NLRP3 inflammasome deficiency attenuates metabolic disturbances involving alterations in the gut microbial profile in mice exposed to high fat diet

Marina Sokolova,Johannes E R Hov,Kuan Yang,Simen H Hansen,Ivar Sjaastad,Rolf K Berge,Bente Halvorsen,Pål Aukrust,Arne Yndestad,Martin Kummen,Trine Ranheim,Mieke C Louwe

doi:10.1038/s41598-020-76497-1

Abstract

Obesity-related diseases (e.g. type 2 diabetes mellitus and cardiovascular disorders) represent an increasing health problem worldwide. NLRP3 inflammasome activation may underlie obesity-induced inflammation and insulin resistance, and NLRP3 deficient mice exposed to high fat diet (HFD) appear to be protected from left ventricle (LV) concentric remodeling. Herein, we investigated if these beneficial effects were associated with alterations in plasma metabolites, using metabolomic and lipidomic analysis, and gut microbiota composition, using 16S rRNA sequencing of cecum content, comparing NLRP3 deficient and wild type (WT) mice on HFD and control diet. Obese NLRP3 deficient mice had lower systemic ceramide levels, potentially resulting attenuating inflammation, altered hepatic expression of fatty acids (FA) with lower mono-saturated FA and higher polyunsaturated FA levels, potentially counteracting development of liver steatosis, downregulated myocardial energy metabolism as assessed by proteomic analyses of LV heart tissue, and different levels of bile acids as compared with WT mice. These changes were accompanied by an altered composition of gut microbiota associated with decreased systemic levels of tri-methylamine-N-oxide and lipopolysaccharide, potentially inducing attenuating systemic inflammation and beneficial effects on lipid metabolism. Our findings support a role of NLRP3 inflammasome in the interface between metabolic and inflammatory stress, involving an altered gut microbiota composition.

Highlights

Obesity-related diseases represent an increasing health problem worldwide
The present study is a follow-up on our previous article, Sokolova et al.[22], where we have shown that NOD-like receptor family pyrin domain-containing 3 (NLRP3) deficiency in mice on high fat diet (HFD) has a beneficial effect on obesity-induced myocardial remodeling and dysfunction with attenuated infiltration of Mac-2 positive cells, insulin sensitivity, systemic inflammation, and liver steatosis
In this follow-up study we investigated if these beneficial effects were associated with alterations in plasma metabolites using a global metabolomic approach and gut microbiota composition, comparing NLRP3 deficient and wild type (WT) mice on HFD

Summary

Introduction

Obesity-related diseases (e.g. type 2 diabetes mellitus and cardiovascular disorders) represent an increasing health problem worldwide. Obese NLRP3 deficient mice had lower systemic ceramide levels, potentially resulting attenuating inflammation, altered hepatic expression of fatty acids (FA) with lower mono-saturated FA and higher polyunsaturated FA levels, potentially counteracting development of liver steatosis, downregulated myocardial energy metabolism as assessed by proteomic analyses of LV heart tissue, and different levels of bile acids as compared with WT mice. These changes were accompanied by an altered composition of gut microbiota associated with decreased systemic levels of tri-methylamine-N-oxide and lipopolysaccharide, potentially inducing attenuating systemic inflammation and beneficial effects on lipid metabolism. The NLRP3 inflammasome could clearly be involved in several of these processes, in particular in relation to LPS-mediated inflammation in abdominal fat tissues, but these issues are far from well understood

Methods

Results

Conclusion