Enterococcus faecalis metalloprotease compromises epithelial barrier and contributes to intestinal inflammation.

Background & Aims: Matrix metalloproteases (MMPs) mediate pathogenesis of chronic intestinal inflammation. We characterized the role of the gelatinase (GelE), a metalloprotease from Enterococcus faecalis, in the development of colitis in mice.

Methods: Germ-free, interleukin-10-deficient (IL-10(-/-)) mice were monoassociated with the colitogenic E faecalis strain OG1RF and isogenic, GelE-mutant strains.

Functional genome analysis of Bifidobacterium breve UCC2003 reveals type IVb tight adherence (Tad) pili as an essential and conserved host-colonization factor.

Development of the human gut microbiota commences at birth, with bifidobacteria being among the first colonizers of the sterile newborn gastrointestinal tract. To date, the genetic basis of Bifidobacterium colonization and persistence remains poorly understood. Transcriptome analysis of the Bifidobacterium breve UCC2003 2.

Targeting the replication checkpoint using SCH 900776, a potent and functionally selective CHK1 inhibitor identified via high content screening.

Checkpoint kinase 1 (CHK1) is an essential serine/threonine kinase that responds to DNA damage and stalled DNA replication. CHK1 is essential for maintenance of replication fork viability during exposure to DNA antimetabolites. In human tumor cell lines, ablation of CHK1 function during antimetabolite exposure led to accumulation of double-strand DNA breaks and cell death.

Minimization of radiation exposure due to computed tomography in inflammatory bowel disease.

Exposure to ionising radiation as a result of diagnostic imaging is increasing among patients with inflammatory bowel disease (IBD), primarily due to the more widespread use of computed tomography (CT). The potentially harmful effects of ionising radiation are a major cause for concern and radiologists, technologists and referring physicians who have a responsibility to the patient to ensure judicious use of those imaging modalities which result in exposure to ionising radiation and, when imaging is necessary, to ensure that a diagnostic quality imaging examination is acquired with lowest possible radiation exposure. This can be achieved by limiting the use of those imaging studies which involve ionising radiation to clinical situations where they are likely to change management, by implementing advances in low-dose CT technology, and, where feasible, by using alternative imaging modalities, such as ultrasonography or magnetic resonance imaging, which avoid radiation exposure.

Biochemical and metabolomic phenotyping in the identification of a vitamin D responsive metabotype for markers of the metabolic syndrome.

Scope: Metabolic phenotyping promises to be a useful tool in human intervention studies. This study examined whether metabolic phenotyping could identify responders to vitamin D supplementation in terms of the metabolic syndrome.

Methods And Results: In a double-blind, randomised placebo-controlled dietary intervention subjects were assigned to receive 15 μg vitamin D(3) or placebo daily.

Recombinant lactobacilli expressing linoleic acid isomerase can modulate the fatty acid composition of host adipose tissue in mice.

We have previously demonstrated that oral administration of a metabolically active Bifidobacterium breve strain, with ability to form cis-9, trans-11 conjugated linoleic acid (CLA), resulted in modulation of the fatty acid composition of the host, including significantly elevated concentrations of c9, t11 CLA and omega-3 (n-3) fatty acids in liver and adipose tissue. In this study, we investigated whether a recombinant lactobacillus expressing linoleic acid isomerase (responsible for production of t10, c12 CLA) from Propionibacterium acnes (PAI) could influence the fatty acid composition of different tissues in a mouse model. Linoleic-acid-supplemented diets (2 %, w/w) were fed in combination with either a recombinant t10, c12 CLA-producing Lactobacillus paracasei NFBC 338 (Lb338), or an isogenic (vector-containing) control strain, to BALB/c mice for 8 weeks.

Bifidobacterium animalis AHC7 protects against pathogen-induced NF-κB activation in vivo.

Background: Bifidobacteria and lactobacilli are among the early and important colonizers of the gastrointestinal tract and are generally considered to be part of a normal, healthy microbiota. It is believed that specific strains within the microbiota can influence host immune-reactivity and may play a role in protection from infection and aberrant inflammatory activity. One such strain, Bifidobacterium animalis AHC7, has been previously shown to protect against Salmonella typhimurium infection in mice and helps resolve acute idiopathic diarrhea in dogs.

Phenotypic enhancement of thymidylate synthetase pathway inhibitors following ablation of Neil1 DNA glycosylase/lyase.

Inhibition of thymidine biosynthesis is a clinically-validated therapeutic approach for multiple cancers. Inhibition of thymidylate synthetase (TS) leads to a decrease in cellular TTP levels, replication stress and increased genomic incorporation of uridine (dUMP). Thus, inhibitors of this pathway (such as methotrexate) can drive a multitude of downstream cell cycle checkpoint and DNA repair processes.

Differential expression of toll-like receptors in patients with irritable bowel syndrome.

Objectives: The pathogenesis of irritable bowel syndrome (IBS) is poorly understood. One contributory factor may be low-grade mucosal inflammation, perhaps initiated by the microbiota. Toll-like receptors (TLRs) are a family of pathogen-recognition receptors of the innate immune system.

Small intestinal bacterial overgrowth in nonalcoholic steatohepatitis: association with toll-like receptor 4 expression and plasma levels of interleukin 8.

Background: Experimental and clinical studies suggest an association between small intestinal bacterial overgrowth (SIBO) and nonalcoholic steatohepatitis (NASH). Liver injury and fibrosis could be related to exposure to bacterial products of intestinal origin and, most notably, endotoxin, including lipopolysaccharide (LPS).

Aim: To compare the prevalence of SIBO and its relationships to LPS receptor levels and systemic cytokines in NASH patients and healthy control subjects.

Pharmabiotic manipulation of the microbiota in gastrointestinal disorders, from rationale to reality.

The viewpoints of enthusiasts and skeptics in relation to the role of probiotics should not be allowed to distract clinicians from the bigger issue, which is the pivotal role of the microbiota in the protection against many disorders and in the pathogenesis of others. However, all probiotics, like all bacteria, are not created equal, and therapeutic deployment in a generic sense is as absurd as the administration of pills or tablets without regard for the nature of the active ingredient and the intended effect. The rationale for therapeutic manipulation or supplementation of the microbiota is sound in conditions where the intestinal ecosystem is poorly developed, such as in low birth weight neonates, or where it is profoundly disturbed, such as after broad-spectrum antibiotics.

Composition and energy harvesting capacity of the gut microbiota: relationship to diet, obesity and time in mouse models.

Background And Aims: Increased efficiency of energy harvest, due to alterations in the gut microbiota (increased Firmicutes and decreased Bacteroidetes), has been implicated in obesity in mice and humans. However, a causal relationship is unproven and contributory variables include diet, genetics and age. Therefore, we explored the effect of a high-fat (HF) diet and genetically determined obesity (ob/ob) for changes in microbiota and energy harvesting capacity over time.

The colonic microflora and probiotic therapy in health and disease.

Purpose Of Review: Host-microbe dialogue is involved not only in maintenance of mucosal homeostasis but also in the pathogenesis of several infectious, inflammatory, and neoplastic disorders of the gut. This has led to a resurgence of interest in the colonic microbiota in health and disease. Recent landmark findings are addressed here.

Degradation of the extracellular matrix components by bacterial-derived metalloproteases: implications for inflammatory bowel diseases.

Background: Proteolytic degradation of the extracellular matrix, a feature of mucosal homeostasis and tissue renewal, also contributes to the complications of intestinal inflammation. Whether this proteolytic activity is entirely host-derived, or, in part, produced by the gut microbiota, is unknown.

Methods: We screened the bacterial colonies for gelatinolytic activity from fecal samples of 20 healthy controls, 23 patients with ulcerative colitis, and 18 with Crohn's disease (CD).

Technical Advance: Function and efficacy of an {alpha}4-integrin antagonist using bioluminescence imaging to detect leukocyte trafficking in murine experimental colitis.

Leukocyte trafficking is a therapeutic target in IBD. The integrins α₄β and α₄β₁ regulate leukocyte migration into tissues and lymphoid organs. Current strategies rely on biologics, such as mAb, to inhibit leukocyte recruitment.

Down-regulation of p38 mitogen-activated protein kinase activation and proinflammatory cytokine production by mitogen-activated protein kinase inhibitors in inflammatory bowel disease.

Crohn's disease and ulcerative colitis are inflammatory bowel diseases (IBD) characterized by chronic relapsing mucosal inflammation. Tumour necrosis factor (TNF)-α, a known agonist of the mitogen-activated protein kinase (MAPK) pathway, is a key cytokine in this process. We aimed first to determine whether p38 MAPK is activated in IBD inflamed mucosa, and then studied the effect of four different p38α inhibitory compounds on MAPK phosphorylation and secretion of proinflammatory cytokines by IBD lamina propria mononuclear cells (LPMCs) and organ culture biopsies.

Use of bioluminescence imaging to track neutrophil migration and its inhibition in experimental colitis.

Inflammatory bowel disease (IBD) is associated with neutrophil infiltration into the mucosa and crypt abscesses. The chemokine interleukin (IL)-8 [murine homologues (KC) and macrophage inflammatory protein (MIP)-2] and its receptor CXCR2 are required for neutrophil recruitment; thus, blocking this engagement is a potential therapeutic strategy. In the present study, we developed a preclinical model of neutrophil migration suitable for investigating the biology of and testing new drugs that target neutrophil trafficking.

Discovery of Dinaciclib (SCH 727965): A Potent and Selective Inhibitor of Cyclin-Dependent Kinases.

Inhibition of cyclin-dependent kinases (CDKs) has emerged as an attractive strategy for the development of novel oncology therapeutics. Herein is described the utilization of an in vivo screening approach with integrated efficacy and tolerability parameters to identify candidate CDK inhibitors with a suitable balance of activity and tolerability. This approach has resulted in the identification of SCH 727965, a potent and selective CDK inhibitor that is currently undergoing clinical evaluation.