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Title: Mice fed a high-fat diet supplemented with resistant starch display marked shifts in the liver metabolome concurrent with altered gut bacteria

Author
item KIEFFER, DOROTHY - University Of California
item PICCOLO, BRIAN - Arkansas Children'S Nutrition Research Center (ACNC)
item MARCO, MARIA - University Of California
item KIM, EUN BAE - University Of California
item GOODSON, MICHAEL - University Of California
item KEENAN, MICHAEL - Louisiana State University
item DUNN, TAMARA - University Of California
item KNUDSEN, KNUD E. BACH - Aarhus University
item MARTIN, ROY - University Of California
item Ferruzzi, Mario

Submitted to: Journal of Nutrition
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 9/27/2016
Publication Date: 11/2/2016
Citation: Kieffer, D.A., Piccolo, B.D., Marco, M.L., Kim, E., Goodson, M.L., Keenan, M.J., Dunn, T.N., Knudsen, K., Martin, R.J., Adams, S.H. 2016. Mice fed a high-fat diet supplemented with resistant starch display marked shifts in the liver metabolome concurrent with altered gut bacteria. Journal of Nutrition. doi:10.3945/jn.116.238931.

Interpretive Summary: Dietary fiber has been shown to have a variety of positive effects on human health, but the mechanisms that underlie these outcomes remain largely unknown. Since fiber feeding alters the mix of naturally-occurring bacteria in the gut (the microbiome), factors produced by the microbiome are very likely involved and can make their way to the circulation. Once in the blood, one of the first organs coming in contact with microbiome-derived factors is the liver. The current studies sought to characterize how high-amylose maize resistant starch type 2 (HAMRS2; 20% by weight in the diet), a fermentable dietary fiber previously shown to improve metabolic health and modify the gut microbiome in mice, influences liver biology and metabolism. We used a large-scale phenotyping approach to characterize HAMRS2-driven shifts in the microbiome, and identified for the first time candidate microbes and metabolites that may drive changes in liver metabolism and gene expression. Despite no differences in food intake, body weight, blood sugar control, fasting plasma insulin, or liver triglycerides, the HAMRS2 mice displayed a reduction in liver amino acids (reduced 15-58% for all measured amino acids except glutamine). This indicates that a dietary fiber can have important effects on the body's ability to manage amino acid building blocks of proteins in the liver. Further analysis indicated that the dietary fiber can modify specific gut bacteria and metabolites that correlate with liver metabolism and gene expression, identifying these factors as important candidates for further exploration. It is proposed that changes in specific bacteria elicit gut-derived signals that reach the liver via enterohepatic circulation, ultimately impacting host liver metabolism in a manner that drives nitrogen balance and protein metabolism. This study forms the foundation for testing which of the specific identified microbe-derived metabolites have activity on liver health.

Technical Abstract: High-amylose maize resistant starch type 2 (HAMRS2) is a fermentable dietary fiber known to alter the gut milieu, including the gut microbiota, which may explain reported effects of resistant starch to ameliorate obesity-associated metabolic dysfunction. Our working hypothesis is that HAMRS2-induced microbiome changes will alter gut-derived signals (i.e., xenometabolites) reaching the liver via portal circulation, in turn altering liver metabolism by regulating gene expression and other pathways. To address this question, we used a multi-omics systems biology approach to characterize HAMRS2-driven shifts to the cecal microbiome, liver metabolome and transcriptome, identifying novel correlates between microbial changes and liver metabolites under obesogenic conditions. Male C57Bl/6J mice were fed an energy dense 45% fat diet for 10 weeks supplemented with either 20% HAMRS2 by wt (n=14) or rapidly digestible starch (n=15). Despite no differences in food intake, body weight, glucose tolerance, fasting plasma insulin, or liver triglycerides, the HAMRS2 mice displayed a reduction in liver amino acids (reduced 15-58% for all measured amino acids except Gln). These metabolites were equivalent in HAMRS2 plasma vs. controls, and transcripts encoding key amino acid transporters were not different in small intestine or liver, suggesting that HAMRS2 effects were not simply due to lower hepatocyte exposure to systemic amino acids. Instead, alterations in gut microbial metabolism could have impacted host nitrogen and amino acid homeostasis: HAMRS2 mice displayed increased 48 hour fecal output (62%, P < 0.0001) and the amount of nitrogen in the feces (41%, P < 0.0001). Beyond amino acid metabolism, liver transcriptomics revealed pathways related to lipid and xenobiotic metabolism, cell proliferation, differentiation, and growth were impacted by HAMRS2-feeding. Together, these changes indicate that HAMRS2 dramatically alters hepatic metabolism and gene expression concurrent with shifts in specific gut bacteria.