title: Vitamin D Signaling through Induction of Paneth Cell Defensins Maintains Gut Microbiota and Improves Metabolic Disorders and Hepatic Steatosis in Animal Models.
abstract: Metabolic syndrome (MetS), characterized as obesity, insulin resistance, and non-alcoholic fatty liver diseases (NAFLD), is associated with vitamin D insufficiency/deficiency in epidemiological studies, while the underlying mechanism is poorly addressed. On the other hand, disorder of gut microbiota, namely dysbiosis, is known to cause MetS and NAFLD. It is also known that systemic inflammation blocks insulin signaling pathways, leading to insulin resistance and glucose intolerance, which are the driving force for hepatic steatosis. Vitamin D receptor (VDR) is highly expressed in the ileum of the small intestine, which prompted us to test a hypothesis that vitamin D signaling may determine the enterotype of gut microbiota through regulating the intestinal interface. Here, we demonstrate that high-fat-diet feeding (HFD) is necessary but not sufficient, while additional vitamin D deficiency (VDD) as a second hit is needed, to induce robust insulin resistance and fatty liver. Under the two hits (HFD+VDD), the Paneth cell-specific alpha-defensins including α-defensin 5 (DEFA5), MMP7 which activates the pro-defensins, as well as tight junction genes, and MUC2 are all suppressed in the ileum, resulting in mucosal collapse, increased gut permeability, dysbiosis, endotoxemia, systemic inflammation which underlie insulin resistance and hepatic steatosis. Moreover, under the vitamin D deficient high fat feeding (HFD+VDD),Helicobacter hepaticus, a known murine hepatic-pathogen, is substantially amplified in the ileum, whileAkkermansia muciniphila, a beneficial symbiotic, is diminished. Likewise, the VD receptor (VDR) knockout mice exhibit similar phenotypes, showing down regulation of alpha-defensins and MMP7 in the ileum, increasedHelicobacter hepaticusand suppressedAkkermansia muciniphila. Remarkably, oral administration of DEFA5 restored eubiosys, showing suppression ofHelicobacter hepaticusand increase ofAkkermansia muciniphilain association with resolving metabolic disorders and fatty liver in the HFD+VDD mice. Anin vitroanalysis showed that DEFA5 peptide could directly suppressHelicobacter hepaticus. Thus, the results of this study reveal critical roles of a vitamin D/VDR axis in optimal expression of defensins and tight junction genes in support of intestinal integrity and eubiosis to suppress NAFLD and metabolic disorders.
authors.affiliation: The Center for Growth, Metabolism and Aging, and the Key Laboratory for Bio-Resource and Eco-Environment of Education of Ministry, College of Life Sciences, Sichuan University Chengdu, China.
authors.forename: Danmei
authors.initials: D
authors.lastname: Su
authors.affiliation: The Center for Growth, Metabolism and Aging, and the Key Laboratory for Bio-Resource and Eco-Environment of Education of Ministry, College of Life Sciences, Sichuan University Chengdu, China.
authors.forename: Yuanyang
authors.initials: Y
authors.lastname: Nie
authors.affiliation: The Center for Growth, Metabolism and Aging, and the Key Laboratory for Bio-Resource and Eco-Environment of Education of Ministry, College of Life Sciences, Sichuan University Chengdu, China.
authors.forename: Airu
authors.initials: A
authors.lastname: Zhu
authors.affiliation: The Center for Growth, Metabolism and Aging, and the Key Laboratory for Bio-Resource and Eco-Environment of Education of Ministry, College of Life Sciences, Sichuan University Chengdu, China.
authors.forename: Zishuo
authors.initials: Z
authors.lastname: Chen
authors.affiliation: The Center for Growth, Metabolism and Aging, and the Key Laboratory for Bio-Resource and Eco-Environment of Education of Ministry, College of Life Sciences, Sichuan University Chengdu, China.
authors.forename: Pengfei
authors.initials: P
authors.lastname: Wu
authors.affiliation: The Center for Growth, Metabolism and Aging, and the Key Laboratory for Bio-Resource and Eco-Environment of Education of Ministry, College of Life Sciences, Sichuan University Chengdu, China.
authors.forename: Li
authors.initials: L
authors.lastname: Zhang
authors.affiliation: The Center for Growth, Metabolism and Aging, and the Key Laboratory for Bio-Resource and Eco-Environment of Education of Ministry, College of Life Sciences, Sichuan UniversityChengdu, China; Chengdu Public Health Clinical CenterChengdu, China.
authors.forename: Mei
authors.initials: M
authors.lastname: Luo
authors.affiliation: The Center for Growth, Metabolism and Aging, and the Key Laboratory for Bio-Resource and Eco-Environment of Education of Ministry, College of Life Sciences, Sichuan University Chengdu, China.
authors.forename: Qun
authors.initials: Q
authors.lastname: Sun
authors.affiliation: The Center for Growth, Metabolism and Aging, and the Key Laboratory for Bio-Resource and Eco-Environment of Education of Ministry, College of Life Sciences, Sichuan University Chengdu, China.
authors.forename: Linbi
authors.initials: L
authors.lastname: Cai
authors.affiliation: The Center for Growth, Metabolism and Aging, and the Key Laboratory for Bio-Resource and Eco-Environment of Education of Ministry, College of Life Sciences, Sichuan University Chengdu, China.
authors.forename: Yuchen
authors.initials: Y
authors.lastname: Lai
authors.affiliation: The Center for Growth, Metabolism and Aging, and the Key Laboratory for Bio-Resource and Eco-Environment of Education of Ministry, College of Life Sciences, Sichuan University Chengdu, China.
authors.forename: Zhixiong
authors.initials: Z
authors.lastname: Xiao
authors.affiliation: Beijing YouAn Hospital, Capital Medical University Beijing, China.
authors.forename: Zhongping
authors.initials: Z
authors.lastname: Duan
authors.affiliation: Beijing YouAn Hospital, Capital Medical University Beijing, China.
authors.forename: Sujun
authors.initials: S
authors.lastname: Zheng
authors.affiliation: Chengdu Public Health Clinical Center Chengdu, China.
authors.forename: Guihui
authors.initials: G
authors.lastname: Wu
authors.affiliation: Olive View-University of California, Los Angeles Medical Center Los Angeles, CA, USA.
authors.forename: Richard
authors.initials: R
authors.lastname: Hu
authors.affiliation: Department of Pathology, Keck School of Medicine of the University of Southern California Los Angeles, CA, USA.
authors.forename: Hidekazu
authors.initials: H
authors.lastname: Tsukamoto
authors.affiliation: Cedars-Sinai Medical Center Los Angeles, CA, USA.
authors.forename: Aurelia
authors.initials: A
authors.lastname: Lugea
authors.affiliation: Cedars-Sinai Medical Center Los Angeles, CA, USA.
authors.forename: Zhenqui
authors.initials: Z
authors.lastname: Liu
authors.affiliation: Cedars-Sinai Medical Center Los Angeles, CA, USA.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Pandol
authors.affiliation: The Center for Growth, Metabolism and Aging, and the Key Laboratory for Bio-Resource and Eco-Environment of Education of Ministry, College of Life Sciences, Sichuan UniversityChengdu, China; Cedars-Sinai Medical CenterLos Angeles, CA, USA.
authors.forename: Yuan-Ping
authors.initials: YP
authors.lastname: Han
keywords: Akkermansia muciniphila; defensins; gut microbiota; helicobacter; metabolic syndrome; non-alcoholic fatty liver disease (NAFLD); non-alcoholic steatohepatitis (NASH); vitamin D