title: Calcium Reduces Liver Injury in Mice on a High-Fat Diet: Alterations in Microbial and Bile Acid Profiles.
abstract: A high-fat "Western-style" diet (HFWD) promotes obesity-related conditions including non-alcoholic steatohepatitis (NASH), the histologic manifestation of non-alcoholic fatty liver disease (NAFLD). In addition to high saturated fat and processed carbohydrates, the typical HFWD is deficient in calcium. Calcium-deficiency is an independent risk factor for many conditions associated with the Western-style diet. However, calcium has not been widely evaluated in the context of NAFLD. The goal of the present study was to determine if dietary calcium supplementation could protect mice fed a HFWD from NAFLD, specifically by decreasing non-alcoholic steatohepatitis (NASH) and its down-stream consequences. Male C57BL/6NCrl mice were maintained for 18-months on a HFWD containing dietary calcium at either 0.41 gm/kg feed (unsupplemented) or 5.25 gm/kg feed (supplemented). Although there was no difference in body weight or steatosis, calcium-supplemented mice were protected against downstream consequences of hepatic steatosis, manifested by lower inflammation, less fibrosis, and by lower overall histologic NAFLD activity scores (NAS). Calcium supplementation correlated with distinctly segregating gut fecal and cecal microbial communities as defined by 16S rRNA gene sequence. Further, calcium supplementation also correlated with decreased hepatic concentration of the major conjugated murine primary bile acid, tauro-β-muricholic acid (as well as a decrease in the parent unconjugated bile acid). Thus, calcium was protective against progression of diet-induced hepatic steatosis to NASH and end-stage liver disease, suggesting that calcium supplementation may effectively protect against adverse hepatic consequences of HFWD in cases where overall diet modification cannot be sustained. This protective effect occurred in concert with calcium-mediated gut microbial community shifts and alterations of the hepatic bile acid pool.
authors.affiliation: The Department of Pathology, The University of Michigan, Ann Arbor, MI, 48109, United States of America.
authors.forename: Muhammad
authors.initials: M
authors.lastname: Nadeem Aslam
authors.affiliation: The Department of Internal Medicine, The University of Michigan, Ann Arbor, MI, 48109, United States of America.
authors.forename: Christine M
authors.initials: CM
authors.lastname: Bassis
authors.affiliation: Michigan Regional Comprehensive Metabolomics Resource Center, The University of Michigan, Ann Arbor, MI, 48109, United States of America.
authors.forename: Li
authors.initials: L
authors.lastname: Zhang
authors.affiliation: The Department of Pathology, The University of Michigan, Ann Arbor, MI, 48109, United States of America.
authors.forename: Sameer
authors.initials: S
authors.lastname: Zaidi
authors.affiliation: The Department of Pathology, The University of Michigan, Ann Arbor, MI, 48109, United States of America.
authors.forename: James
authors.initials: J
authors.lastname: Varani
authors.affiliation: The Unit for Laboratory Animal Medicine, The University of Michigan, Ann Arbor, MI, 48109, United States of America.
authors.forename: Ingrid L
authors.initials: IL
authors.lastname: Bergin
mesh_terms: D000818:Animals; D001647:Bile Acids and Salts / Q000378:metabolism*; D015415:Biomarkers / Q000097:blood; D002118:Calcium / Q000494:pharmacology*; D002432:Cecum / Q000382:microbiology; D016207:Cytokines / Q000097:blood; D059305:Diet, High-Fat / Q000009:adverse effects*; D005243:Feces / Q000382:microbiology; D000069196:Gastrointestinal Microbiome / Q000187:drug effects*; D006965:Hyperplasia; D008099:Liver / Q000293:injuries* / Q000378:metabolism / Q000473:pathology; D008103:Liver Cirrhosis / Q000097:blood / Q000473:pathology; D008297:Male; D008810:Mice, Inbred C57BL; D065626:Non-alcoholic Fatty Liver Disease / Q000097:blood / Q000473:pathology
chemical_list: D001647:Bile Acids and Salts; D015415:Biomarkers; D016207:Cytokines; D002118:Calcium