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High-fat diet determines the composition of the murine gut microbiome independently of obesity.

ABSTRACT: The composition of the gut microbiome is affected by host phenotype, genotype, immune function, and diet. Here, we used the phenotype of RELMbeta knockout (KO) mice to assess the influence of these factors.Both wild-type and RELMbeta KO mice were lean on a standard chow diet, but, upon switching to a high-fat diet, wild-type mice became obese, whereas RELMbeta KO mice remained comparatively lean. To investigate the influence of diet, genotype, and obesity on microbiome composition, we used deep sequencing to characterize 25,790 16S rDNA sequences from uncultured bacterial communities from both genotypes on both diets.We found large alterations associated with switching to the high-fat diet, including a decrease in Bacteroidetes and an increase in both Firmicutes and Proteobacteria. This was seen for both genotypes (ie, in the presence and absence of obesity), indicating that the high-fat diet itself, and not the obese state, mainly accounted for the observed changes in the gut microbiota. The RELMbeta genotype also modestly influenced microbiome composition independently of diet. Metagenomic analysis of 537,604 sequence reads documented extensive changes in gene content because of a high-fat diet, including an increase in transporters and 2-component sensor responders as well as a general decrease in metabolic genes. Unexpectedly, we found a substantial amount of murine DNA in our samples that increased in proportion on a high-fat diet.These results demonstrate the importance of diet as a determinant of gut microbiome composition and suggest the need to control for dietary variation when evaluating the composition of the human gut microbiome.

SUBMITTER: Hildebrandt MA

PROVIDER: S-EPMC2770164 | biostudies-literature | 2009 Nov

REPOSITORIES: biostudies-literature

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High-fat diet determines the composition of the murine gut microbiome independently of obesity.

Hildebrandt Marie A MA Hoffmann Christian C Sherrill-Mix Scott A SA Keilbaugh Sue A SA Hamady Micah M Chen Ying-Yu YY Knight Rob R Ahima Rexford S RS Bushman Frederic F Wu Gary D GD

Gastroenterology 20090823 5

<h4>Background & aims</h4>The composition of the gut microbiome is affected by host phenotype, genotype, immune function, and diet. Here, we used the phenotype of RELMbeta knockout (KO) mice to assess the influence of these factors.<h4>Methods</h4>Both wild-type and RELMbeta KO mice were lean on a standard chow diet, but, upon switching to a high-fat diet, wild-type mice became obese, whereas RELMbeta KO mice remained comparatively lean. To investigate the influence of diet, genotype, and obesit ...[more]

PMID: 19706296

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Project description:BackgroundObesity has been associated with a more severe disease course in inflammatory bowel disease (IBD) and epidemiological data identified dietary fats but not obesity as risk factors for the development of IBD. Crohn's disease is one of the two major IBD phenotypes and mostly affects the terminal ileum. Despite recent observations that high fat diets (HFD) impair intestinal barrier functions and drive pathobiont selection relevant for chronic inflammation in the colon, mechanisms of high fat diets in the pathogenesis of Crohn's disease are not known. The aim of this study was to characterize the effect of HFD on the development of chronic ileal inflammation in a murine model of Crohn's disease-like ileitis.MethodsTNF(?ARE/WT) mice and wildtype C57BL/6 littermates were fed a HFD compared to control diet for different durations. Intestinal pathology and metabolic parameters (glucose tolerance, mesenteric tissue characteristics) were assessed. Intestinal barrier integrity was characterized at different levels including polyethylene glycol (PEG) translocation, endotoxin in portal vein plasma and cellular markers of barrier function. Inflammatory activation of epithelial cells as well as immune cell infiltration into ileal tissue were determined and related to luminal factors.ResultsHFD aggravated ileal inflammation but did not induce significant overweight or typical metabolic disorders in TNF(?ARE/WT). Expression of the tight junction protein Occludin was markedly reduced in the ileal epithelium of HFD mice independently of inflammation, and translocation of endotoxin was increased. Epithelial cells showed enhanced expression of inflammation-related activation markers, along with enhanced luminal factors-driven recruitment of dendritic cells and Th17-biased lymphocyte infiltration into the lamina propria.ConclusionsHFD feeding, independently of obesity, accelerated disease onset of small intestinal inflammation in Crohn's disease-relevant mouse model through mechanisms that involve increased intestinal permeability and altered luminal factors, leading to enhanced dendritic cell recruitment and promoted Th17 immune responses.

Project description:INTRODUCTION:High-fat diet (HFD)-induced obesity is accompanied by compromised nitric oxide (NO) signaling and gut microbiome dysregulation. Inorganic dietary nitrate, which acts as a NO donor, exerts beneficial effects on metabolic disorders. Here, we evaluated the effects of dietary nitrate on HFD-induced obesity and provided insights into the underlying mechanism. RESEARCH DESIGN AND METHODS:To investigate the preventive effect of dietary nitrate on HFD-induced obesity, C57BL/6 mice were randomly assigned into four groups (n=10/group), including normal control diet group (normal water and chow diet), HFD group (normal water and HFD), HFD+NaNO3 group (water containing 2 mM NaNO3 and HFD), and HFD+NaCl group (water containing 2 mM NaCl and HFD). During the experiment, body weight was monitored and glucolipid metabolism was evaluated. The mechanism underlying the effects of nitrate on HFD-induced obesity was investigated by the following: the NO3 --NO2 --NO pathway; endothelial NO synthase (eNOS) and cyclic guanosine monophosphate (cGMP) levels; gut microbiota via 16SRNA analysis. RESULTS:Dietary nitrate reduced the body weight gain and lipid accumulation in adipose and liver tissues in HFD-fed mice. Hyperlipidemia and insulin resistance caused by HFD were improved in mice supplemented with nitrate. The level of eNOS was upregulated by nitrate in the serum, liver, and inguinal adipose tissue. Nitrate, nitrite, and cGMP levels were decreased in mice fed on HFD but reversed in the HFD+NaNO3 group. Nitrate also rebalanced the colon microbiota and promoted a normal gut microbiome profile by partially attenuating the impacts of HFD. Bacteroidales S24-7, Alistipes, Lactobacillus, and Ruminococcaceae abundances were altered, and Bacteroidales S24-7 and Alistipes abundances were higher in the HFD+NaNO3 group than that in the HFD group. CONCLUSIONS:Inorganic dietary nitrate alleviated HFD-induced obesity and ameliorated disrupted glucolipid metabolism via NO3 --NO2 --NO pathway activation and gut microbiome modulation.

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High-fat diet determines the composition of the murine gut microbiome independently of obesity.

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High-fat diet determines the composition of the murine gut microbiome independently of obesity.

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