Antimicrobial peptides and the enteric mucus layer act in concert to protect the intestinal mucosa.
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ABSTRACT:
SUBMITTER: Dupont A
PROVIDER: S-EPMC4615892 | biostudies-other | 2014
REPOSITORIES: biostudies-other
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Project description:The overall composition of the mammalian intestinal microbiota varies between individuals: within each individual there are differences along the length of the intestinal tract related to host nutrition, intestinal motility and secretions. Mucus is a highly regenerative protective lubricant glycoprotein sheet secreted by host intestinal goblet cells; the inner mucus layer is nearly sterile. Here we show that the outer mucus of the large intestine forms a unique microbial niche with distinct communities, including bacteria without specialized mucolytic capability. Bacterial species present in the mucus show differential proliferation and resource utilization compared with the same species in the intestinal lumen, with high recovery of bioavailable iron and consumption of epithelial-derived carbon sources according to their genome-encoded metabolic repertoire. Functional competition for existence in this intimate layer is likely to be a major determinant of microbiota composition and microbial molecular exchange with the host.
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Project description:Mucus is a protein-based gel secreted by specialized epithelial cells that protects the gastrointestinal mucosa from microorganism attack and irritating agents. Experiments in mice have demonstrated that when the mucosa is infected or inflamed, the mucus becomes enriched with broad-spectrum bactericidal compounds known as antimicrobial peptides (AMPs). Although AMP gene expression has been identified in both immune and epithelial cells, how inflammation regulates AMP secretion in the mucus remains unclear, and the efficacy of AMP-enriched mucus in defending against microorganisms has not been assessed. We have developed a “mucosoid” culture model that simulates the healthy human stomach epithelium. In these cultures, epithelial cells form a barrier and can differentiate into mucus-secreting cells. The accumulation of mucus on the apical side facilitates the detection of AMPs and the assessment of their bactericidal properties. We report that cytokines TNFa, IL1b and IFNg enhance the secretion of the AMPs lactotransferrin, lipocalin2, C3A, and CXCL9 into the mucus. The mucus from inflamed cells which contains the aforementioned AMPs partially kills Helicobacter pylori, the sole stomach pathogen. However, H. pylori can inhibit this defence by reducing AMP gene expression in inflamed epithelial cells. These results reveal that secreted mucus is a relevant effector of epithelial immunity but pathogens like H. pylori can subvert these defences to persist in the mucosa.
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Project description:BackgroundLubiprostone has been used to treat constipation through its effects to stimulate Cl(-) secretion, resulting in water and electrolyte secretion.AimPotential associated changes in intestinal mucus and the colonizing bacteria (microbiome) have not been studied. As mucus obstructions may play a role in cystic fibrosis, the hypothesis that lubiprostone alters intestinal mucus and the microbiome was investigated.MethodsIon transport studies were performed ex vivo. For mucus and microbiome studies, mice were gavaged daily with lubiprostone or vehicle. Mucin from intestinal sections was analyzed in Carnoy's fixed tissues stained with Alcian blue. Microbiome composition was analyzed by 16S rRNA gene-based sequencing.ResultsLubiprostone stimulated short circuit current in all mouse intestinal segments after both serosal and mucosal additions, albeit at lower concentrations in the latter. Current was Cl-dependent and blocked by mucosal diphenylcarboxylic acid, serosal bumetanide, and serosal Ba(++). The CFTR inhibitor CFTRinh172 had a marginal effect. Mucus near epithelial cells (inner layer mucus) was not present in the small intestine of any mice. Proximal colon inner mucus layer was thicker in ∆F/∆F compared with +/∆F and +/+ mice. Lubiprostone decreased inner mucus layer thickness in both proximal and distal colon of all mice. Furthermore, lubiprostone altered the intestinal microbiome by increasing abundance of Lactobacillus and Alistipes.ConclusionsLubiprostone activates non-CFTR Cl(-) secretion and alters the colonic inner mucus layer, which is associated with changes in the composition of the enteric microbiome.
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Project description:The innate immune system provides protection from infection by producing essential effector molecules, such as antimicrobial peptides (AMPs) that possess broad-spectrum activity. This is also the case for bumblebees, Bombus terrestris, when infected by the trypanosome, Crithidia bombi Furthermore, the expressed mixture of AMPs varies with host genetic background and infecting parasite strain (genotype). Here, we used the fact that clones of C. bombi can be cultivated and kept as strains in medium to test the effect of various combinations of AMPs on the growth rate of the parasite. In particular, we used pairwise combinations and a range of physiological concentrations of three AMPs, namely Abaecin, Defensin and Hymenoptaecin, synthetized from the respective genomic sequences. We found that these AMPs indeed suppress the growth of eight different strains of C. bombi, and that combinations of AMPs were typically more effective than the use of a single AMP alone. Furthermore, the most effective combinations were rarely those consisting of maximum concentrations. In addition, the AMP combination treatments revealed parasite strain specificity, such that strains varied in their sensitivity towards the same mixtures. Hence, variable expression of AMPs could be an alternative strategy to combat highly variable infections.This article is part of the themed issue 'Evolutionary ecology of arthropod antimicrobial peptides'.
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