Inflammasome activation links enteric Typhimurium infection to a rapid, cytokine-dependent increase in intestinal mucin release.

The host restricts serovar Typhimurium infection of the gut via inflammasome-dependent sloughing of infected epithelial cells. Here we determined that concurrent caspase 1/11-dependent release of the goblet cell-derived mucin, Muc2, into the intestinal lumen also controls burdens in infected mice. The increased release of mucins from goblet cells in the cecum and nearby proximal colon, and the subsequent thickening of the protective mucus barrier layer in the distal colon, were all dependent on the cytokines interleukin (IL)-18 and IL-22, as deficiencies in either cytokine resulted in reduced mucin secretion.

Sialic acid plays a pivotal role in licensing transition from the intestinal lumen to a mucosal adherent niche.

Enteric bacterial pathogens pose significant threats to human health; however, the mechanisms by which they infect the mammalian gut in the face of daunting host defenses and an established microbiota remain poorly defined. For the attaching and effacing (A/E) bacterial family member and murine pathogen , its virulence strategy likely involves metabolic adaptation to the host's intestinal luminal environment, as a necessary precursor to reach and infect the mucosal surface. Suspecting this adaptation involved the intestinal mucus layer, we found that was able to catabolize sialic acid, a monosaccharide derived from mucins, and utilize it as its sole carbon source for growth.

Highly Sensitive, Flow Cytometry-Based Measurement of Intestinal Permeability in Models of Experimental Colitis.

Background & Aims: Increased intestinal permeability is seen in a variety of inflammatory conditions such as enteric infections and inflammatory bowel disease. Because barrier function can provide a key biomarker of disease severity, it often is assayed in animal models. A common methodology involves gavaging mice with fluorescein isothiocyanate-conjugated dextran (FITC-D), followed by cardiac puncture to assay plasma fluorescence on a spectrophotometer.

Fasting increases microbiome-based colonization resistance and reduces host inflammatory responses during an enteric bacterial infection.

Reducing food intake is a common host response to infection, yet it remains unclear whether fasting is detrimental or beneficial to an infected host. Despite the gastrointestinal tract being the primary site of nutrient uptake and a common route for infection, studies have yet to examine how fasting alters the host's response to an enteric infection. To test this, mice were fasted before and during oral infection with the invasive bacterium Salmonella enterica serovar Typhimurium.

Interleukin-37 regulates innate immune signaling in human and mouse colonic organoids.

Intestinal epithelial cells (IEC) reside in close proximity to the gut microbiota and are hypo-responsive to bacterial products, likely to prevent maladaptive inflammatory responses. This is in part due to their strong expression of Single Ig IL-1 related receptor (SIGIRR), a negative regulator of interleukin (IL)-1 and toll-like receptor signaling. IL-37 is an anti-inflammatory cytokine that inhibits innate signaling in diverse cells by signaling through SIGIRR.

Microbial Respiration in the Colon: Using HO to Catch Your Breath.

To colonize the nutritionally competitive environment of the gut, invading bacteria must utilize unique metabolites. Two reports in this issue of Cell Host & Microbe describe how Citrobacter rodentium and Escherichia coli leverage colonocyte derived HO to drive two distinct respiratory pathways that support their proliferation in the mouse intestine.

Salmonella enterica Infection of Murine and Human Enteroid-Derived Monolayers Elicits Differential Activation of Epithelium-Intrinsic Inflammasomes.

Recent studies have determined that inflammasome signaling plays an important role in driving intestinal epithelial cell (IEC) responses to bacterial infections, such as serovar Typhimurium. There are two primary inflammasome pathways, canonical (involving caspase-1) and noncanonical (involving caspase-4 and -5 in humans and caspase-11 in mice). Prior studies identified the canonical inflammasome as the major pathway leading to interleukin-18 (IL-18) release and restriction of Typhimurium replication in the mouse cecum.

Intestinal restriction of Salmonella Typhimurium requires caspase-1 and caspase-11 epithelial intrinsic inflammasomes.

We investigated the role of the inflammasome effector caspases-1 and -11 during Salmonella enterica serovar Typhimurium infection of murine intestinal epithelial cells (IECs). Salmonella burdens were significantly greater in the intestines of caspase-1/11 deficient (Casp1/11-/-), Casp1-/- and Casp11-/- mice, as compared to wildtype mice. To determine if this reflected IEC-intrinsic inflammasomes, enteroid monolayers were derived and infected with Salmonella.

The Intestinal Epithelium: Central Coordinator of Mucosal Immunity.

The gastrointestinal (GI) tract represents a unique challenge to the mammalian immune system. It must tolerate the presence of the luminal microbiota and thus not respond to their products, but still protect the intestinal mucosa from potentially harmful dietary antigens and invading pathogens. The intestinal epithelium, composed of a single layer of cells, is crucial for preserving gut homeostasis and acts both as a physical barrier and as a coordinating hub for immune defense and crosstalk between bacteria and immune cells.

Frontline defenders: goblet cell mediators dictate host-microbe interactions in the intestinal tract during health and disease.

Goblet cells (GCs) are the predominant secretory epithelial cells lining the luminal surface of the mammalian gastrointestinal (GI) tract. Best known for their apical release of mucin 2 (Muc2), which is critical for the formation of the intestinal mucus barrier, GCs have often been overlooked for their active contributions to intestinal protection and host defense. In part, this oversight reflects the limited tools available to study their function but also because GCs have long been viewed as relatively passive players in promoting intestinal homeostasis and host defense.

Milk Fat Globule Membrane Supplementation in Formula Modulates the Neonatal Gut Microbiome and Normalizes Intestinal Development.

Breast milk has many beneficial properties and unusual characteristics including a unique fat component, termed milk fat globule membrane (MFGM). While breast milk yields important developmental benefits, there are situations where it is unavailable resulting in a need for formula feeding. Most formulas do not contain MFGM, but derive their lipids from vegetable sources, which differ greatly in size and composition.

Noncanonical inflammasomes: Antimicrobial defense that does not play by the rules.

Although much research has focused on defining the actions of caspase-1 containing canonical inflammasomes in promoting host defense, noncanonical inflammasomes have received comparatively little attention. Exciting new concepts have recently emerged detailing their atypical mechanism of activation, importance in defending against cytosolic Gram-negative pathogens, and role in innate immune defenses of nonmyeloid cells, which has revamped interest in the study of noncanonical inflammmasomes. Here, we will discuss these latest findings about caspase-4, -5, and -11 containing inflammasomes in the context of their role in pathogen elimination in mice and humans.

Salmonella and the Inflammasome: Battle for Intracellular Dominance.

Inflammasomes are macromolecular cytoplasmic complexes that act as signaling platforms for the activation of inflammatory caspases. Their activation triggers the processing and secretion of the pro-inflammatory cytokines IL-1β and IL-18, as well as the induction of a specialized form of inflammatory cell death termed pyroptosis. Here, we review the mechanisms of inflammasome activation triggered by the intracellular pathogen Salmonella enterica serovar Typhimurium.

Active Transport of Phosphorylated Carbohydrates Promotes Intestinal Colonization and Transmission of a Bacterial Pathogen.

Efficient acquisition of extracellular nutrients is essential for bacterial pathogenesis, however the identities and mechanisms for transport of many of these substrates remain unclear. Here, we investigate the predicted iron-binding transporter AfuABC and its role in bacterial pathogenesis in vivo. By crystallographic, biophysical and in vivo approaches, we show that AfuABC is in fact a cyclic hexose/heptose-phosphate transporter with high selectivity and specificity for a set of ubiquitous metabolites (glucose-6-phosphate, fructose-6-phosphate and sedoheptulose-7-phosphate).

Noncanonical inflammasome activation of caspase-4/caspase-11 mediates epithelial defenses against enteric bacterial pathogens.

Inflammasome-mediated host defenses have been extensively studied in innate immune cells. Whether inflammasomes function for innate defense in intestinal epithelial cells, which represent the first line of defense against enteric pathogens, remains unknown. We observed enhanced Salmonella enterica serovar Typhimurium colonization in the intestinal epithelium of caspase-11-deficient mice, but not at systemic sites.

A novel mouse model of Campylobacter jejuni gastroenteritis reveals key pro-inflammatory and tissue protective roles for Toll-like receptor signaling during infection.

Campylobacter jejuni is a major source of foodborne illness in the developed world, and a common cause of clinical gastroenteritis. Exactly how C. jejuni colonizes its host's intestines and causes disease is poorly understood.

Intestinal epithelium-specific MyD88 signaling impacts host susceptibility to infectious colitis by promoting protective goblet cell and antimicrobial responses.

Intestinal epithelial cells (IECs), including secretory goblet cells, form essential physiochemical barriers that separate luminal bacteria from underlying immune cells in the intestinal mucosa. IECs are common targets for enteric bacterial pathogens, with hosts responding to these microbes through innate toll-like receptors that predominantly signal through the MyD88 adaptor protein. In fact, MyD88 signaling confers protection against several enteric bacterial pathogens, including Salmonella enterica serovar Typhimurium and Citrobacter rodentium.

Phase variable expression of capsular polysaccharide modifications allows Campylobacter jejuni to avoid bacteriophage infection in chickens.

Bacteriophages are estimated to be the most abundant entities on earth and can be found in every niche where their bacterial hosts reside. The initial interaction between phages and Campylobacter jejuni, a common colonizer of poultry intestines and a major source of foodborne bacterial gastroenteritis in humans, is not well understood. Recently, we isolated and characterized a phage F336 resistant variant of C.

Differential progression of magnetization transfer imaging changes depending on severity of cerebral hypoxic-ischemic injury.

We hypothesized that magnetic resonance magnetization transfer (MT) imaging would be sensitive for detecting cerebral ischemic injury in white matter of neonatal brain. We compared the progression of changes in T(2) and the MT ratio (MTR) after cerebral hypoxic-ischemic insults of differing severity in neonatal rats. Magnetization transfer imaging parameters were first optimized, and then MTR and T(2) maps were acquired at various times after a mild (rather selective white matter) or substantial insult produced by unilateral cerebral hypoxia-ischemia.