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Altered intestinal functions and increased local inflammation in insulin-resistant obese subjects: a gene-expression profile analysis.

ABSTRACT: Metabolic alterations relevant to postprandial dyslipidemia were previously identified in the intestine of obese insulin-resistant subjects. The aim of the study was to identify the genes deregulated by systemic insulin resistance in the intestine of severely obese subjects.Transcripts from duodenal samples of insulin-sensitive (HOMA-IR < 3, n = 9) and insulin-resistant (HOMA-IR > 7, n = 9) obese subjects were assayed by microarray (Illumina HumanHT-12).A total of 195 annotated genes were identified as differentially expressed between these two groups (Fold change > 1.2). Of these genes, 36 were found to be directly involved in known intestinal functions, including digestion, extracellular matrix, endocrine system, immunity and cholesterol metabolism. Interestingly, all differentially expressed genes (n = 8) implicated in inflammation and oxidative stress were found to be upregulated in the intestine of insulin-resistant compared to insulin-sensitive subjects. Metabolic pathway analysis revealed that several signaling pathways involved in immunity and inflammation were significantly enriched in differently expressed genes and were predicted to be activated in the intestine of insulin-resistant subjects. Using stringent criteria (Fold change > 1.5; FDR < 0.05), three genes were found to be significantly and differently expressed in the intestine of insulin-resistant compared to insulin-sensitive subjects: the transcripts of the insulinotropic glucose-dependant peptide (GIP) and of the β-microseminoprotein (MSMB) were significantly reduced, but that of the humanin like-1 (MTRNR2L1) was significantly increased.These results underline that systemic insulin resistance is associated with remodeling of key intestinal functions. Moreover, these data indicate that small intestine metabolic dysfunction is accompanied with a local amplification of low-grade inflammatory process implicating several pathways. Genes identified in this study are potentially triggered throughout the development of intestinal metabolic abnormalities, which could contribute to dyslipidemia, a component of metabolic syndrome and diabetes.

SUBMITTER: Veilleux A

PROVIDER: S-EPMC4574092 | biostudies-other | 2015 Sep

REPOSITORIES: biostudies-other

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Altered intestinal functions and increased local inflammation in insulin-resistant obese subjects: a gene-expression profile analysis.

Veilleux Alain A Mayeur Sylvain S Bérubé Jean-Christophe JC Beaulieu Jean-François JF Tremblay Eric E Hould Frédéric-Simon FS Bossé Yohan Y Richard Denis D Levy Emile E

BMC gastroenterology 20150916

<h4>Background</h4>Metabolic alterations relevant to postprandial dyslipidemia were previously identified in the intestine of obese insulin-resistant subjects. The aim of the study was to identify the genes deregulated by systemic insulin resistance in the intestine of severely obese subjects.<h4>Methods</h4>Transcripts from duodenal samples of insulin-sensitive (HOMA-IR < 3, n = 9) and insulin-resistant (HOMA-IR > 7, n = 9) obese subjects were assayed by microarray (Illumina HumanHT-12).<h4>Res ...[more]

PMID: 26376914

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Project description:Metabolic alterations relevant to postprandial dyslipidemia were previously identified in the intestine of obese subjects with systemic insulin resistance. These dysregulations were closely associated with an amplification of intestinal lipogenesis and lipoprotein output, which was triggered by insulin resistance likely sustained by oxidative stress and inflammation. The aim of the study was to identify the genes deregulated by the presence of systemic insulin resistance in the intestine of severely obese subjects. Transcripts from duodenal samples of insulin-sensitive (HOMA-IR<3, n=9) and insulin-resistant (HOMA-IR>7, n=9) obese subjects were assayed by microarray (Illumina HumanHT-12). The small intestine exhibits a highly specific mRNA expression profile that was similar between insulin-sensitive and insulin-resistant individuals. A total of 195 annotated genes were identified as differentially expressed between these two groups with a fold change higher than 1.2. Metabolic pathway analysis revealed that 36 differently expressed genes were directly involved in known intestinal functions, including digestion, extracellular matrix, endocrine system, immunity, inflammation/oxidative stress and cholesterol metabolism. Several signaling pathways involved in immunity and inflammation were significantly enriched in differently expressed genes and were predicted to be activated in the intestine of insulin-resistant subjects. Using stringent criteria (Fold change>1.5; FDR<0.05), only three genes were found to be significantly and differently expressed in the intestine of insulin-resistant compared to insulin-sensitive subjects: the transcripts of the insulinotropic glucose-dependant peptide (GIP) and of the β-microseminoprotein (MSMB) were significantly reduced, but that of the humanin like-1 (HNL1) protein was significantly increased. These results underline that systemic insulin resistance is associated with an amplification of local inflammatory process and remodeling of key intestinal functions. Genes identified in this study are potentially triggered throughout the development of intestinal metabolic alterations, which could contribute to dyslipidemia, a component of metabolic syndrome and diabetes.

Project description:The overall gut microbial profile of patients with small intestinal bacterial overgrowth (SIBO) has not been thoroughly investigated. We investigated the microbial communities of mucosal specimens from the duodenum, ileum, sigmoid colon, and feces of patients with and without SIBO, as diagnosed by lactulose breath testing. The bacteria present in the mucosal and fecal samples were identified using 16S rRNA gene sequencing. Further analysis was performed using the linear discriminant analysis (LDA) effect size method, random forest analysis, and receiver operating characteristic analysis. The microbial diversities of the fecal samples were significantly lower than those of the mucosal samples from the duodenum, ileum, and sigmoid colon (P < 0.001, P < 0.001, and P < 0.001, respectively), while the bacterial compositions of the ileac mucosal samples and sigmoid mucosal samples were similar. The bacterial composition of either the fecal or duodenal mucosal samples were significantly different from those of the other three groups (ANOSIM R = 0.305, P = 0.001). The bacterial compositions of the mucosal samples of the duodenum, ileum, and sigmoid colon in the SIBO + subjects were significantly different from those of the SIBO- subjects (ANOSIM P = 0.039, 0.002, and 0.007, respectively). The relative abundances of 7, 18, and 8 genera were significantly different (LDA score > 3) in the mucosal samples of the duodenum, ileum, and sigmoid colon between the SIBO + and SIBO- groups. Four genera (Lactobacillus, Prevotella_1, Dialister, and norank_f__Ruminococcaceae) showed similar changes among the mucosal samples of the duodenum, ileum, and sigmoid colon in the SIBO + subjects. A signature consisting of four genera in the duodenal mucosa, three genera in the ileac mucosa, or six genera in the mucosa of the sigmoid colon exhibited predictive power for SIBO (area under the curve = 0.9, 0.93, and 0.87, respectively). This study provides a comprehensive profile of the gut microbiota in patients with SIBO. Dysbiosis was observed in the mucosa-associated gut microbiome but not in the fecal microbiome of patients with SIBO. Furthermore, we identified mucosa-associated taxa that may be potential biomarkers or therapeutic targets of SIBO. Further investigation is needed on their mechanisms and roles in SIBO.

Dataset Information

Altered intestinal functions and increased local inflammation in insulin-resistant obese subjects: a gene-expression profile analysis.

Publications

Altered intestinal functions and increased local inflammation in insulin-resistant obese subjects: a gene-expression profile analysis.

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