Highlights d The expanding microbiota at weaning induces a vigorous immune reaction d The weaning reaction occurs during a specific time window d The weaning reaction prevents susceptibility to inflammatory pathologies in the adult d Microbiota-induced Treg cells are required for a protective weaning reaction

The ontogeny and maturation of the immune system is modulated by the microbiota. During fetal life, the mother's microbiota produces compounds that are transferred to the fetus and offspring, and enhance the generation of innate immune cells. After birth, the colonizing microbiota induces the development of intestinal lymphoid tissues and maturation of myeloid and lymphoid cells, and imprints the immune system with a reactivity level that persists long after weaning into adulthood. When the cross-talk between host and microbiota is perturbed early in life, a pathological imprinting may develop that is characterized by excessive immune reactivity in adulthood, which translates into increased susceptibility to inflammatory pathologies. In this review, we discuss the recent data that demonstrate the existence of a time window of opportunity early in life during which mice and human have to be exposed to microbiota in order to develop a balanced immune system. We also discuss the factors involved in imprinting, such as the microbiota, immune cells and stromal cells, as well as the nature of imprinting.Mucosal Immunology (2020) 13:183-189; https://doi.

Nucleotide-binding oligomerization domain 2 (NOD2) is an intracellular pattern recognition receptor that senses bacterial peptidoglycan (PGN)-conserved motifs in cytosol and stimulates host immune response. The association of NOD2 mutations with a number of inflammatory pathologies, including Crohn disease (CD), Graft-versus-host disease (GVHD), and Blau syndrome, highlights its pivotal role in host–pathogen interactions and inflammatory response. Stimulation of NOD2 by its ligand (muramyl dipeptide) activates pro-inflammatory pathways such as nuclear factor-κB (NF-κB), mitogen-activated protein kinases (MAPKs), and Caspase-1. A loss of NOD2 function may result in a failure in the control of microbial infection, thereby initiating systemic responses and aberrant inflammation. Because the ligand of Nod2 is conserved in both gram-positive and gram-negative bacteria, NOD2 detects a wide variety of microorganisms. Furthermore, current literature evidences that NOD2 is also able to control viruses’ and parasites’ infections. In this review, we present and discuss recent developments about the role of NOD2 in shaping the gut commensal microbiota and pathogens, including bacteria, viruses, and parasites, and the mechanisms by which Nod2 mutations participate in disease occurrence.

The pathophysiology of necrotizing enterocolitis (NEC) remains poorly understood. We assessed the relation between feeding strategies, intestinal microbiota composition, and the development of NEC. We performed a prospective nationwide population-based study, EPIPAGE 2 (Etude Epidémiologique sur les Petits Ages Gestationnels), including preterm infants born at <32 wk of gestation in France in 2011. From individual characteristics observed during the first week of life, we calculated a propensity score for the risk of NEC (Bell's stage 2 or 3) after day 7 of life. We analyzed the relation between neonatal intensive care unit (NICU) strategies concerning the rate of progression of enteral feeding, the direct-breastfeeding policy, and the onset of NEC using general linear mixed models to account for clustering by the NICU. An ancillary propensity-matched case-control study, EPIFLORE (Etude Epidémiologique de la flore), in 20 of the 64 NICUs, analyzed the intestinal microbiota by culture and 16S ribosomal RNA gene sequencing. Among the 3161 enrolled preterm infants, 106 (3.4%; 95% CI: 2.8%, 4.0%) developed NEC. Individual characteristics were significantly associated with NEC. Slower and intermediate rates of progression of enteral feeding strategies were associated with a higher risk of NEC, with an adjusted OR of 2.3 (95% CI: 1.2, 4.5; = 0.01) and 2.0 (95% CI: 1.1, 3.5; = 0.02), respectively. Less favorable and intermediate direct-breastfeeding policies were associated with higher NEC risk as well, with an adjusted OR of 2.5 (95% CI: 1.1, 5.8; = 0.03) and 2.3 (95% CI: 1.1, 4.8; = 0.02), respectively. Microbiota analysis performed in 16 cases and 78 controls showed an association between and with NEC ( = 0.001 and = 0.002). A slow rate of progression of enteral feeding and a less favorable direct-breastfeeding policy are associated with an increased risk of developing NEC. For a given level of risk assessed by propensity score, colonization by and/or is significantly associated with NEC. This trial (EPIFLORE study) was registered at clinicaltrials.gov as NCT01127698.

No abstract

Nod2 deficiency is associated with a specific dominant dysbiosis which does not drive mucosal tissue and immune alterations.

Nucleotide-binding oligomerization domain 2 (NOD2) is an intracellular pattern recognition receptor that senses bacterial peptidoglycan-conserved motifs in cytosol and stimulates host immune response including epithelial and immune cells. The association of NOD2 mutations with a number of inflammatory pathologies including Crohn’s disease (CD), graft-versus-host diseases, or Blau syndrome, highlights its pivotal role in inflammatory response and the associated-carcinogenesis development. Since its identification in 2001 and its association with CD, the role of NOD2 in epithelial cells and immune cells has been investigated extensively but the precise mechanism by which NOD2 mutations lead to CD and the associated carcinogenesis development is largely unknown. In this review, we present and discuss recent developments about the role of NOD2 inside epithelial cells on the control of the inflammatory process and its linked carcinogenesis development.

Our study demonstrates how hematopoietic and nonhematopoietic Nod2 regulate intestinal barrier function, improving our knowledge on the mechanisms involved in CD pathogenesis.