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Lack of Adrenomedullin Results in Microbiota Changes and Aggravates Azoxymethane and Dextran Sulfate Sodium-Induced Colitis in Mice.

ABSTRACT: The link between intestinal inflammation, microbiota, and colorectal cancer is intriguing and the potential underlying mechanisms remain unknown. Here we evaluate the influence of adrenomedullin (AM) in microbiota composition and its impact on colitis with an inducible knockout (KO) mouse model for AM. Microbiota composition was analyzed in KO and wild type (WT) mice by massive sequencing. Colitis was induced in mice by administration of azoxymethane (AOM) followed by dextran sulfate sodium (DSS) in the drinking water. Colitis was evaluated using a clinical symptoms index, histopathological analyses, and qRT-PCR. Abrogation of the adm gene in the whole body was confirmed by PCR and qRT-PCR. KO mice exhibit significant changes in colonic microbiota: higher proportion of ?-Proteobacteria class; of Coriobacteriales order; and of other families and genera was observed in KO feces. Meanwhile these mice had a lower proportion of beneficial bacteria, such as Lactobacillus gasseri and Bifidobacterium choerinum. TLR4 gene expression was higher (p < 0.05) in KO animals. AM deficient mice treated with DSS exhibited a significantly worse colitis with profound weight loss, severe diarrhea, rectal bleeding, colonic inflammation, edema, infiltration, crypt destruction, and higher levels of pro-inflammatory cytokines. No changes were observed in the expression levels of adhesion molecules. In conclusion, we have shown that lack of AM leads to changes in gut microbiota population and in a worsening of colitis conditions, suggesting that endogenous AM is a protective mediator in this pathology.

SUBMITTER: Martinez-Herrero S

PROVIDER: S-EPMC5127798 | biostudies-literature | 2016

REPOSITORIES: biostudies-literature

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Lack of Adrenomedullin Results in Microbiota Changes and Aggravates Azoxymethane and Dextran Sulfate Sodium-Induced Colitis in Mice.

Martínez-Herrero Sonia S Larrayoz Ignacio M IM Narro-Íñiguez Judit J Villanueva-Millán María J MJ Recio-Fernández Emma E Pérez-Matute Patricia P Oteo José A JA Martínez Alfredo A

Frontiers in physiology 20161130

The link between intestinal inflammation, microbiota, and colorectal cancer is intriguing and the potential underlying mechanisms remain unknown. Here we evaluate the influence of adrenomedullin (AM) in microbiota composition and its impact on colitis with an inducible knockout (KO) mouse model for AM. Microbiota composition was analyzed in KO and wild type (WT) mice by massive sequencing. Colitis was induced in mice by administration of azoxymethane (AOM) followed by dextran sulfate sodium (DSS ...[more]

PMID: 27965594

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Project description:Objective: Inflammatory bowel disease (IBD) is characterized by gut microbiota dysbiosis, which is also frequently observed in patients with non-alcoholic fatty liver disease. Whether gut microbiota dysbiosis in IBD patients promotes the development of non-alcoholic steatohepatitis (NASH) remains unclear. We aimed to explore the role of gut microbiota dysbiosis in the development of NASH in mice with dextran sulfate sodium salt (DSS) induced colitis. Design: Dextran sulfate sodium salt was used to induce colitis, and high fat (HF), in combination with a high-fructose diet, was used to induce NASH in C57BL/6J male mice. Mice were treated with (1%) DSS to induce colitis in cycles, and each cycle consisted of 7 days of DSS administration followed by a 10-day interval. The cycles were repeated throughout the experimental period of 19 weeks. Pathological alterations in colitis and NASH were validated by hematoxylin and eosin (H&E), oil red O, Sirius red staining, and immunofluorescence. Gut microbiota was examined by 16S rRNA sequencing, and gene expression profiles of hepatic non-parenchymal cells (NPCs) were detected by RNA sequencing. Results: Dextran sulfate sodium salt administration enhanced the disruption of the gut-vascular barrier and aggravated hepatic inflammation and fibrosis in mice with NASH. DSS-induced colitis was accompanied by gut microbiota dysbiosis, characterized by alteration in the core microbiota composition. Compared with the HF group, the abundance of p_Proteobacteria and g_Bacteroides increased, while that of f_S24-7 decreased in the DSS + HF mice. Specifically, gut microbiota dysbiosis was characterized by enrichment of lipopolysaccharide producing bacteria and decreased abundance of short-chain fatty acid-producing bacteria. Gene expression analysis of liver NPCs indicated that compared with the HF group, genes related to both inflammatory response and angiocrine signaling were altered in the DSS + HF group. The expression levels of inflammation-related and vascular development genes correlated significantly with the abundance of p_Proteobacteria, g_Bacteroides, or f_S24-7 in the gut microbiota, implying that gut microbiota dysbiosis induced by DSS might aggravate hepatic inflammation and fibrosis by altering the gene expression in NPCs. Conclusion: Dextran sulfate sodium salt-induced colitis may promote the progression of liver inflammation and fibrosis by inducing microbiota dysbiosis, which triggers an inflammatory response and disrupts angiocrine signaling in liver NPCs. The abundance of gut microbiota was associated with expression levels of inflammation-related genes in liver NPCs and may serve as a potential marker for the progression of NASH.

Dataset Information

Lack of Adrenomedullin Results in Microbiota Changes and Aggravates Azoxymethane and Dextran Sulfate Sodium-Induced Colitis in Mice.

Publications

Lack of Adrenomedullin Results in Microbiota Changes and Aggravates Azoxymethane and Dextran Sulfate Sodium-Induced Colitis in Mice.

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