Mice Fed a High-Fat Diet Supplemented with Resistant Starch Display Marked Shifts in the Liver Metabolome Concurrent with Altered Gut Bacteria.
BACKGROUND
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 the reported effects of resistant starch to ameliorate obesity-associated metabolic dysfunction.


OBJECTIVE
Our working hypothesis was that HAMRS2-induced microbiome changes alter gut-derived signals (i.e., xenometabolites) reaching the liver via the portal circulation, in turn altering liver metabolism by regulating gene expression and other pathways.


METHODS
We used a multi-omics systems biology approach to characterize HAMRS2-driven shifts to the cecal microbiome, liver metabolome, and transcriptome, identifying correlates between microbial changes and liver metabolites under obesogenic conditions that, to our knowledge, have not previously been recognized. Five-week-old male C57BL/6J mice were fed an energy-dense 45% lard-based-fat diet for 10 wk supplemented with either 20% HAMRS2 by weight (n = 14) or rapidly digestible starch (control diet; n = 15).


RESULTS
Despite no differences in food intake, body weight, glucose tolerance, fasting plasma insulin, or liver triglycerides, the HAMRS2 mice showed a 15-58% reduction in all measured liver amino acids, except for Gln, compared with control mice. These metabolites were equivalent in the plasma of HAMRS2 mice compared with controls, and transcripts encoding key amino acid transporters were not different in the 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 affected host nitrogen and amino acid homeostasis: HAMRS2 mice showed a 62% increase (P < 0.0001) in 48-h fecal output and a 41% increase (P < 0.0001) in fecal nitrogen compared with control mice. Beyond amino acid metabolism, liver transcriptomics revealed pathways related to lipid and xenobiotic metabolism; and pathways related to cell proliferation, differentiation, and growth were affected by HAMRS2 feeding.


CONCLUSIONS
Together, these differences indicate that HAMRS2 dramatically alters hepatic metabolism and gene expression concurrent with shifts in specific gut bacteria in C57BL/6J mice.
Graduate Group in Nutritional Biology and.|Department of Nutrition.|Obesity and Metabolism Research Unit, USDA-Agricultural Research Service Western Human Nutrition Research Center, Davis, CA.
Dorothy A
DA
Kieffer
Arkansas Children's Nutrition Center and.|Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, AR.
Brian D
BD
Piccolo
Food Science and Technology Department, and.
Maria L
ML
Marco
Food Science and Technology Department, and.|Department of Animal Life Science, College of Animal Life Sciences, Kangwon National University, Chuncheon, Gangwon-do, Republic of Korea.
Eun Bae
EB
Kim
Department of Microbiology, University of California, Davis, CA.
Michael L
ML
Goodson
Louisiana State University AgCenter, Baton Rouge, LA; and.
Michael J
MJ
Keenan
Graduate Group in Nutritional Biology and.|Department of Nutrition.|Obesity and Metabolism Research Unit, USDA-Agricultural Research Service Western Human Nutrition Research Center, Davis, CA.
Tamara N
TN
Dunn
Department of Animal Science, Aarhus University, Aarhus, Denmark.
Knud Erik Bach
KE
Knudsen
Graduate Group in Nutritional Biology and rmartin@agcenter.lsu.edu shadams@uams.edu.|Department of Nutrition.|Obesity and Metabolism Research Unit, USDA-Agricultural Research Service Western Human Nutrition Research Center, Davis, CA.
Roy J
RJ
Martin
Graduate Group in Nutritional Biology and rmartin@agcenter.lsu.edu shadams@uams.edu.|Department of Nutrition.|Arkansas Children's Nutrition Center and.|Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, AR.
Sean H
SH
Adams
D050154:Adiposity; D000818:Animals; D001419:Bacteria / Q000145:classification*; D004041:Dietary Fats / Q000008:administration & dosage*; D041981:Gastrointestinal Tract / Q000382:microbiology*; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009765:Obesity; D011897:Random Allocation; D013213:Starch / Q000008:administration & dosage* / Q000737:chemistry
D004041:Dietary Fats; D013213:Starch
dietary fiber; gut microbiota; liver; metabolomics; transcriptomics