Transitions in Oral and Intestinal Microflora Composition and Innate Immune Receptor-Dependent Stimulation during Mouse Development

Abstract

Commensal bacteria possess immunostimulatory activities that can modulate host responses to affect development and homeostasis in the intestine. However, how different populations of resident bacteria stimulate the immune system remains largely unknown. We characterized here the ability of intestinal and oral microflora to stimulate individual pattern recognition receptors (PRRs) in bone marrow-derived macrophages and mesothelial cells. The intestinal but not oral microflora elicited age-and cell type-specific immunostimulation. The immunostimulatory activity of the intestinal microflora varied among individual mice but was largely mediated via Toll-like receptor 4 (TLR4) during breast-feeding, whereas it became TLR4 independent after weaning. This transition was associated with a change from a microflora rich in TLR4-stimulatory proteobacteria to one dominated by Bacteroidales and/or Clostridiales that poorly stimulate TLR4. The major stimulatory activity of the intestinal microflora was still intact in NOD1-, NOD2-, TLR2-, TLR4-, TLR5-, TLR9-, TLR11-, ASC-, or RICK-deficient cells but still relied on the adaptor MyD88. These studies demonstrate a transition in the intestinal microflora accompanied by a dynamic change of its ability to stimulate different PRRs which control intestinal homeostasis.Accumulating evidence indicates that environmental bacteria can regulate the development and homeostasis of the host immune system, particularly within the gut, and affect susceptibility to a variety of diseases (3,5,6,9,10,40,44). Both humans and animals harbor a large number of nonpathogenic residential bacteria, especially in the intestine and oral cavity (41). Uncontrolled translocation of bacteria or bacterial components into systemic tissues of the host often results in bacteremia and sepsis (8), which causes significant mortality worldwide each year. On the other hand, intestinal bacteria contain immunostimulatory molecules that can regulate local immunity, epithelial development, immunotolerance, and susceptibility to inflammatory bowel disease (2, 41). The bacteriumderived molecules are recognized by innate immune receptors, including Toll-like receptors (TLRs) and Nod-like receptors (NLRs) (8,20). TLRs and NLRs, often referred as pattern recognition receptors (PRRs), are involved in the recognition of commensal and pathogenic bacteria, as well as in the clearance of pathogens through interaction with their cognate microbial molecules (8,20). Interactions between PRRs and commensal bacteria have been demonstrated to be important for gut homeostasis. MyD88, an essential adaptor for TLR signaling, has been shown to be important for epithelial homeostasis (40) and IgA secretion in the intestine (3, 44), and TLR9 has been shown to be important for the balance of regulatory T/Th17/Th1 cells (10). In addition, NOD1, an NLR family member, was shown to play a role in the development of intestinal lymphoid tissue via the recognition of commensal bacteria (5). Finally, genetic variation in NOD1 affects the susceptibilit...

Toll-like receptor-4 genotype influences the survival of cystic fibrosis mice

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Nucleotide-Binding Oligomerization Domain 1 Mediates Recognition of Clostridium difficile and Induces Neutrophil Recruitment and Protection against the Pathogen

“…2). Because the composition of the gut microbiota may affect susceptibility to C. difficile infection, we examined the microbiota of Nod1 2/2 and control mice before and after C. difficile infection by denaturing gradient gel electrophoresis (DGGE) (15). We found that the composition of the intestinal microbiota was comparable in Nod1 2/2 and heterozygous Nod1…”

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