The development of colitis in DSS model was accompanied with reduced microbial diversity and dysbiosis of gut microbiota at lower taxonomical levels.

Postnatal maturation of immune regulation is largely driven by exposure to microbes. The gastrointestinal tract is the largest source of microbial exposure, as the human gut microbiome contains up to 1014 bacteria, which is 10 times the number of cells in the human body. Several studies in recent years have shown differences in the composition of the gut microbiota in children who are exposed to different conditions before, during, and early after birth. A number of maternal factors are responsible for the establishment and colonization of gut microbiota in infants, such as the conditions surrounding the prenatal period, time and mode of delivery, diet, mother’s age, BMI, smoking status, household milieu, socioeconomic status, breastfeeding and antibiotic use, as well as other environmental factors that have profound effects on the microbiota and on immunoregulation during early life. Early exposures impacting the intestinal microbiota are associated with the development of childhood diseases that may persist to adulthood such as asthma, allergic disorders (atopic dermatitis, rhinitis), chronic immune-mediated inflammatory diseases, type 1 diabetes, obesity, and eczema. This overview highlights some of the exposures during the pre- and postnatal time periods that are key in the colonization and development of the gastrointestinal microbiota of infants as well as some of the diseases or disorders that occur due to the pattern of initial gut colonization.

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BackgroundThe cholinergic anti-inflammatory pathway (CAP) is based on vagus nerve (VN) activity that regulates macrophage and dendritic cell responses in the spleen through alpha-7 nicotinic acetylcholine receptor (a7nAChR) signaling. Inflammatory bowel disease (IBD) patients present dysautonomia with decreased vagus nerve activity, dendritic cell and T cell over-activation. The aim of this study was to investigate whether central activation of the CAP alters the function of dendritic cells (DCs) and sequential CD4+/CD25−T cell activation in the context of experimental colitis.MethodsThe dinitrobenzene sulfonic acid model of experimental colitis in C57BL/6 mice was used. Central, intracerebroventricular infusion of the M1 muscarinic acetylcholine receptor agonist McN-A-343 was used to activate CAP and vagus nerve and/or splenic nerve transection were performed. In addition, the role of α7nAChR signaling and the NF-kB pathway was studied. Serum amyloid protein (SAP)-A, colonic tissue cytokines, IL-12p70 and IL-23 in isolated splenic DCs, and cytokines levels in DC-CD4+CD25−T cell co-culture were determined.ResultsMcN-A-343 treatment reduced colonic inflammation associated with decreased pro-inflammatory Th1/Th17 colonic and splenic cytokine secretion. Splenic DCs cytokine release was modulated through α7nAChR and the NF-kB signaling pathways. Cholinergic activation resulted in decreased CD4+CD25−T cell priming. The anti-inflammatory efficacy of central cholinergic activation was abolished in mice with vagotomy or splenic neurectomy.ConclusionsSuppression of splenic immune cell activation and altered interaction between DCs and T cells are important aspects of the beneficial effect of brain activation of the CAP in experimental colitis. These findings may lead to improved therapeutic strategies in the treatment of IBD.

Background and aimsPostnatal maturation of the immune system is largely driven by exposure to microbes, and thus the nature of intestinal colonization may be associated with development of childhood diseases that may persist into adulthood. We investigated whether antepartum antibiotic (ATB) therapy can increase offspring susceptibility to experimental colitis through alteration of the gut microbiota.MethodsPregnant C57Bl/6 mice were treated with cefazolin at 160 mg/kg body weight or with saline starting six days before due date. At 7 weeks, fecal samples were collected from male offspring after which they received 4% dextran sulfate sodium (DSS) in drinking water for 5 days. Disease activity index, histology, colonic IL-6, IL-1β and serum C-reactive protein (CRP) were determined. The V3-V4 region of colonic and fecal bacterial 16S rRNA was sequenced. Alpha-, beta-diversity and differences at the phylum and genus levels were determined, while functional pathways of classified bacteria were predicted.ResultsATB influenced fecal bacterial composition and hence bacterial functional pathways before induction of colitis. After induction of colitis, ATB increased onset of clinical disease, histologic score, and colonic IL-6. In addition, ATB decreased fecal microbial richness, changed fecal and colon microbial composition, which was accompanied by a modification of microbial functional pathways. Also, several taxa were associated with ATB at lower taxonomical levels.ConclusionsThe results support the hypothesis that antepartum antibiotics modulate offspring intestinal bacterial colonization and increase susceptibility to develop colonic inflammation in a murine model of colitis, and may guide future interventions to restore physiologic intestinal colonization in offspring born by antibiotic-exposed mothers.