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. 2017 May 11;7(1):1748.
doi: 10.1038/s41598-017-01576-9.

Gender Differences in Bile Acids and Microbiota in Relationship with Gender Dissimilarity in Steatosis Induced by Diet and FXR Inactivation

Lili Sheng  1 , Prasant Kumar Jena  1 , Hui-Xin Liu  1 , Karen M Kalanetra  2 , Frank J Gonzalez  3 , Samuel W French  4 , Viswanathan V Krishnan  1   5 , David A Mills  2 , Yu-Jui Yvonne Wan  6
Affiliations

Gender Differences in Bile Acids and Microbiota in Relationship with Gender Dissimilarity in Steatosis Induced by Diet and FXR Inactivation

Lili Sheng et al. Sci Rep. .

Abstract

This study aims to uncover how specific bacteria and bile acids (BAs) contribute to steatosis induced by diet and farnesoid X receptor (FXR) deficiency in both genders. A control diet (CD) and Western diet (WD), which contains high fat and carbohydrate, were used to feed wild type (WT) and FXR knockout (KO) mice followed by phenotyping characterization as well as BA and microbiota profiling. Our data revealed that male WD-fed FXR KO mice had the most severe steatosis and highest hepatic and serum lipids as well as insulin resistance among the eight studied groups. Gender differences in WD-induced steatosis, insulin sensitivity, and predicted microbiota functions were all FXR-dependent. FXR deficiency enriched Desulfovibrionaceae, Deferribacteraceae, and Helicobacteraceae, which were accompanied by increased hepatic taurine-conjugated cholic acid and β-muricholic acid as well as hepatic and serum lipids. Additionally, distinct microbiota profiles were found in WD-fed WT mice harboring simple steatosis and CD-fed FXR KO mice, in which the steatosis had a potential to develop into liver cancer. Together, the presented data revealed FXR-dependent concomitant relationships between gut microbiota, BAs, and metabolic diseases in both genders. Gender differences in BAs and microbiota may account for gender dissimilarity in metabolism and metabolic diseases.

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Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Figure 1
Figure 1
Histological and phenotypic changes in control diet and Western diet-fed wild type and FXR KO mice of both genders. (A) Body weight gain. (B) Percentage of liver to body weight ratio. (C) Serum alanine aminotransferase (ALT). (D) Serum endotoxin level. (E) Representative liver morphology and H&E-stained liver sections. Scale bars, 100 µm. Hepatic triglycerides (F) and cholesterol (G) level. Serum triglycerides (H) and cholesterol (I) level. n = 6 per group. Data are expressed as mean ± SD. One-way ANOVA with Tukey’s correction. *p < 0.05, **p < 0.01, ***p < 0.001 for diet comparison; # p < 0.05, ## p < 0.01, ### p < 0.001 for genotype comparison; & p < 0.05, && p < 0.01, &&& p < 0.001 for gender comparison.
Figure 2
Figure 2
Insulin and glucose tolerance tests in control diet and Western diet -fed wild type and FXR KO mice of both genders. (A) Blood glucose level after 6 h fasting. (B) Insulin tolerance test (ITT). (C) Glucose tolerance test (GTT). The area under curve (AUC) is showed. n = 6 per group. Data are expressed as mean ± SD. One-way ANOVA with Tukey’s correction. *p < 0.05, **p < 0.01, ***p < 0.001 for diet comparison; # p < 0.05, ## p < 0.01, ### p < 0.001 for genotype comparison; & p < 0.05, && p < 0.01, &&& p < 0.001 for gender comparison.
Figure 3
Figure 3
Hepatic bile acid profile in control diet and Western diet-fed wild type and FXR KO mice of both genders. (A) Total hepatic bile acids. Data are expressed as mean ± SD. One-way ANOVA with Tukey’s correction, ### p < 0.001 for genotype comparison. (B) Hepatic bile acid profile. n = 16 in male groups, n = 6 in female groups.
Figure 4
Figure 4
Hepatic gene expression in control diet and Western diet -fed wild type and FXR KO mice of both genders. (A) Lipid and glucose related genes. (B) Bile acid related genes. n = 6 per group. Data are expressed as mean ± SD. One-way ANOVA with Tukey’s correction. *p < 0.05, **p < 0.01, ***p < 0.001 for diet comparison; # p < 0.05, ## p < 0.01, ### p < 0.001 for genotype comparison; & p < 0.05, && p < 0.01, &&& p < 0.001 for gender comparison.
Figure 5
Figure 5
Diet and FXR deficiency changed gut microbiota composition in both genders. (A) Cecal microbiota at phylum level. (B) Firmicutes to Bacteroidetes ratio. Principal component analysis plots of cecal microbiota at family level based on diet (C), phenotype (D), and gender difference (E). (F) and (G), relative abundance of cecal microbiota at family level (Kruskal-Wallis test). Box plots display the median, 25th percentile, and 75th percentile; whiskers display minimum and maximum values. (H) Targeted functional quantitative PCR analysis of microbial genes. (B,H), data are expressed as mean ± SD. One-way ANOVA with Tukey’s correction. n = 16 in male groups, n = 6 in female groups. *p < 0.05, **p < 0.01, ***p < 0.001 for diet comparison; # p < 0.05, ## p < 0.01, ### p < 0.001 for genotype comparison; & p < 0.05, && p < 0.01, &&& p < 0.001 for gender comparison.
Figure 6
Figure 6
Spearman’s correlation analysis. Heatmaps of Spearman’s correlation analysis between abundance of bacterial families and phenotypes, bacterial families and hepatic bile acids (A), between mouse phenotypes and hepatic bile acids (B), and between abundance of bacterial families and genes (C) *p < 0.05.
Figure 7
Figure 7
The differences between Western diet-fed wild type mice and control diet-fed FXR KO mice of both genders. (A) Heatmaps of bile acid profile and mouse phenotypes. Bile acids and phenotypes were displayed with fold change (WD-fed WT vs. CD-fed FXR KO) ≥1.5 or ≤0.67 in at least one gender. (B) Principal component analysis plots of cecal microbiota at family level. (C) Bacterial families are shown (mean relative abundance >0.2%) with significant difference between WD-fed WT and CD-fed FXR KO mice in at least one gender.
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References

    1. Geer EB, Shen W. Gender differences in insulin resistance, body composition, and energy balance. Gend Med. 2009;6(Suppl 1):60–75. doi: 10.1016/j.genm.2009.02.002. - DOI - PMC - PubMed
    1. Steinberger J, Daniels SR. American Heart Association Atherosclerosis, H., Obesity in the Young, C. & American Heart Association Diabetes, C. Obesity, insulin resistance, diabetes, and cardiovascular risk in children: an American Heart Association scientific statement from the Atherosclerosis, Hypertension, and Obesity in the Young Committee (Council on Cardiovascular Disease in the Young) and the Diabetes Committee (Council on Nutrition, Physical Activity, and Metabolism) Circulation. 2003;107:1448–1453. doi: 10.1161/01.CIR.0000060923.07573.F2. - DOI - PubMed
    1. Liu HX, Keane R, Sheng L, Wan YJ. Implications of microbiota and bile acid in liver injury and regeneration. J Hepatol. 2015;63:1502–1510. doi: 10.1016/j.jhep.2015.08.001. - DOI - PMC - PubMed
    1. Xu Y, et al. Farnesoid X receptor activation increases reverse cholesterol transport by modulating bile acid composition and cholesterol absorption in mice. Hepatology. 2016;64:1072–1085. doi: 10.1002/hep.28712. - DOI - PMC - PubMed
    1. Liu HX, Rocha CS, Dandekar S, Wan YJY. Functional analysis of the relationship between intestinal microbiota and the expression of hepatic genes and pathways during the course of liver regeneration. J Hepatol. 2016;64:641–650. doi: 10.1016/j.jhep.2015.09.022. - DOI - PMC - PubMed

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