOE, illustrating a stepwise APOE2-APOE3-APOE4 pattern of association. The Clostridia class, Clostridiales order, Ruminococacceae family and related genera increased with APOE2 status. The Erysipelotrichia phylogenetic branch increased with APOE4 status, a finding that extended to humans.Conclusions: In this study wherein mice were maintained in an ideal fashion for microbiome studies, gut microbiome profiles were strongly and significantly associated with APOE status in male APOE-TR mice. Erysipelotrichia in particular appears to increase with APOE4 in both mice and humans. Further evaluation of these findings in humans, as well as studies evaluating the impact of the APOE-associated microbiota on disease-relevant phenotypes, will be necessary to determine if alterations in the gut microbiome represents a novel mechanism whereby APOE alleles impact disease.

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BIOBOARD

Asia-Pacific Biotech News ◽

10.1142/s0219030318000800 ◽

2018 ◽

Vol 22 (11) ◽

pp. 61-64

Keyword(s):

Neuropathic Pain ◽

Side Effects ◽

Precision Medicine ◽

Nobel Prize ◽

Gut Microbiome ◽

Asia Pacific ◽

Chemotherapy Side Effects ◽

The World

ASIA-PACIFIC – Precision medicine for diagnosing and treating neuropathic pain. ASIA-PACIFIC – Antibiotics overuse causes imbalanced gut microbiome. ASIA-PACIFIC – Bright lights, big CITI. REST OF THE WORLD – 2018 Nobel Prize in Physiology or Medicine winners. REST OF THE WORLD – Women more prone to selected chemotherapy side-effects.

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

mSystems ◽

10.1128/msystems.00048-19 ◽

2019 ◽

Vol 4 (4) ◽

Cited By ~ 9

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.

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Letrozole treatment of pubertal female mice results in activational effects on reproduction, metabolism and the gut microbiome

PLoS ONE ◽

10.1371/journal.pone.0223274 ◽

2019 ◽

Vol 14 (9) ◽

pp. e0223274 ◽

Cited By ~ 4

Author(s):

Pablo Arroyo ◽

Bryan S. Ho ◽

Lillian Sau ◽

Scott T. Kelley ◽

Varykina G. Thackray

Keyword(s):

Gut Microbiome ◽

Female Mice ◽

Letrozole Treatment

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

Nutrients ◽

10.3390/nu13020637 ◽

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.

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No influence of antibiotic on locomotion inDrosophila nigrosparsaafter recovery, but influence on microbiome, possibly mediating wing-morphology change

10.1101/2021.03.09.434651 ◽

2021 ◽

Author(s):

Simon O. Weiland ◽

Matsapume Detcharoen ◽

Birgit C. Schlick-Steiner ◽

Florian M. Steiner

Keyword(s):

Side Effects ◽

Gut Microbiome ◽

Bacterial Abundance ◽

Control Group ◽

Direct And Indirect Effects ◽

Wing Morphology ◽

Long Term Effects ◽

Two Generations ◽

Reducing Potential

ABSTRACTAntibiotics, such as tetracycline, has been frequently used to cure endosymbiontWolbachiain arthropods. After the symbionts had been removed, the hosts must be waited for some generations to recover from side effects of the antibiotics. Knowledge of potential long-term effects of the antibiotic is important. Here, we treatedDrosophila nigrosparsawith and without antibiotic tetracycline for three generations and two generations recovering time to investigate effects of the tetracycline on the flies concerning locomotion of larvae and adults, wing morphology, and gut microbiome of adults. In addition, gut-microbiome restoration was tested as a solution to reducing potential side effects of tetracycline on the flies’ microbiome more quickly. We found significant differences in larval and adult locomotion within groups but no significant differences among the control, antibiotic-treated, and gut-restoration groups. We found a slight differentiation of wing morphology into the three groups and significant differences in bacterial abundance among groups. The influence of tetracycline on the gut microbiome may have contributed to wing-morphology differences among groups, which would be an indirect effect of the antibiotic. Together with the absence of an effect on locomotion, this suggests that checking for both direct and indirect effects of tetracycline after a particular recovery time before using tetracycline curing is important. The microbiome of the gut-restoration group was not like that of the control group. Therefore, gut restoration cannot be used to remove effects of tetracycline inD. nigrosparsa, at least in the setup used here.

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