Effects of Gliadin consumption on the Intestinal Microbiota and Metabolic Homeostasis in Mice Fed a High-fat Diet

Li Zhang,Christian Sina,Niels Banhos Danneskiold-Samsøe,Ilinca Daria Radulescu,Daniel Andersen,Henrik Munch Roager,Susanne Brix,Camilla Hartmann Friis Hansen,Karsten Kristiansen,Martin Iain Bahl,Tine Rask Licht,Axel Kornerup Hansen,Henrik Lauritz Frandsen,Lars I Hellgren

doi:10.1038/srep44613

Abstract

Dietary gluten causes severe disorders like celiac disease in gluten-intolerant humans. However, currently understanding of its impact in tolerant individuals is limited. Our objective was to test whether gliadin, one of the detrimental parts of gluten, would impact the metabolic effects of an obesogenic diet. Mice were fed either a defined high-fat diet (HFD) containing 4% gliadin (n = 20), or a gliadin-free, isocaloric HFD (n = 20) for 23 weeks. Combined analysis of several parameters including insulin resistance, histology of liver and adipose tissue, intestinal microbiota in three gut compartments, gut barrier function, gene expression, urinary metabolites and immune profiles in intestinal, lymphoid, liver and adipose tissues was performed. Mice fed the gliadin-containing HFD displayed higher glycated hemoglobin and higher insulin resistance as evaluated by the homeostasis model assessment, more hepatic lipid accumulation and smaller adipocytes than mice fed the gliadin-free HFD. This was accompanied by alterations in the composition and activity of the gut microbiota, gut barrier function, urine metabolome, and immune phenotypes within liver and adipose tissue. Our results reveal that gliadin disturbs the intestinal environment and affects metabolic homeostasis in obese mice, suggesting a detrimental effect of gluten intake in gluten-tolerant subjects consuming a high-fat diet.

Highlights

Dietary gluten causes severe disorders like celiac disease in gluten-intolerant humans
We tested the effects of the specific wheat gluten component, gliadin, in a high-fat diet (HFD) mouse model, and found that a number of physiological parameters including long-term blood glucose levels (HbA1c), Homeostasis Model Assessment of Insulin Resistance (HOMA-IR), as well as total area of hepatic lipid droplets and epididymal white adipose tissue (eWAT) adipocyte size, were affected by gliadin intake (Fig. 1)
To elucidate the mechanisms behind the observed macroscopic effects, we investigated the impact of gliadin on gut microbiota, gut barrier function, urinary metabolome and immune responses in liver and adipose tissue (Fig. 7)

Summary

Introduction

Dietary gluten causes severe disorders like celiac disease in gluten-intolerant humans. Besides the recognized symptoms related to diagnosed gluten intolerance such as wheat allergy, celiac disease and nonceliac gluten sensitivity[1], gluten may hold disease-driving potentials in so-called gluten-tolerant individuals This is especially evident in gluten elimination studies undertaken in subjects suffering from Irritable Bowel Syndrome, which report reduced bowel symptoms after short term intake of gluten-free diets[2,3], but gluten-free diets may have a beneficial effect on human type 1 diabetes[4]. The gliadin-derived proline-rich peptides are resistant to proteolysis by digestive enzymes[12], which means that gliadin peptides, including the gut-permeating peptides designated 111–130 and 151–170, the cytotoxic peptide 31–43, and the immune-modulating 33-mer peptide 57–8913, remain partly undigested and biologically active in the gastrointestinal tract Activities of these peptides are not limited to induction of autoimmunity, but may affect gluten-tolerant individuals[14,15]

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