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 δ-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.

Recurrence of primary sclerosing cholangitis after liver transplantation is associated with specific changes in the gut microbiome pretransplant – a pilot study

“…In addition, the genus Acinetobacter, one of the main genera of the Proteobacteria phyla to contribute to IBD disease activity [48], was significantly more abundant in IBD-PSC patients as compared to PSC patients without IBD. An increased abundance of Fusobacteriaceae, Stenotrophomonas and Micrococcus was seen in inflamed tissues, which is in accordance with previous investigations of IBD disease activity [49][50][51], while the found reduced levels of Bacteroidetes (phylum) and Caulobacterales (order) in inflamed tissue are consistent with mouse studies of colitis [52]. Thus, these findings are in line with previously published results for IBD and inflammation [53], indicating that the microbial signature present in the biopsies accurately represent disease state and that our sample is therefore useful for further exploration regarding rPSC.…”

Small molecules related to adrenomedullin reduce tumor burden in a mouse model of colitis-associated colon cancer

“…Previous studies have shown a strong positive effect using AM as treatment for colitis symptoms in rodents 22 and humans 15 , 23 . Besides, this study shows that AM negative modulation by 16311 exacerbates colitis symptoms suggesting that AM prevents the symptoms of the disease in line with previous experiments 20 , 36 . Microscopic analysis of colonic sections confirmed data from macroscopic observations reflecting a tumor reduction in 145425-treated mice.…”

“…Furthermore, AM and PAMP are antimicrobial peptides found in most epithelial surfaces and body secretions 24 , 25 and their presence or absence modifies the composition of gut microbiota 20 .…”

Anti‐Inflammatory Effects of PEGylated Human Adrenomedullin in a Mouse DSS‐Induced Colitis Model

“…In addition, myeloperoxidase (MPO), reactive oxygen species (ROS) and nitric oxide (NO) are associated with the development of IBD. Notably, hAM treatment reduces TNFα, IL‐1β, and IL‐6 levels [Hayashi et al, ], and hAM‐knockout mice with DSS‐induced colitis had changes in gut microbiota populations and increased TNFα, IL‐1β, IL‐6, IL‐10, IL‐17 and IL‐22 mRNA expression [Martinez‐Herrero et al, ]. It can therefore be deduced that PEG‐hAM treatment inhibits production of these proinflammatory cytokines.…”