Cancer Metabolic Phenotype

AbstractGut microbiomes, such as the microbial community that colonizes the rumen, have vast catabolic potential and play a vital role in host health and nutrition. By expanding our understanding of metabolic pathways in these ecosystems, we will garner foundational information for manipulating microbiome structure and function to influence host physiology. Currently, our knowledge of metabolic pathways relies heavily on inferences derived from metagenomics or culturing bacteria in vitro. However, novel approaches targeting specific cell physiologies can illuminate the functional potential encoded within microbial (meta)genomes to provide accurate assessments of metabolic abilities. Using fluorescently labeled polysaccharides, we visualized carbohydrate metabolism performed by single bacterial cells in a complex rumen sample, enabling a rapid assessment of their metabolic phenotype. Specifically, we identified bovine-adapted strains of Bacteroides thetaiotaomicron that metabolized yeast mannan in the rumen microbiome ex vivo and discerned the mechanistic differences between two distinct carbohydrate foraging behaviors, referred to as “medium grower” and “high grower.” Using comparative whole-genome sequencing, RNA-seq, and carbohydrate-active enzyme fingerprinting, we could elucidate the strain-level variability in carbohydrate utilization systems of the two foraging behaviors to help predict individual strategies of nutrient acquisition. Here, we present a multi-faceted study using complimentary next-generation physiology and “omics” approaches to characterize microbial adaptation to a prebiotic in the rumen ecosystem.

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Hyper‐metabolic B cells in the spleens of old mice make antibodies with autoimmune specificities

Immunity & Ageing ◽

10.1186/s12979-021-00222-3 ◽

2021 ◽

Vol 18 (1) ◽

Author(s):

Daniela Frasca ◽

Maria Romero ◽

Denisse Garcia ◽

Alain Diaz ◽

Bonnie B. Blomberg

Keyword(s):

B Cells ◽

B Cell ◽

Inflammatory Markers ◽

Cell Subset ◽

Antibody Responses ◽

Metabolic Phenotype ◽

Cellular Mechanisms ◽

Autoimmune Antibodies ◽

B Cell Subsets ◽

Old Mice

Abstract Background Aging is associated with increased intrinsic B cell inflammation, decreased protective antibody responses and increased autoimmune antibody responses. The effects of aging on the metabolic phenotype of B cells and on the metabolic programs that lead to the secretion of protective versus autoimmune antibodies are not known. Methods Splenic B cells and the major splenic B cell subsets, Follicular (FO) and Age-associated B cells (ABCs), were isolated from the spleens of young and old mice and left unstimulated. The RNA was collected to measure the expression of markers associated with intrinsic inflammation and autoimmune antibody production by qPCR. B cells and B cell subsets were also stimulated with CpG and supernatants collected after 7 days to measure autoimmune IgG secretion by ELISA. Metabolic measures (oxygen consumption rate, extracellular acidification rate and glucose uptake) were performed using a Seahorse XFp extracellular flux analyzer. Results Results have identified the subset of ABCs, whose frequencies and numbers increase with age and represent the most pro-inflammatory B cell subset, as the cell type mainly if not exclusively responsible for the expression of inflammatory markers and for the secretion of autoimmune antibodies in the spleen of old mice. Hyper-inflammatory ABCs from old mice are also hyper-metabolic, as compared to those from young mice and to the subset of FO B cells, a feature needed not only to support their higher expression of RNA for inflammatory markers but also their higher autoimmune antibody secretion. Conclusions These results identify a relationship between intrinsic inflammation, metabolism and autoimmune B cells and suggest possible ways to understand cellular mechanisms that lead to the generation of pathogenic B cells, that are hyper-inflammatory and hyper-metabolic, and secrete IgG antibodies with autoimmune specificities.

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Effects of exogenous adiponectin supplementation in early pregnant PCOS mice on the metabolic syndrome of adult female offspring

Journal of Ovarian Research ◽

10.1186/s13048-020-00755-z ◽

2021 ◽

Vol 14 (1) ◽

Author(s):

Meng Zuo ◽

Guotao Liao ◽

Wenqian Zhang ◽

Dan Xu ◽

Juan Lu ◽

...

Keyword(s):

Adult Female ◽

Early Pregnancy ◽

Testosterone Level ◽

Metabolic Disorders ◽

Serum Testosterone ◽

Female Offspring ◽

Metabolic Phenotype ◽

Serum Testosterone Level ◽

The Metabolic Syndrome ◽

Pcos Group

Abstract Objective PCOS is a heterogeneous endocrine disorder with both reproductive and metabolic abnormalities. At present, PCOS has been confirmed to have a certain genetic background. Compared with healthy women, the vast majority of PCOS patients have hyperandrogenemia, and this excessive androgen exposure during pregnancy may affect the development of female fetuses. The aim of the current study was to investigate the effect of adiponectin intervention during early pregnancy of obese mice with PCOS on the metabolic phenotype of adult female offspring. Methods After the PCOS model was established, C57BL/6J mice were divided into maternal-control, maternal-PCOS, and maternal-PCOS + APN groups. DHEA-induced PCOS mice were supplemented with adiponectin (10 mg/kg/day) in the early pregnancy in order to eliminate adverse hormone exposure and then traced for endocrine indicators in their adult female offspring, which were observed for metabolism syndrome or endocrine disturbance and exhibited the main effects of APN. To further explore the underlying mechanism, the relative expressions of phosphorylated AMPK, PI3K, and Akt were detected in the ovaries of offspring mice. Results The serum testosterone level of the maternal-PCOS + APN group in early pregnancy was significantly lower than that of the maternal-PCOS group (p < 0.01). The serum testosterone level in the offspring-PCOS + APN group was significantly lower than in the offspring-PCOS group (p <0.05), the diestrus time characterized by massive granulocyte aggregation in the estrus cycle was significantly shorter than in the offspring-PCOS group (p<0.05), and the phenotypes of PCOS-like reproductive disorders and metabolic disorders, such as obesity, insulin resistance, impaired glucose tolerance, and hyperlipidemia, were also significantly improved in the offspring-PCOS + APN group (p < 0.05). Compared with the control group, the expression levels of phosphorylated AMPK, PI3K, and Akt in the offspring-PCOS group were significantly decreased (p < 0.05), while those in the offspring-PCOS + APN group were significantly increased (p < 0.05). Conclusions APN intervention in early pregnancy significantly reduced the adverse effects of maternal obesity and high androgen levels during pregnancy on female offspring and corrected the PCOS-like endocrine phenotype and metabolic disorders of adult female offspring. This effect may be caused by the activation of the AMPK/PI3K-Akt signaling pathway in PCOS offspring mice.

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The influence of recipient SLCO1B1 rs2291075 polymorphism on tacrolimus dose–corrected trough concentration in the early period after liver transplantation

European Journal of Clinical Pharmacology ◽

10.1007/s00228-020-03058-w ◽

2021 ◽

Author(s):

Yi Wu ◽

Fang Fang ◽

Zhaowen Wang ◽

Peihao Wen ◽

Junwei Fan

Keyword(s):

Liver Transplantation ◽

Stationary Phase ◽

Trough Concentration ◽

Transmembrane Protein ◽

Early Period ◽

Metabolic Phenotype ◽

Combined Analysis ◽

D Values ◽

Tacrolimus Dose ◽

Convalescence Phase

Abstract Purpose To explore the relationship between rs2291075 polymorphism in SLCO1B1 gene, which encodes an influx transmembrane protein transporter, and tacrolimus dose–corrected trough concentration (C/D, ng ml−1 mg−1 kg−1) in the early period after liver transplantation. Methods CYP3A5 rs776746 and SLCO1B1 rs2291075 polymorphisms of 210 liver transplantation patients and their corresponding donor livers were assessed by PCR amplification and DNA sequencing. The influence of gene polymorphisms on C/D values of tacrolimus was analyzed. The early postoperative period after liver transplantation was divided into the convalescence phase (1–14 days) and stationary phase (15–28 days) according to the change of liver function and tacrolimus C/D values. Results The combined analysis of donor and recipient CYP3A5 rs776746 could distinguish the metabolic phenotype of tacrolimus into three groups: fast elimination (FE), intermediate elimination (IE), and slow elimination (SE), which was entitled the FIS classification system. Tacrolimus C/D ratios of recipient SLCO1B1 rs2291075 CT and TT carriers were very close and were significantly lower than those of recipient SLCO1B1 rs2291075 CC genotype carriers in convalescence phase (p = 0.0195) and in stationary phase (p = 0.0152). There were no statistically significant differences between tacrolimus C/D ratios of patients carried with SLCO1B1 rs2291075 CT, TT genotype donors, and those carried with SLCO1B1 rs2291075 CC genotype donors. A model consisting of tacrolimus daily dose, total bilirubin, FIS classification, and recipient SLCO1B1 rs2291075 could predict tacrolimus C/D ratios in the convalescence phase by multivariate analysis. However, recipient SLCO1B1 rs2291075 genotype failed to enter forecast model for C/D ratios in stationary phase. Recipient SLCO1B1 rs2291075 genotype had significant effect on tacrolimus C/D ratios in convalescence phase (p = 0.0300) and stationary phase (p = 0.0400) in subgroup, which excluded the interference come from donor and recipient CYP3A5 rs776746. Conclusion SLCO1B1 rs2291075 could be a novel genetic locus associated with tacrolimus metabolism. The combined analysis of donor and recipient CYP3A5 rs776746, recipient SLCO1B1 rs2291075 genotypes, could be helpful to guide the personalized administration of tacrolimus in early period after liver transplantation.

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