Intestinal lysozyme liberates Nod1 ligands from microbes to direct insulin trafficking in pancreatic beta cells

Qin Zhang,Hong Wei,Ying Pan,Pingping Li,Zhuo-Xian Meng,Hui Li,Haifang Wang,Zhengjun Chen,Qian Jiang,Zhihua Liu,Benhua Zeng,Xiaojiao Zheng,Xueying Shen,Jiaxu Zhao

doi:10.1038/s41422-019-0190-3

Abstract

Long-range communication between intestinal symbiotic bacteria and extra-intestinal organs can occur through circulating bacterial signal molecules, through neural circuits, or through cytokines or hormones from host cells. Here we report that Nod1 ligands derived from intestinal bacteria act as signal molecules and directly modulate insulin trafficking in pancreatic beta cells. The cytosolic peptidoglycan receptor Nod1 and its downstream adapter Rip2 are required for insulin trafficking in beta cells in a cell-autonomous manner. Mechanistically, upon recognizing cognate ligands, Nod1 and Rip2 localize to insulin vesicles, recruiting Rab1a to direct insulin trafficking through the cytoplasm. Importantly, intestinal lysozyme liberates Nod1 ligands into the circulation, thus enabling long-range communication between intestinal microbes and islets. The intestine-islet crosstalk bridged by Nod1 ligands modulates host glucose tolerance. Our study defines a new type of inter-organ communication based on circulating bacterial signal molecules, which has broad implications for understanding the mutualistic relationship between microbes and host.

Highlights

Commensal microbes play a vital role in modulating host metabolism.[1,2,3] It is of critical importance to understand how the microbiota regulates host metabolism
Intestinal microbes affect insulin distribution in pancreatic beta cells in a cell-autonomous manner To understand whether insulin trafficking in beta cells is affected by intestinal microbes, we examined the cellular distribution of insulin and proinsulin in islets from conventionally raised specific pathogen-free (SPF) mice, germ-free (GF) mice and colonized GF mice, by immunofluorescence staining and confocal imaging
In beta cells from SPF mice, insulin and proinsulin staining was clearly segregated, with insulin+ mature dense core vesicles (DCVs) dispersed ubiquitously throughout the cytoplasm and proinsulin+ immature DCVs restricted to the perinuclear region (Fig. 1a)

Summary

Introduction

Commensal microbes play a vital role in modulating host metabolism.[1,2,3] It is of critical importance to understand how the microbiota regulates host metabolism. Intestinal colonization by bacteria is associated with enhanced energy harvesting, increased body fat content, and reduced insulin sensitivity.[1,3,5] For instance, colonization of adult germ-free (GF) C57BL/6 mice with a normal microbiota produces relative insulin resistance within 14 days despite reduced food intake.[1] Bacterial ligands modulate insulin sensitivity.[4] Nod[1] ligands promote insulin resistance, especially in the murine model of diet-induced obesity (DIO), a phenomenon that has been attributed to the activation of innate immunity.[6,7,8,9] whether the bacterial Nod[1] ligands have more complex roles in metabolism besides promoting inflammation and insulin resistance is unclear

Methods

Results

Conclusion