宿主遗传背景和肠道微生物群有助于解释小鼠对果糖摄入的不同代谢反应。

Host Genetic Background and Gut Microbiota Contribute to Differential Metabolic Responses to Fructose Consumption in Mice.

机构信息

Department of Integrative Biology and Physiology, University of California, Los Angeles, CA, USA.

Department of Medicine, Division of Cardiology, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.

出版信息

J Nutr. 2020 Oct 12;150(10):2716-2728. doi: 10.1093/jn/nxaa239.

DOI:10.1093/jn/nxaa239

PMID:32856048

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7549307/

Abstract

BACKGROUND

It is unclear how high fructose consumption induces disparate metabolic responses in genetically diverse mouse strains.

OBJECTIVE

We aimed to investigate whether the gut microbiota contributes to differential metabolic responses to fructose.

METHODS

Eight-week-old male C57BL/6J (B6), DBA/2J (DBA), and FVB/NJ (FVB) mice were given 8% fructose solution or regular water (control) for 12 wk. The gut microbiota composition in cecum and feces was analyzed using 16S ribosomal DNA sequencing, and permutational multivariate ANOVA (PERMANOVA) was used to compare community across mouse strains, treatments, and time points. Microbiota abundance was correlated with metabolic phenotypes and host gene expression in hypothalamus, liver, and adipose tissues using Biweight midcorrelation. To test the causal role of the gut microbiota in determining fructose response, we conducted fecal transplants from B6 to DBA mice and vice versa for 4 wk, as well as gavaged antibiotic-treated DBA mice with Akkermansia for 9 wk, accompanied with or without fructose treatment.

RESULTS

Compared with B6 and FVB, DBA mice had significantly higher Firmicutes to Bacteroidetes ratio and lower baseline abundance of Akkermansia and S24-7 (P < 0.05), accompanied by metabolic dysregulation after fructose consumption. Fructose altered specific microbial taxa in individual mouse strains, such as a 7.27-fold increase in Akkermansia in B6 and 0.374-fold change in Rikenellaceae in DBA (false discovery rate <5%), which demonstrated strain-specific correlations with host metabolic and transcriptomic phenotypes. Fecal transplant experiments indicated that B6 microbes conferred resistance to fructose-induced weight gain in DBA mice (F = 43.1, P < 0.001), and Akkermansia colonization abrogated the fructose-induced weight gain (F = 17.8, P < 0.001) and glycemic dysfunctions (F = 11.8, P = 0.004) in DBA mice.

CONCLUSIONS

Our findings support that differential microbiota composition between mouse strains is partially responsible for host metabolic sensitivity to fructose, and that Akkermansia is a key bacterium that confers resistance to fructose-induced metabolic dysregulation.

摘要

背景

目前尚不清楚高果糖摄入如何导致不同遗传背景的小鼠品系产生不同的代谢反应。

目的

我们旨在研究肠道微生物群是否有助于解释果糖代谢反应的差异。

方法

8 周龄雄性 C57BL/6J（B6）、DBA/2J（DBA）和 FVB/NJ（FVB）小鼠分别给予 8%果糖溶液或普通水（对照）12 周。使用 16S 核糖体 DNA 测序分析盲肠和粪便中的肠道微生物群落组成，采用置换多元方差分析（PERMANOVA）比较不同小鼠品系、处理和时间点的群落差异。使用 Biweight midcorrelation 分析微生物群丰度与下丘脑、肝脏和脂肪组织中代谢表型和宿主基因表达的相关性。为了检验肠道微生物群在决定果糖反应中的因果作用，我们进行了为期 4 周的 B6 到 DBA 小鼠的粪便移植和相反方向的移植，以及用 Akkermansia 处理抗生素处理的 DBA 小鼠 9 周，并伴有或不伴有果糖处理。

结果

与 B6 和 FVB 相比，DBA 小鼠的厚壁菌门与拟杆菌门的比例显著升高，Akkermansia 和 S24-7 的基线丰度较低（P < 0.05），果糖摄入后代谢失调。果糖改变了个体小鼠品系的特定微生物类群，如 B6 中的 Akkermansia 增加了 7.27 倍，DBA 中的 Rikenellaceae 减少了 0.374 倍（假发现率<5%），这表明与宿主代谢和转录组表型具有品系特异性相关性。粪便移植实验表明，B6 微生物赋予 DBA 小鼠对果糖诱导的体重增加的抗性（F = 43.1，P < 0.001），Akkermansia 定植消除了果糖诱导的体重增加（F = 17.8，P < 0.001）和血糖紊乱（F = 11.8，P = 0.004）在 DBA 小鼠中。