Typing of feces-derived Candida albicans strains using a novel seven-locus microsatellite panel reveals associations with yeast phenotype in individuals with inflammatory bowel disease.

Inflammatory diseases of the human gastrointestinal tract are affected by the microbes that reside in the mucosal surfaces. Patients with inflammatory bowel diseases (IBD) have altered bacterial and fungal intestinal compositions, including higher levels of fecal Candida yeasts. Ongoing research indicates that genetic and phenotypic diversity of Candida albicans may be linked with disease severity.

Carboxylesterase-1 Assisted Targeting of HDAC Inhibitors to Mononuclear Myeloid Cells in Inflammatory Bowel Disease.

Background And Aims: Histone deacetylase inhibitors [HDACi] exert potent anti-inflammatory effects. Because of the ubiquitous expression of HDACs, clinical utility of HDACi is limited by off-target effects. Esterase-sensitive motif [ESM] technology aims to deliver ESM-conjugated compounds to human mononuclear myeloid cells, based on their expression of carboxylesterase 1 [CES1].

Dietary Curdlan Enhances Bifidobacteria and Reduces Intestinal Inflammation in Mice.

β-glucan consumption is known for its beneficial health effects, but the mode of action is unclear. While humans and mice lack the required enzymes to digest β-glucans, certain intestinal microbes can digest β-glucans, triggering gut microbial changes. Curdlan, a particulate β-glucan isolated from , is used as a food additive.

Exclusive enteral nutrition mediates gut microbial and metabolic changes that are associated with remission in children with Crohn's disease.

A nutritional intervention, exclusive enteral nutrition (EEN) can induce remission in patients with pediatric Crohn's disease (CD). We characterized changes in the fecal microbiota and metabolome to identify the mechanism of EEN. Feces of 43 children were collected prior, during and after EEN.

Miltefosine treatment reduces visceral hypersensitivity in a rat model for irritable bowel syndrome via multiple mechanisms.

Irritable bowel syndrome (IBS) is a heterogenic, functional gastrointestinal disorder of the gut-brain axis characterized by altered bowel habit and abdominal pain. Preclinical and clinical results suggested that, in part of these patients, pain may result from fungal induced release of mast cell derived histamine, subsequent activation of sensory afferent expressed histamine-1 receptors and related sensitization of the nociceptive transient reporter potential channel V1 (TRPV1)-ion channel. TRPV1 gating properties are regulated in lipid rafts.

Intestinal Fungal Dysbiosis Is Associated With Visceral Hypersensitivity in Patients With Irritable Bowel Syndrome and Rats.

Background & Aims: Visceral hypersensitivity is one feature of irritable bowel syndrome (IBS). Bacterial dysbiosis might be involved in the activation of nociceptive sensory pathways, but there have been few studies of the role of the mycobiome (the fungal microbiome) in the development of IBS. We analyzed intestinal mycobiomes of patients with IBS and a rat model of visceral hypersensitivity.

Effects of Dietary Plant Sterols and Stanol Esters with Low- and High-Fat Diets in Chronic and Acute Models for Experimental Colitis.

In this study, we evaluated the effects of dietary plant sterols and stanols as their fatty acid esters on the development of experimental colitis. The effects were studied both in high- and low-fat diet conditions in two models, one acute and another chronic model of experimental colitis that resembles gene expression in human inflammatory bowel disease (IBD). In the first experiments in the high fat diet (HFD), we did not observe a beneficial effect of the addition of plant sterols and stanols on the development of acute dextran sulphate sodium (DSS) colitis.

Orally delivered β-glucans aggravate dextran sulfate sodium (DSS)-induced intestinal inflammation.

β-Glucans have beneficial health effects due to their immune modulatory properties. Oral administration of β-glucans affects tumour growth, microbial infection, sepsis, and wound healing. We hypothesized that pre-treatment with orally delivered soluble and particulate β-glucans could ameliorate the development of aggravate dextran sulfate sodium (DSS) induced intestinal inflammation.

Dectin-1 deficiency does not affect atherosclerosis development in mice.

Objective: Recent data suggest the involvement of dectin-1 in atherosclerosis through regulation of local reactive oxygen species production. The aim of the current study was to assess the effect of dectin-1 deficiency on atherosclerotic plaque development.

Methods: Using immunohistochemistry dectin-1 expression was observed on foamy macrophages in atherosclerotic lesions in mice.

Human type 1 innate lymphoid cells accumulate in inflamed mucosal tissues.

Innate lymphoid cells (ILCs) are effectors of innate immunity and regulators of tissue modeling. Recently identified ILC populations have a cytokine expression pattern that resembles that of the helper T cell subsets T(H)2, T(H)17 and T(H)22. Here we describe a distinct ILC subset similar to T(H)1 cells, which we call 'ILC1'.

Genetic deletion of dectin-1 does not affect the course of murine experimental colitis.

Background: It is believed that inflammatory bowel diseases (IBD) result from an imbalance in the intestinal immune response towards the luminal microbiome. Dectin-1 is a widely expressed pattern recognition receptor that recognizes fungi and upon recognition it mediates cytokine responses and skewing of the adaptive immune system. Hence, dectin-1 may be involved in the pathogenesis of IBD.

Fungal recognition enhances mannose receptor shedding through dectin-1 engagement.

The mannose receptor (MR) is an endocytic type I membrane molecule with a broad ligand specificity that is involved in both hemostasis and pathogen recognition. Membrane-anchored MR is cleaved by a metalloproteinase into functional soluble MR (sMR) composed of the extracellular domains of intact MR. Although sMR production was initially considered a constitutive process, enhanced MR shedding has been observed in response to the fungal pathogen Pneumocystis carinii.

The role of macrophages in inflammatory bowel diseases.

The small and large intestine contain the largest number of macrophages in the body and these cells are strategically located directly underneath the epithelial layer, enabling them to sample the lumen. Such intestinal macrophages have a different phenotype from other tissue macrophages in that they ingest and may kill microbes but they do not mediate strong pro-inflammatory responses upon microbial recognition. These properties are essential for maintaining a healthy intestine.

Actin and phosphoinositide recruitment to fully formed Candida albicans phagosomes in mouse macrophages.

Candida albicans is a dimorphic yeast that enters macrophages (Mphi) via the beta-glucan receptor dectin-1. Phagocytosis of C. albicans is characterized by actin polymerization, Syk kinase activation and rapid acquisition of phagolysosomal markers.

Stage-specific sampling by pattern recognition receptors during Candida albicans phagocytosis.

Candida albicans is a medically important pathogen, and recognition by innate immune cells is critical for its clearance. Although a number of pattern recognition receptors have been shown to be involved in recognition and phagocytosis of this fungus, the relative role of these receptors has not been formally examined. In this paper, we have investigated the contribution of the mannose receptor, Dectin-1, and complement receptor 3; and we have demonstrated that Dectin-1 is the main non-opsonic receptor involved in fungal uptake.

Ligation of the adhesion-GPCR EMR2 regulates human neutrophil function.

At present, approximately 150 different members of the adhesion-G protein-coupled receptor (GPCR) family have been identified in metazoans. Surprisingly, very little is known about their function, although they all possess large extracellular domains coupled to a seven-transmembrane domain, suggesting a potential role in cell adhesion and signaling. Here, we demonstrate how the human-restricted adhesion-GPCR, EMR2 (epidermal growth factor-like module-containing mucin-like hormone receptor), regulates neutrophil responses by potentiating the effects of a number of proinflammatory mediators and show that the transmembrane region is critical for adhesion-GPCR function.

Impaired phagocytic mechanism in annexin 1 null macrophages.

The role of the anti-inflammatory protein annexin-A1 (Anx-A1) in the phagocytic process has been investigated using a murine bone marrow culture-derived macrophage model from Anx-A1(+/+) and Anx-A1(-/-) mice. Macrophages prepared from Anx-A1(-/-) mice exhibited a reduced ingestion of zymosan, Neisseria meningitidis or sheep red blood cells, when compared to Anx-A1(+/+) cells and in the case of zymosan this effect was also mirrored by a reduced clearance in vivo when particles were injected into the peritoneal cavity of Anx-A1(-/-) mice. The ablation of the Anx-A1 gene did not cause any apparent cytoskeletal defects associated with particle ingestion but the cell surface expression of the key adhesion molecule CD11b was depressed in the Anx-A1(-/-) cells providing a possible explanation for the attenuated phagocytic potential of these cells.

Expression of functionally different dectin-1 isoforms by murine macrophages.

Dectin-1 is a specific receptor for beta-glucans and a major receptor for fungal particles on macrophages (Mphi). It is a type II membrane receptor that has a C-terminal, NK-like, C-type lectin-like domain separated from the cell membrane by a short stalk region and a cytoplasmic immunoreceptor tyrosine-based activation-like motif. We observed functional differences in dectin-1-dependent recognition of fungal particles by Mphi from different mouse strains.

Uptake of branched polypeptides with poly[L-lys] backbone by bone-marrow culture-derived murine macrophages: the role of the class a scavenger receptor.

Selective delivery of antiparasitic or antibacterial drugs into infected macrophages could be a promising approach for improved therapies. Methotrexate conjugate with branched chain polypeptides exhibited pronounced anti-Leishmania activity in vitro and in vivo as reported here earlier. To identify structural requirements for efficient uptake of branched polypeptides, we have studied murine bone marrow culture-derived macrophages (BMMphi) from 129/ICR mice.

Dectin-2 is predominantly myeloid restricted and exhibits unique activation-dependent expression on maturing inflammatory monocytes elicited in vivo.

Dectin-2 is a recently described dendritic-cell-associated receptor, suggested to be involved in the initiation and maintenance of UV-induced tolerance. To understand the physiological relevance of the proposed functions of this C-type lectin-like receptor, we have generated monoclonal antibodies against its extracellular domain and performed a detailed study of its expression. In naive mice, Dectin-2 has a novel distribution pattern compared with other myeloid markers, but is predominantly expressed by a wide variety of tissue macrophages.