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Active phase prebiotic feeding alters gut microbiota, induces weight-independent alleviation of hepatic steatosis and serum cholesterol in high-fat diet-fed mice.

ABSTRACT: Growing evidence suggests that prebiotics may induce weight loss and alleviate non-alcoholic fatty liver disease (NAFLD) via modulation of the gut microbiota. However, key members of the gut microbiota that may mediate the beneficial effects of prebiotics remain elusive. Here, we find that restricted prebiotic feeding during active phase (HF-ARP) induced weight-independent alleviation of liver steatosis and reduced serum cholesterol in high-fat diet (HF) fed mice more significantly than unrestricted feeding (HF-UP). HF-ARP mice also showed concomitantly altered gut microbiota structure that was different from HF-UP group along with significantly increased production of total short-chain fatty-acids (SCFAs). Amplicon sequence variants (ASVs) were clustered into co-abundant groups (CAGs) as potential functional groups that may respond distinctively to prebiotic consumption and prebiotic feeding regime. Prebiotic feeding induces significant alterations in CAG abundances by day 7. Eight of 32 CAGs were promoted by prebiotics, including CAG17 with the most abundant ASV from Parabacteroides, CAG22 with Bacteroides thetaiotamicron and CAG32 with Fecalibaculum and Akkermansia. Among the prebiotic-promoted CAGs, CAG20 with ASVs from Lachnospiraceae and CAG21 with ASVs from Bifidobacterium and Lachnospiraceae were significantly enhanced in HF-ARP compared to HF-UP. Moreover, most of the prebiotic-promoted CAGs were also significantly associated with improvements in hepatic steatosis, reduction in serum cholesterol and increased cecal propionate production. Together, these results suggest that the impact of prebiotics on weight-independent alleviation of liver steatosis and cholesterol-lowering effect can be optimized by restricting prebiotic intake to active phase and is associated with a distinct change of gut microbiota with increased SCFA production.

SUBMITTER: Ghosh S

PROVIDER: S-EPMC7806547 | biostudies-literature | 2021

REPOSITORIES: biostudies-literature

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Active phase prebiotic feeding alters gut microbiota, induces weight-independent alleviation of hepatic steatosis and serum cholesterol in high-fat diet-fed mice.

Ghosh Shreya S Yang Xin X Wang Linghua L Zhang Chenhong C Zhao Liping L

Computational and structural biotechnology journal 20201224

Growing evidence suggests that prebiotics may induce weight loss and alleviate non-alcoholic fatty liver disease (NAFLD) via modulation of the gut microbiota. However, key members of the gut microbiota that may mediate the beneficial effects of prebiotics remain elusive. Here, we find that restricted prebiotic feeding during active phase (HF-ARP) induced weight-independent alleviation of liver steatosis and reduced serum cholesterol in high-fat diet (HF) fed mice more significantly than unrestri ...[more]

PMID: 33510856

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Project description:BACKGROUND:Non-alcoholic fatty liver disease (NAFLD) is one of the most common liver diseases worldwide, although its pathogenesis remains to be elucidated. A recent study revealed that hepatic Niemann-Pick C1-Like 1 (NPC1L1), a cholesterol re-absorber from bile to the liver expressed on the bile canalicular membrane, is an exacerbation factor of NAFLD. Indeed, transgenic mice with hepatic expression of human NPC1L1 under a liver-specific promoter (L1-Tg mice) developed steatosis with a high-fat diet (HFD) containing cholesterol within a few weeks. However, the mechanism underlying diet-induced hepatic NPC1L1-mediated lipid accumulation is poorly defined. METHODS:To achieve a deeper understanding of steatosis development in L1-Tg mice, the biochemical features of hepatic NPC1L1-mediated steatosis were investigated. Hemizygous L1-Tg mice and wild-type littermate controls fed a HFD or control-fat diet were used. At the indicated time points, the livers were evaluated for cholesterol and triglyceride (TG) contents as well as mRNA levels of hepatic genes involved in the maintenance of lipid homeostasis. The hepatic ability to secrete very low-density lipoprotein (VLDL)-TG was also investigated. RESULTS:Unlike the livers of wild-type mice that have little expression of hepatic Npc1l1, the livers of L1-Tg mice displayed time-dependent changes that indicated steatosis formation. In steatosis, there were three different stages of development: mild accumulation of hepatic cholesterol and TG (early stage), acceleration of hepatic TG accumulation (middle stage), and further accumulation of hepatic cholesterol (late stage). In the early stage, between WT and L1-Tg mice fed a HFD for 2?weeks, there were no significant differences in the hepatic expression of Ppar?, Acox1, Fat/Cd36, Srebf1, and Srebf2; however, the hepatic ability to secrete VLDL-TG decreased in L1-Tg mice (P?<?0.05). Furthermore, this decrease was completely prevented by administration of ezetimibe, an NPC1L1-selective inhibitor. CONCLUSION:Hepatic NPC1L1 exacerbates diet-induced steatosis, which was accompanied by decreased hepatic ability of VLDL-TG secretion. The obtained results provide a deeper understanding of L1-Tg mice as a promising NAFLD animal model that is able to re-absorb biliary-secreted cholesterol similar to humans. Furthermore, this work supports further studies of the pathophysiological impact of re-absorbed biliary cholesterol on the regulation of hepatic lipid homeostasis.

Dataset Information

Active phase prebiotic feeding alters gut microbiota, induces weight-independent alleviation of hepatic steatosis and serum cholesterol in high-fat diet-fed mice.

Publications

Active phase prebiotic feeding alters gut microbiota, induces weight-independent alleviation of hepatic steatosis and serum cholesterol in high-fat diet-fed mice.

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