Dietary ingredient change induces a transient MyD88-dependent mucosal enteric glial cell response and promotes obesity

ABSTRACT

Objective

Consumption of a modern Western-type high-fat low-fiber diet increases the risk of obesity. However, how a host responds to such a diet, especially during the early period of dietary transition from a previous low-fat and fiber-rich diet, remains poorly explored.

Methods

Wild-type C57BL/6 mice were fed a normal chow diet or a high-fat diet. Enteric glial cell (EGC) activation was detected through quantitative real-time PCR (qRT-PCR), immunoblotting and immunohistology analysis. Fluorocitrate or genetic deletion of glial fibrillary acidic protein (GFAP)-positive glial-intrinsic myeloid differentiation factor 88 (Myd88) was used to inhibit EGC activation, and the effect of a high-fat diet on obesity was further investigated. The role of MYD88-dependent sensing of commensal products in adipocyte was observed to analyze the effect of obesity.

Results

A dietary shift from a normal chow diet to a high-fat diet in mice induced a transient early-phase emergence of a GFAP-positive EGC network in the lamina propria of the ileum, accompanied with an increase in glial-derived neurotrophic factor production. Inhibition of glial cell activity blocked this response. GFAP-positive glial Myd88 knockout mice gained less body weight after high-fat diet (HFD) feeding than littermate controls. In contrast, adipocyte deletion of Myd88 in mice had no effect on weight gain but instead exacerbated glucose intolerance. Furthermore, short-term fluorocitrate intervention during HFD feeding attenuated body weight gain.

Conclusions

Our findings indicate that EGCs are early responders to intestinal ecosystem changes and the GFAP-positive glial Myd88 signaling participates in regulating obesity.

KEYWORDS:

• Diet
• enteric glial cell
• gut
• neurotrophic factor‌
• ‌myeloid differentiation primary response 88
• obesity
• metabolic disorder
• fluorocitrate

Data availability statement

Data are available from the corresponding author upon reasonable request.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Additional information

Funding

This work was supported by the National Natural Science Foundation of China [grant number 81770853, YgW; grant number 82002157, ZL], the Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD) in the year of 2014 [grant number KYLX14-1448], Natural Science Foundation of the Higher Education Institutions of Jiangsu Province, China [grant number 16KJB310016], the Starting Foundation for Talents of Xuzhou Medical University [grant number D2016029, YgW].

Notes on contributors

Zhuanzhuan Liu

Zhuanzhuan Liu is associate professor, working in the Department of Pathogenic Biology and Immunology, Laboratory of Infection and Immunity, Jiangsu Key Laboratory of Immunity and Metabolism, Xuzhou Medical University. Her work focuses on enteric neuroimmunity.

Hongxiang Sun

Hongxiang Sun is master student of Xuzhou Medical University, now working in the Department of Laboratory, Xuzhou First People's Hospital, China.

Shihong Xu

Shihong Xu is master student of Xuzhou Medical University. His work focuses on the pathogenesis of metabolic disorders.

Hanying Wang

Hanying Wang is master student of Xuzhou Medical University.

Zhiwei Zhang

Zhiwei Zhang is master student of Xuzhou Medical University.

Yanxia Wei

Yanxia Wei is professor, working in the Department of Pathogenic Biology and Immunology, Laboratory of Infection and Immunity, Jiangsu Key Laboratory of Immunity and Metabolism, Xuzhou Medical University. Her work focuses on the interaction of microbiota metabolites and obesity.

Yanbo Kou

Yanbo Kou is associate professor, working in the Department of Pathogenic Biology and Immunology, Laboratory of Infection and Immunity, Jiangsu Key Laboratory of Immunity and Metabolism, Xuzhou Medical University. His work focuses on the pathogenesis of metabolic disorders.

Yugang Wang

Yugang Wang is professor, working in the Department of Pathogenic Biology and Immunology, Laboratory of Infection and Immunity, Jiangsu Key Laboratory of Immunity and Metabolism, Xuzhou Medical University. His work focuses on the pathogenesis of metabolic disorders. Additional projects focus on the role of enteric glial cells in regulating obesity.