Ming Song1,2, Fang Yuan3,4,5,6, Xiaohong Li7, Xipeng Ma3,4,5,6, Xinmin Yin3,4,5,6, Eric C Rouchka7, Xiang Zhang3,4,5,6,8, Zhongbin Deng3,9,10, Russell A Prough3,11, Craig J McClain12,3,4,8,13. 1. Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition, University of Louisville School of Medicine, Louisville, KY, 40202, USA. m0song03@louisville.edu. 2. Hepatobiology&Toxicology Program, University of Louisville, Louisville, KY, 40202, USA. m0song03@louisville.edu. 3. Hepatobiology&Toxicology Program, University of Louisville, Louisville, KY, 40202, USA. 4. University of Louisville Alcohol Research Center, University of Louisville, Louisville, KY, 40202, USA. 5. Department of Chemistry, University of Louisville, Louisville, KY, 40208, USA. 6. Center for Regulatory and Environmental Analytical Metabolomics, University of Louisville, Louisville, KY, 40208, USA. 7. KBRIN Bioinformatics Core, Louisville, KY, 40292, USA. 8. Department of Pharmacology and Toxicology, University of Louisville School of Medicine, Louisville, KY, 40202, USA. 9. Department of Microbiology & Immunology, Brown Cancer Center, University of Louisville, Louisville, KY, 40202, USA. 10. James Graham Brown Cancer Center, University of Louisville, Louisville, KY, 40202, USA. 11. Department of Biochemistry and Molecular Genetics, University of Louisville School of Medicine, Louisville, KY, 40202, USA. 12. Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition, University of Louisville School of Medicine, Louisville, KY, 40202, USA. 13. Robley Rex Veterans Affairs Medical Center, Louisville, KY, 40206, USA.
Abstract
BACKGROUND: Inadequate copper intake and increased fructose consumption represent two important nutritional problems in the USA. Dietary copper-fructose interactions alter gut microbial activity and contribute to the development of nonalcoholic fatty liver disease (NAFLD). The aim of this study is to determine whether dietary copper-fructose interactions alter gut microbial activity in a sex-differential manner and whether sex differences in gut microbial activity are associated with sex differences in hepatic steatosis. METHODS: Male and female weanling Sprague-Dawley (SD) rats were fed ad libitum with an AIN-93G purified rodent diet with defined copper content for 8 weeks. The copper content is 6 mg/kg and 1.5 mg/kg in adequate copper diet (CuA) and marginal copper diet (CuM), respectively. Animals had free access to either deionized water or deionized water containing 10% fructose (F) (w/v) as the only drink during the experiment. Body weight, calorie intake, plasma alanine aminotransferase, aspartate aminotransferase, and liver histology as well as liver triglyceride were evaluated. Fecal microbial contents were analyzed by 16S ribosomal RNA (16S rRNA) sequencing. Fecal and cecal short-chain fatty acids (SCFAs) were determined by gas chromatography-mass spectrometry (GC-MS). RESULTS: Male and female rats exhibit similar trends of changes in the body weight gain and calorie intake in response to dietary copper and fructose, with a generally higher level in male rats. Several female rats in the CuAF group developed mild steatosis, while no obvious steatosis was observed in male rats fed with CuAF or CuMF diets. Fecal 16S rRNA sequencing analysis revealed distinct alterations of the gut microbiome in male and female rats. Linear discriminant analysis (LDA) effect size (LEfSe) identified sex-specific abundant taxa in different groups. Further, total SCFAs, as well as, butyrate were decreased in a more pronounced manner in female CuMF rats than in male rats. Of note, the decreased SCFAs are concomitant with the reduced SCFA producers, but not correlated to hepatic steatosis. CONCLUSIONS: Our data demonstrated sex differences in the alterations of gut microbial abundance, activities, and hepatic steatosis in response to dietary copper-fructose interaction in rats. The correlation between sex differences in metabolic phenotypes and alterations of gut microbial activities remains elusive.
BACKGROUND: Inadequate copper intake and increased fructose consumption represent two important nutritional problems in the USA. Dietary copper-fructose interactions alter gut microbial activity and contribute to the development of nonalcoholic fatty liver disease (NAFLD). The aim of this study is to determine whether dietary copper-fructose interactions alter gut microbial activity in a sex-differential manner and whether sex differences in gut microbial activity are associated with sex differences in hepatic steatosis. METHODS: Male and female weanling Sprague-Dawley (SD) rats were fed ad libitum with an AIN-93G purified rodent diet with defined copper content for 8 weeks. The copper content is 6 mg/kg and 1.5 mg/kg in adequate copper diet (CuA) and marginal copper diet (CuM), respectively. Animals had free access to either deionized water or deionized water containing 10% fructose (F) (w/v) as the only drink during the experiment. Body weight, calorie intake, plasma alanine aminotransferase, aspartate aminotransferase, and liver histology as well as liver triglyceride were evaluated. Fecal microbial contents were analyzed by 16S ribosomal RNA (16S rRNA) sequencing. Fecal and cecal short-chain fatty acids (SCFAs) were determined by gas chromatography-mass spectrometry (GC-MS). RESULTS: Male and female rats exhibit similar trends of changes in the body weight gain and calorie intake in response to dietary copper and fructose, with a generally higher level in male rats. Several female rats in the CuAF group developed mild steatosis, while no obvious steatosis was observed in male rats fed with CuAF or CuMF diets. Fecal 16S rRNA sequencing analysis revealed distinct alterations of the gut microbiome in male and female rats. Linear discriminant analysis (LDA) effect size (LEfSe) identified sex-specific abundant taxa in different groups. Further, total SCFAs, as well as, butyrate were decreased in a more pronounced manner in female CuMFrats than in male rats. Of note, the decreased SCFAs are concomitant with the reduced SCFA producers, but not correlated to hepatic steatosis. CONCLUSIONS: Our data demonstrated sex differences in the alterations of gut microbial abundance, activities, and hepatic steatosis in response to dietary copper-fructose interaction in rats. The correlation between sex differences in metabolic phenotypes and alterations of gut microbial activities remains elusive.
Entities:
Keywords:
Copper; Fructose; Gut microbiota; Nonalcoholic fatty liver disease; Sex
Authors: Rohit Loomba; Victor Seguritan; Weizhong Li; Tao Long; Niels Klitgord; Archana Bhatt; Parambir Singh Dulai; Cyrielle Caussy; Richele Bettencourt; Sarah K Highlander; Marcus B Jones; Claude B Sirlin; Bernd Schnabl; Lauren Brinkac; Nicholas Schork; Chi-Hua Chen; David A Brenner; William Biggs; Shibu Yooseph; J Craig Venter; Karen E Nelson Journal: Cell Metab Date: 2017-05-02 Impact factor: 27.287
Authors: Xiaosen Ouyang; Pietro Cirillo; Yuri Sautin; Shannon McCall; James L Bruchette; Anna Mae Diehl; Richard J Johnson; Manal F Abdelmalek Journal: J Hepatol Date: 2008-03-10 Impact factor: 25.083
Authors: Justin Kuczynski; Christian L Lauber; William A Walters; Laura Wegener Parfrey; José C Clemente; Dirk Gevers; Rob Knight Journal: Nat Rev Genet Date: 2011-12-16 Impact factor: 53.242