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.
Highlights
Gastrointestinal diseases are emerging as an important global health problem (Ponder and Long, 2013)
The AM receptor consists on a 7-transmembrane domain protein called calcitonin receptor-like receptor (CLR) in combination with a single transmembrane domain protein known as receptor activity modifying protein (RAMP) (Poyner et al, 2002)
AM and proadrenomedullin N-terminal peptide (PAMP) are antimicrobial peptides which are found in mostly all epithelial surfaces and body secretions (Martínez et al, 1997) and it has been demonstrated that Gram-positive and Gram-negative bacteria isolated from the skin, oral cavity, and respiratory and gastrointestinal tract are sensitive to AM (Allaker et al, 1999)
Summary
Gastrointestinal diseases are emerging as an important global health problem (Ponder and Long, 2013). Many of them are idiopathic, chronic, relapsing disorders of the gastrointestinal tract, such as inflammatory bowel diseases (IBD), which encompass ulcerative colitis and Crohn’s disease. IBD is widely accepted as one of the main risk factors leading to colorectal cancer (CRC) (Kim and Chang, 2014), mediated by chronic intestinal inflammation (Yashiro, 2014). Adrenomedullin (AM) and proadrenomedullin N-terminal 20 peptide (PAMP) are two biologically active peptides produced by the same gene, adm, with ubiquitous distribution and Adrenomedullin Regulates Microbiota and Colitis many physiological functions (López and Martinez, 2002). Specific binding and production sites for AM are located in many tissues and cell types (López and Martinez, 2002), including the gastrointestinal tract (Martínez-Herrero and Martínez, 2016), being especially abundant in the neuroendocrine cells of the gastrointestinal mucosa, suggesting that AM and PAMP may act as gut hormones regulating many physiological and pathological conditions. AM and PAMP are antimicrobial peptides which are found in mostly all epithelial surfaces and body secretions (Martínez et al, 1997) and it has been demonstrated that Gram-positive and Gram-negative bacteria isolated from the skin, oral cavity, and respiratory and gastrointestinal tract are sensitive to AM (Allaker et al, 1999)
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