Small Intestinal Goblet Cells Control Humoral Immune Responses and Mobilization During Enteric Infection.

Humoral immune responses within the gut play diverse roles including pathogen clearance during enteric infections, maintaining tolerance, and facilitating the assemblage and stability of the gut microbiota. How these humoral immune responses are initiated and contribute to these processes are well studied. However, the signals promoting the expansion of these responses and their rapid mobilization to the gut mucosa are less well understood.

Gut microbiota induces weight gain and inflammation in the gut and adipose tissue independent of manipulations in diet, genetics, and immune development.

Obesity and the metabolic syndrome are complex disorders resulting from multiple factors including genetics, diet, activity, inflammation, and gut microbes. Animal studies have identified roles for each of these, however the contribution(s) specifically attributed to the gut microbiota remain unclear, as studies have used combinations of genetically altered mice, high fat diet, and/or colonization of germ-free mice, which have an underdeveloped immune system. We investigated the role(s) of the gut microbiota driving obesity and inflammation independent of manipulations in diet and genetics in mice with fully developed immune systems.

Vancomycin-induced gut microbial dysbiosis alters enteric neuron-macrophage interactions during a critical period of postnatal development.

Vancomycin is a broad-spectrum antibiotic widely used in cases of suspected sepsis in premature neonates. While appropriate and potentially lifesaving in this setting, early-life antibiotic exposure alters the developing microbiome and is associated with an increased risk of deadly complications, including late-onset sepsis (LOS) and necrotizing enterocolitis (NEC). Recent studies show that neonatal vancomycin treatment disrupts postnatal enteric nervous system (ENS) development in mouse pups, which is in part dependent upon neuroimmune interactions.

Neonatal development of intestinal neuroimmune interactions.

Interactions between the enteric nervous system (ENS), immune system, and gut microbiota regulate intestinal homeostasis in adults, but their development and role(s) in early life are relatively underexplored. In early life, these interactions are dynamic, because the mucosal immune system, microbiota, and the ENS are developing and influencing each other. Moreover, disrupting gut microbiota and gut immune system development, and potentially ENS development, by early-life antibiotic exposure increases the risk of diseases affecting the gut.

Identification of Gut Bacteria such as Lactobacillus johnsonii that Disseminate to Systemic Tissues of Wild Type and MyD88-/- Mice.

In healthy hosts the gut microbiota is restricted to gut tissues by several barriers some of which require MyD88-dependent innate immune sensor pathways. Nevertheless, some gut taxa have been reported to disseminate to systemic tissues. However, the extent to which this normally occurs during homeostasis in healthy organisms is still unknown.

Maternal activation of the EGFR prevents translocation of gut-residing pathogenic in a model of late-onset neonatal sepsis.

Late-onset sepsis (LOS) is a highly consequential complication of preterm birth and is defined by a positive blood culture obtained after 72 h of age. The causative bacteria can be found in patients' intestinal tracts days before dissemination, and cohort studies suggest reduced LOS risk in breastfed preterm infants through unknown mechanisms. Reduced concentrations of epidermal growth factor (EGF) of maternal origin within the intestinal tract of mice correlated to the translocation of a gut-resident human pathogen , which spreads systemically and caused a rapid, fatal disease in pups.

In vivo labeling of epithelial cell-associated antigen passages in the murine intestine.

The intestinal immune system samples luminal contents to induce adaptive immune responses that include tolerance in the steady state and protective immunity during infection. How luminal substances are delivered to the immune system has not been fully investigated. Goblet cells have an important role in this process by delivering luminal substances to the immune system through the formation of goblet cell-associated antigen passages (GAPs).

Goblet cell associated antigen passages support the induction and maintenance of oral tolerance.

Tolerance to innocuous antigens from the diet and the commensal microbiota is a fundamental process essential to health. Why tolerance is efficiently induced to substances arising from the hostile environment of the gut lumen is incompletely understood but may be related to how these antigens are encountered by the immune system. We observed that goblet cell associated antigen passages (GAPs), but not other pathways of luminal antigen capture, correlated with the acquisition of luminal substances by lamina propria (LP) antigen presenting cells (APCs) and with the sites of tolerance induction to luminal antigens.