Diet-Independent Correlations between Bacteria and Dysfunction of Gut, Adipose Tissue, and Liver: A Comprehensive Microbiota Analysis in Feces and Mucosa of the Ileum and Colon in Obese Mice with NAFLD.

Eveline Gart,Christa De Ruiter,Kanita Salic,Lars Verschuren,Joline Attema,Robert Kleemann,Everton Souto Lima,Frank Schuren,Martine Morrison,Jaap Keijer

doi:10.3390/ijms20010001

Abstract

Development of non-alcoholic fatty liver disease (NAFLD) is linked to obesity, adipose tissue inflammation, and gut dysfunction, all of which depend on diet. So far, studies have mainly focused on diet-related fecal microbiota changes, but other compartments may be more informative on host health. We present a first systematic analysis of microbiota changes in the ileum and colon using multiple diets and investigating both fecal and mucosal samples. Ldlr−/−.Leiden mice received one of three different energy-dense (ED)-diets (n = 15/group) for 15 weeks. All of the ED diets induced obesity and metabolic risk factors, altered short-chain fatty acids (SCFA), and increased gut permeability and NAFLD to various extents. ED diets reduced the diversity of high-abundant bacteria and increased the diversity of low-abundant bacteria in all of the gut compartments. The ED groups showed highly variable, partially overlapping microbiota compositions that differed significantly from chow. Correlation analyses demonstrated that (1) specific groups of bacteria correlate with metabolic risk factors, organ dysfunction, and NAFLD endpoints, (2) colon mucosa had greater predictive value than other compartments, (3) correlating bacteria differed per compartment, and (4) some bacteria correlated with plasma SCFA levels. In conclusion, this comprehensive microbiota analysis demonstrates correlations between the microbiota and dysfunctions of gut, adipose tissue, and liver, independent of a specific disease-inducing diet.

Highlights

Non-alcoholic fatty liver disease (NAFLD) has become a major health problem worldwide [1]
All ED Diets Resulted in NAFLD in the Context of Obesity, White Adipose Tissue Dysfunction, and Gut Dysfunction
Quantitative histopathological analysis revealed that a butter fat with fructose diet (BF), lard fat with sucrose diet (LS), and the same lard fat–sucrose (LS) diet with 10% fructose in the drinking water (LS+FW) induced extensive macrovesicular steatosis (Figure 1B) relative to chow-fed controls (0.0 ± 0.0% in chow; 19.3 ± 2.8% in butter fat–fructose (BF), p < 0.001; 22.1 ± 3.5%, p < 0.001 in LS; 24.8 ± 1.9% in LS+FW, p < 0.001)

Summary

Introduction

Non-alcoholic fatty liver disease (NAFLD) has become a major health problem worldwide [1]. Alterations of microbiota-derived metabolites such as short-chain fatty acids (SCFAs), and increased gut permeability [7]. Together, these dysfunctions are thought to propel the progression of NAFLD from the relative benign hepatic lipid accumulation (steatosis) toward non-alcoholic steatohepatitis (NASH), which is the severe stage of NAFLD that is characterized by steatosis and liver inflammation [8]. It is possible that an analysis of specific gut microbial compartments may be more informative on host health than the conventional analysis, which is solely based on fecal microbiota. A systematic analysis of multiple microbial compartments of the gut in relation to obesity and NAFLD endpoints has not been performed to date

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