In-hospital Mortality Following Suicidal Burns: A Propensity Score-Matched Analysis.

We carried out a retrospective single-center study and analyzed all patients who have been admitted to our intensive care burn unit following suicide attempt and accidental burns within 14 years. Clinical and demographic parameters were collected and evaluated. Propensity score matching was performed in order to minimize the confounding effect of the parameters age, sex, total body surface area (TBSA), and the presence of full-thickness burns and inhalation injury. 45 burn patients following attempted suicide by burning and 1266 patients following accidental burn injury were admitted. Patients with suicidal burn injuries were significantly younger and showed significantly higher burn severity, reflected by larger TBSA affected, higher incidence of full-thickness burns and inhalation injury. They also experienced increased hospital length of stay (LOS) and longer ventilation durations. Their in-hospital mortality was significantly higher. Following propensity score matching in 42 case pairs, no differences were detected with regard to in-hospital mortality, hospital LOS, duration of mechanical ventilation, and frequency of surgical interventions. Attempted suicide by burning is associated with overall worse outcomes and higher mortality rates. Following propensity score matching, significant differences in outcomes were no longer detectable. Given the comparable survival probability compared to accidentally burned patients, life-sustaining treatment should not be withheld in burn patients following suicide attempt.

Outcomes following burn injury in intensive care patients with major psychiatric disorders.

AIMS: Patients with psychiatric comorbidity have been shown to experience high rates of burn injury. Burn epidemiology, etiology, and outcomes have been sparsely documented for patients with major psychiatric disorders. The aim of this study was to analyze the epidemiologic characteristics and outcomes in intensive care burn patients with pre-existing and acute major psychiatric disorders . METHODS: A retrospective study was performed including intensive care burn patients admitted between March 2007 and December 2020. Demographic, clinical and epidemiological data were collected and analyzed. Major psychiatric co-morbidities were collected according to ICD-9 and ICD-10 classifications. Patients were stratified according to F-diagnoses. RESULTS: A total of 1325 patients were included. 16.6 % of all patients had one or more major psychiatric disorders- 9.3 % with anxiety, dissociative, stress-related, somatoform and other nonpsychotic mental disorders, 9.2 % with mood (affective) disorders, 3.5 % with schizophrenia and other non-mood psychotic disorders, and 1.8 % with disorders of adult personality and behavior. Patients with major psychiatric disorders presented with significantly higher burn severity, reflected by higher abbreviated burn severity index (ABSI) scores (5.9 vs. 5.3, p < 0.001) and larger total body surface area (TBSA) affected (15.9 vs. 12.5 %, p = 0.002). Burned TBSA ≥ 30 and inhalation injuries were observed more frequently in patients with MDP, however without statistical significance. They also experienced prolonged hospital length-of-stay (LOS) (25.5 vs. 16.3 days, p < 0.001), prolonged intensive care unit LOS (14.8 vs. 7.7 days, p < 0.001), underwent surgical interventions (3.5 vs. 2.3, p < 0.001) and mechanical ventilation more frequently (34.1 % vs. 16.5 %, p = 0.43) and had significantly longer ventilation durations (73.5 vs. 31.2 h, p = 0.002). Mortality rates were lower compared to patients without major psychiatric disorders (5.9 vs. 8.1, p < 0.001). CONCLUSIONS: The prevalence of major psychiatric disorders in burn patients is considerably high. Patients with psychiatric comorbidities were found to have greater burn severity, prolonged total hospital and ICU LOS, underwent surgical interventions and mechanical ventilation more frequently and had prolonged ventilation duration. Our results highlight the importance of identifying burn patients with major psychiatric disorders who may necessitate additional resources and require extensive inpatient psychiatric care and counseling.

Attempted Suicide by Burning: A Cross-sectional Analysis at a Regional Burn Center in Germany.

Attempted suicide by self-immolation or burning constitutes an uncommon form of attempted suicide in high income countries, presenting substantial challenges to burn units. The aim of this study was to analyze the epidemiologic characteristics and outcomes in intensive care burn patients treated for attempted suicide by burning. For this purpose, we examined intensive care burn patients admitted to a single major burn unit between March 2007 and December 2020. Demographic, clinical, epidemiological, and mortality data were collected and analyzed. Major psychiatric comorbidities were evaluated according to ICD-9 and ICD-10 classifications. A total of 1325 intensive care unit burn patients were included. Suicide by burning was attempted in 45 cases (3.4%). Attempted suicide victims presented with significantly higher burn severity, reflected by higher abbreviated burn severity index scores, and larger TBSA affected. Burned TBSA ≥30% and inhalation injuries were observed more frequently in suicidal patients. These patients also experienced prolonged hospital and intensive care unit length of stay, required surgical interventions and mechanical ventilation more frequently, and had significantly longer periods on ventilation, causing an overall higher mortality rate (24.4%). Psychiatric comorbidities were present in 75.6% of patients who attempted suicide. Despite the low prevalence, burn severity and mortality are considerably high in patients who attempted suicide by burning, presenting a significant challenge for healthcare providers. The majority of patients had a history of psychiatric disorder, highlighting the importance of identifying patients at high-risk who may profit from increased psychiatric intervention.

Epidemiology and outcome analysis of 1359 intensive care burn patients: A 14-year retrospective study in a major burn center.

AIMS: Globally, burn-related morbidity and mortality still remain high. In order to identify regional high-risk populations and to suggest appropriate prevention measure allocation, we aimed at analyzing epidemiological characteristics, etiology and outcomes of our 14-year experience with an intensive care unit (ICU) burn patient population. METHODS: A retrospective observational study was conducted including patients treated between March 2007 and December 2020 in our intensive care burn unit. Demographic, clinical and epidemiological data were collected and analyzed. RESULTS: A total of 1359 patients were included. 68% of the subjects were males and the largest age group affected entailed 45-64-year-old adults (34%). Regarding etiology, flame and contact burns were the most common in all age groups. Mean affected total body surface area (TBSA) was 13 ± 14.5% in all subjects. Most of the burns occurred domestically or during recreational activities. Mean hospital stay was 17.77 ± 19.7 days. The average mortality was 7.7%. The mortality rate showed an overall decreasing trend whilst burn severity remained consistent from 2007 to 2020. CONCLUSIONS: Despite consistent burn severity presentations of annual ICU admissions, burn injury mortality showed a decreasing trend, which was in part attributed to substantial progress in burn care and treatment and improved burn prevention awareness. Statistically significant age and gender differences could be detected with regard to burn etiology and seasonality, as well as outcomes, which highlight the importance of individualized primary prevention programs.

Ether lipid and sphingolipid expression patterns are estrogen receptor-dependently altered in breast cancer cells.

Identifying co-expression of lipid species is challenging, but indispensable to identify novel therapeutic targets for breast cancer treatment. Lipid metabolism is often dysregulated in cancer cells, and changes in lipid metabolism affect cellular processes such as proliferation, autophagy, and tumor development. In addition to mRNA analysis of sphingolipid metabolizing enzymes, we performed liquid chromatography time-of-flight mass spectrometry analysis in three breast cancer cell lines. These breast cancer cell lines differ in estrogen receptor and G-protein coupled estrogen receptor 1 status. Our data show that sphingolipids and non-sphingolipids are strongly increased in SKBr3 cells. SKBr3 cells are estrogen receptor negative and G-protein coupled estrogen receptor 1 positive. Treatment with G15, a G-protein coupled estrogen receptor 1 antagonist, abolishes the effect of increased sphingolipid and non-sphingolipid levels in SKBr3 cells. In particular, ether lipids are expressed at much higher levels in cancer compared to normal cells and are strongly increased in SKBr3 cells. Our analysis reveals that this is accompanied by increased sphingolipid levels such as ceramide, sphingadiene-ceramide and sphingomyelin. This shows the importance of focusing on more than one lipid class when investigating molecular mechanisms in breast cancer cells. Our analysis allows unbiased screening for different lipid classes leading to identification of co-expression patterns of lipids in the context of breast cancer. Co-expression of different lipid classes could influence tumorigenic potential of breast cancer cells. Identification of co-regulated lipid species is important to achieve improved breast cancer treatment outcome.

UGCG overexpression leads to increased glycolysis and increased oxidative phosphorylation of breast cancer cells.

The only enzyme in the glycosphingolipid (GSL) metabolic pathway, which produces glucosylceramide (GlcCer) de novo is UDP-glucose ceramide glucosyltransferase (UGCG). UGCG is linked to pro-cancerous processes such as multidrug resistance development and increased proliferation in several cancer types. Previously, we showed an UGCG-dependent glutamine metabolism adaption to nutrient-poor environment of breast cancer cells. This adaption includes reinforced oxidative stress response and fueling the tricarboxylic acid (TCA) cycle by increased glutamine oxidation. In the current study, we investigated glycolytic and oxidative metabolic phenotypes following UGCG overexpression (OE). UGCG overexpressing MCF-7 cells underwent a metabolic shift from quiescent/aerobic to energetic metabolism by increasing both glycolysis and oxidative glucose metabolism. The energetic metabolic phenotype was not associated with increased mitochondrial mass, however, markers of mitochondrial turnover were increased. UGCG OE altered sphingolipid composition of the endoplasmic reticulum (ER)/mitochondria fractions that may contribute to increased mitochondrial turnover and increased cell metabolism. Our data indicate that GSL are closely connected to cell energy metabolism and this finding might contribute to development of novel therapeutic strategies for cancer treatment.

UGCG influences glutamine metabolism of breast cancer cells.

UDP-glucose ceramide glucosyltransferase (UGCG) is the key enzyme in glycosphingolipid (GSL) metabolism by being the only enzyme that generates glucosylceramide (GlcCer) de novo. Increased UGCG synthesis is associated with pro-cancerous processes such as increased proliferation and multidrug resistance in several cancer types. We investigated the influence of UGCG overexpression on glutamine metabolism in breast cancer cells. We observed adapted glucose and glutamine uptake in a limited energy supply environment following UGCG overexpression. Glutamine is used for reinforced oxidative stress response shown by increased mRNA expression of glutamine metabolizing proteins such as glutathione-disulfide reductase (GSR) resulting in increased reduced glutathione (GSH) level. Augmented glutamine uptake is also used for fueling the tricarboxylic acid (TCA) cycle to maintain the proliferative advantage of UGCG overexpressing cells. Our data reveal a link between GSL and glutamine metabolism in breast cancer cells, which is to our knowledge a novel correlation in the field of sphingolipid research.

GPER1 influences cellular homeostasis and cytostatic drug resistance via influencing long chain ceramide synthesis in breast cancer cells.

The G protein-coupled estrogen receptor 1 (GPER1) is involved in the regulation of physiological processes such as cellular growth and proliferation, but also in pathophysiological processes such as tumor development. The role of GPER1 in breast cancer is contradictory. Therefore, we investigated the influence of GPER1 overexpression on cellular processes in MCF-7 breast cancer cells. GPER1 overexpression leads to a cell cycle arrest in the G1 phase, induction of autophagy and reduced proliferation. Reduced proliferation was accompanied by a reduced basal respiration and reduced glycolysis rate in GPER1 overexpressing cells. This is presumably ascribable to mitophagy induction following GPER1 overexpression. However, GPER1 overexpressing cells were less sensitive against doxorubicin as compared to control cells. In previous work we showed the effect of transient GPER1 overexpression on the synthesis of several ceramide synthases (CerS) thereby influencing the sphingolipid pathway. Therefore, we investigated CerS expression and sphingolipid level in stable GPER1 overexpressing and control cells. Stable GPER1 overexpression strongly reduced CerS4, CerS5 and CerS6 promoter activity and CerS5 and CerS6 mRNA expression, whereas CerS2 mRNA expression was upregulated. The GPER1 effect on CerS5 promoter is mediated by GSK-3ß signaling. In addition, other enzymes of the sphingolipid pathway were upregulated. Our study provides new insights into the role of GPER1 and the activated sphingolipid pathways and how GPER1 may influence cellular processes such as cancer cell survival following chemotherapy. Further studies are needed to investigate the molecular mechanisms leading to these cellular effects. Finding new therapeutic targets for modulating specifically GPER1 in breast tumors may improve endocrine breast cancer therapy.

Access to new highly potent antileukemia, antiviral and antimalarial agents via hybridization of natural products (homo)egonol, thymoquinone and artemisinin.

Hybridization of natural products has high potential to further improve their activities and may produce synergistic effects between linked pharmacophores. Here we report synthesis of nine new hybrids of natural products egonol, homoegonol, thymoquinone and artemisinin and evaluation of their activities against P. falciparum 3D7 parasites, human cytomegalovirus, sensitive and multidrug-resistant human leukemia cells. Most of the new hybrids exceed their parent compounds in antimalarial, antiviral and antileukemia activities and in some cases show higher in vitro efficacy than clinically used reference drugs chloroquine, ganciclovir and doxorubicin. Combined, our findings stress the high potency of these hybrids and encourages further use of the hybridization concept in applied pharmacological research.

Treatment of Multidrug-Resistant Leukemia Cells by Novel Artemisinin-, Egonol-, and Thymoquinone-Derived Hybrid Compounds.

Two major obstacles for successful cancer treatment are the toxicity of cytostatics and the development of drug resistance in cancer cells during chemotherapy. Acquired or intrinsic drug resistance is responsible for almost 90% of treatment failure. For this reason, there is an urgent need for new anticancer drugs with improved efficacy against cancer cells, and with less toxicity on normal cells. There are impressive examples demonstrating the success of natural plant compounds to fight cancer, such as Vinca alkaloids, taxanes, and anthracyclines. Artesunic acid (ARTA), a drug for malaria treatment, also exerts cytotoxic activity towards cancer cells. Multidrug resistance often results from drug efflux pumps (ABC-transporters) that reduce intracellular drug levels. Hence, it would be interesting to know, whether ARTA could overcome drug resistance of tumor cells, and in what way ABC-transporters are involved. Different derivatives showing improved features concerning cytotoxicity and pharmacokinetic behavior have been developed. Considering both drug sensitivity and resistance, we chose a sensitive and a doxorubicin-resistant leukemia cell line and determined the killing effect of ARTA on these cells. Molecular docking and doxorubicin efflux assays were performed to investigate the interaction of the derivatives with P-glycoprotein. Using single-cell gel electrophoresis (alkaline comet assay), we showed that the derivatives of ARTA induce DNA breakage and accordingly programmed cell death, which represents a promising strategy in cancer treatment. ARTA activated apoptosis in cancer cells by the iron-mediated generation of reactive oxygen species (ROS). In conclusion, ARTA derivatives may bear the potential to be further developed as anticancer drugs.

UDP-glucose ceramide glucosyltransferase activates AKT, promoted proliferation, and doxorubicin resistance in breast cancer cells.

The UDP-glucose ceramide glucosyltransferase (UGCG) is a key enzyme in the synthesis of glycosylated sphingolipids, since this enzyme generates the precursor for all complex glycosphingolipids (GSL), the GlcCer. The UGCG has been associated with several cancer-related processes such as maintaining cancer stem cell properties or multidrug resistance induction. The precise mechanisms underlying these processes are unknown. Here, we investigated the molecular mechanisms occurring after UGCG overexpression in breast cancer cells. We observed alterations of several cellular properties such as morphological changes, which enhanced proliferation and doxorubicin resistance in UGCG overexpressing MCF-7 cells. These cellular effects seem to be mediated by an altered composition of glycosphingolipid-enriched microdomains (GEMs), especially an accumulation of globotriaosylceramide (Gb3) and glucosylceramide (GlcCer), which leads to an activation of Akt and ERK1/2. The induction of the Akt and ERK1/2 signaling pathway results in an increased gene expression of multidrug resistance protein 1 (MDR1) and anti-apoptotic genes and a decrease of pro-apoptotic gene expression. Inhibition of the protein kinase C (PKC) and phosphoinositide 3 kinase (PI3K) reduced MDR1 gene expression. This study discloses how changes in UGCG expression impact several cellular signaling pathways in breast cancer cells resulting in enhanced proliferation and multidrug resistance.

The UDP-glucose ceramide glycosyltransferase (UGCG) and the link to multidrug resistance protein 1 (MDR1).

The UDP-glucose ceramide glycosyltransferase (UGCG) is a key enzyme in the sphingolipid metabolism by generating glucosylceramide (GlcCer), the precursor for all glycosphingolipids (GSL), which are essential for proper cell function. Interestingly, the UGCG is also overexpressed in several cancer types and correlates with multidrug resistance protein 1 (MDR1) gene expression. This membrane protein is responsible for efflux of toxic substances and protects cancer cells from cell damage through chemotherapeutic agents. Studies showed a connection between UGCG and MDR1 overexpression and multidrug resistance development, but the precise underlying mechanisms are unknown. Here, we give an overview about the UGCG and its connection to MDR1 in multidrug resistant cells. Furthermore, we focus on UGCG transcriptional regulation, the impact of UGCG on cellular signaling pathways and the effect of UGCG and MDR1 on the lipid composition of membranes and how this could influence multidrug resistance development. To our knowledge, this is the first review presenting an overview about UGCG with focus on the relationship to MDR1 in the process of multidrug resistance development.

Highly potent artemisinin-derived dimers and trimers: Synthesis and evaluation of their antimalarial, antileukemia and antiviral activities.

New pharmaceutically active compounds can be obtained by modification of existing drugs to access more effective agents in the wake of drug resistance amongst others. To achieve this goal the concept of hybridization was established during the last decade. We employed this concept by coupling two artemisinin-derived precursors to obtain dimers or trimers with increased in vitro activity against Plasmodiumfalciparum 3D7 strain, leukemia cells (CCRF-CEM and multidrug-resistant subline CEM/ADR5000) and human cytomegalovirus (HCMV). Dimer 4 (IC50 of 2.6 nM) possess superior antimalarial activity compared with its parent compound artesunic acid(3) (IC50 of 9.0 nM). Dimer5 and trimers6 and 7 display superior potency against both leukemia cell lines (IC50 up to 0.002 µM for CCRF-CEM and IC50 up to 0.20 µM for CEM/ADR5000) and are even more active than clinically used doxorubicin (IC50 1.61 µM for CEM/ADR5000). With respect to anti-HCMV activity, trimer6 is the most efficient hybrid (IC50 0.04 µM) outperforming ganciclovir (IC50 2.6 µM), dihydroartemisinin(IC50 >10 µM) and artesunic acid (IC50 3.8 µM).

Maternal High-fat Diet Accelerates Development of Crohn's Disease-like Ileitis in TNFΔARE/WT Offspring.

BACKGROUND: Maternal high-fat diet (HFD) and obesity increases the risk of the offspring to develop inflammatory processes in various organs including the gut. We hypothesized that maternal diet-induced obesity programs the fetal gut towards inflammation in a mouse model of genetically-driven Crohn's disease (CD)-like ileitis. METHODS: TNF(WT/WT) and TNF(ΔARE/WT) dams were fed an experimental control diet (CTRLD; 13 kJ% fat) or HFD (48 kJ%). Offspring mice were fed CTRLD or HFD at 4 weeks of age. Metabolic characteristics and severity of CD-like ileitis was assessed in 8- and 12-week old WT and ARE offspring measuring tissue histopathology and markers of inflammation in the distal ileum as well as plasma cytokine and LPS levels. To study prenatal effects, we laser microdissected fetal intestinal epithelial cells at 17.5 days postconception and performed microarray-based global gene expression analysis. RESULTS: Maternal HFD significantly accelerated the severity of CD-like ileitis in HFD-fed ARE mice at early life stages associated with increased mucosal neutrophil infiltration, Il12p40 expression, and portal vein LPS levels. In contrast to WT mice, metabolic characteristics of ARE offspring were not affected by maternal HFD. Gene expression patterns in fetal intestinal epithelial cells of ARE mice remained largely unchanged under conditions of maternal diet-induced obesity suggesting that the positive association of intestinal inflammation, portal vein endotoxemia, and plasma TNF levels is independent of prenatal conditioning of the gut epithelium. CONCLUSIONS: Maternal HFD promotes the early onset of severe CD-like ileitis in genetically susceptible offspring independent of metabolic alterations.

Cytotoxicity of cardiotonic steroids in sensitive and multidrug-resistant leukemia cells and the link with Na(+)/K(+)-ATPase.

Cardiotonic steroids have long been in clinical use for treatment of heart failure and are now emerging as promising agents in various diseases, especially cancer. Their main target is Na(+)/K(+)-ATPase, a membrane protein involved in cellular ion homeostasis. Na(+)/K(+)-ATPase has been implicated in cancer biology by affecting several cellular events and signaling pathways in both sensitive and drug-resistant cancer cells. Hence, we investigated the cytotoxic activities of 66 cardiotonic steroids and cardiotonic steroid derivatives in sensitive CCRF-CEM and multidrug-resistant CEM/ADR5000 leukemia cells. Data were then subjected to quantitative structure-activity relationship analysis (QSAR) and molecular docking into Na(+)/K(+)-ATPase, which both indicated a possible differential expression of the pump in the mentioned cell lines. This finding was confirmed by western blotting, intracellular potassium labeling and next generation sequencing which showed that Na(+)/K(+)-ATPase was less expressed in multidrug-resistant than in sensitive cells.

Properties of myenteric neurones and mucosal functions in the distal colon of diet-induced obese mice.

Colonic transit and mucosal integrity are believed to be impaired in obesity. However, a comprehensive assessment of altered colonic functions, inflammatory changes and neuronal signalling of obese animals is missing. In mice, we studied the impact of diet-induced obesity (DIO) on: (i) in vivo colonic transit; (ii) signalling in the myenteric plexus by recording responses to nicotine and 2-methyl-5-hydroxytryptamine (2-methyl-5-HT), together with the expression of tryptophan hydroxylase (TPH) 1 and 2, serotonin reuptake transporter, choline acetyltransferase and the paired box gene 4; and (iii) expression of proinflammatory cytokines, epithelial permeability and density of macrophages, mast cells and enterochromaffin cells. Compared with controls, colon transit and neuronal sensitivity to nicotine and 2-methyl-5-HT were enhanced in DIO mice fed for 12 weeks. This was associated with increased tissue acetylcholine and 5-hydroxytryptamine (5-HT) content, and increased expression of TPH1 and TPH2. In DIO mice, upregulation of proinflammatory cytokines was found in fat tissue, but not in the gut wall. Accordingly, mucosal permeability or integrity was unaltered without signs of immune cell infiltration in the gut wall. Body weight showed positive correlations with adipocyte markers, tissue levels of 5-HT and acetylcholine, and the degree of neuronal sensitization. DIO mice fed for 4 weeks showed no neuronal sensitization, had no signs of gut wall inflammation and showed a smaller increase in leptin, interleukin-6 and monocyte chemoattractant protein 1 expression in fat tissue. DIO is associated with faster colonic transit and impacts on acetylcholine and 5-HT metabolism with enhanced responsiveness of enteric neurones to both mediators after 12 weeks of feeding. Our study demonstrates neuronal plasticity in DIO prior to the development of a pathological histology or abnormal mucosal functions. This questions the common assumption that increased mucosal inflammation and permeability initiate functional disorders in obesity.

High fat diet accelerates pathogenesis of murine Crohn's disease-like ileitis independently of obesity.

BACKGROUND: Obesity has been associated with a more severe disease course in inflammatory bowel disease (IBD) and epidemiological data identified dietary fats but not obesity as risk factors for the development of IBD. Crohn's disease is one of the two major IBD phenotypes and mostly affects the terminal ileum. Despite recent observations that high fat diets (HFD) impair intestinal barrier functions and drive pathobiont selection relevant for chronic inflammation in the colon, mechanisms of high fat diets in the pathogenesis of Crohn's disease are not known. The aim of this study was to characterize the effect of HFD on the development of chronic ileal inflammation in a murine model of Crohn's disease-like ileitis. METHODS: TNF(ΔARE/WT) mice and wildtype C57BL/6 littermates were fed a HFD compared to control diet for different durations. Intestinal pathology and metabolic parameters (glucose tolerance, mesenteric tissue characteristics) were assessed. Intestinal barrier integrity was characterized at different levels including polyethylene glycol (PEG) translocation, endotoxin in portal vein plasma and cellular markers of barrier function. Inflammatory activation of epithelial cells as well as immune cell infiltration into ileal tissue were determined and related to luminal factors. RESULTS: HFD aggravated ileal inflammation but did not induce significant overweight or typical metabolic disorders in TNF(ΔARE/WT). Expression of the tight junction protein Occludin was markedly reduced in the ileal epithelium of HFD mice independently of inflammation, and translocation of endotoxin was increased. Epithelial cells showed enhanced expression of inflammation-related activation markers, along with enhanced luminal factors-driven recruitment of dendritic cells and Th17-biased lymphocyte infiltration into the lamina propria. CONCLUSIONS: HFD feeding, independently of obesity, accelerated disease onset of small intestinal inflammation in Crohn's disease-relevant mouse model through mechanisms that involve increased intestinal permeability and altered luminal factors, leading to enhanced dendritic cell recruitment and promoted Th17 immune responses.

Semisynthetic diet ameliorates Crohn's disease-like ileitis in TNFΔARE/WT mice through antigen-independent mechanisms of gluten.

BACKGROUND: Enteral nutrition is used to treat a subset of patients with inflammatory bowel diseases. Because dietary factors may contribute to an aggressive immune response toward the intestinal microbiota in the disease susceptible host, we used TNFΔARE/WT mice to study the therapeutic effect of a semisynthetic experimental diet in the pathogenesis of Crohn's disease (CD)-like inflammation in the ileum. METHODS: TNFΔARE/WT mice were fed chow and experimental diets partially fortified with gluten in a dose and time-dependent manner. Histopathology, markers of inflammation, intraepithelial lymphocytes phenotypes, and antigen-specific reactivation of CD4⁺ T cells were determined. RESULTS: TNFΔARE/WT mice being transferred to an experimental diet with 7 but not with 10 or 14 weeks of age were protected from development of Crohn's disease-like ileitis. Although disease-related CD8αß⁺ intraepithelial lymphocytes were increased irrespective of dietary intervention, the protective effect of experimental diet was associated with decreased expression of inflammation markers in ileal tissues. In addition, CD4⁺ T-cell reactivation in bacterial antigen-primed dendritic cell cocultures was not altered between semisynthetic and chow diet-fed TNFΔARE/WT mice, suggesting bacteria-independent mechanisms. Most importantly, gluten-fortified experimental diet induced chronic ileitis in TNFΔARE/WT mice, despite the fact that gluten-derived peptides failed to induce CD4⁺ T-cell activation. Reduced occludin expression levels suggest a negative role of gluten-fortified experimental diet on intestinal barrier integrity. CONCLUSIONS: Crohn's disease-like ileitis can be prevented at early stages of disease development using a semisynthetic experimental diet. Gluten was identified as antigen-independent dietary factor relevant for the induction of chronic inflammation in the small intestine of TNFΔARE/WT mice.

Nutrigenomics and nutrigenetics in inflammatory bowel diseases.

Inflammatory bowel diseases (IBD) including ulcerative colitis and Crohn's disease are chronically relapsing, immune-mediated disorders of the gastrointestinal tract. A major challenge in the treatment of IBD is the heterogenous nature of these pathologies. Both, ulcerative colitis and Crohn's disease are of multifactorial etiology and feature a complex interaction of host genetic susceptibility and environmental factors such as diet and gut microbiota. Genome-wide association studies identified disease-relevant single-nucleotide polymorphisms in approximately 100 genes, but at the same time twin studies also clearly indicated a strong environmental impact in disease development. However, attempts to link dietary factors to the risk of developing IBD, based on epidemiological observations showed controversial outcomes. Yet, emerging high-throughput technologies implying complete biological systems might allow taking nutrient-gene interactions into account for a better classification of patient subsets in the future. In this context, 2 new scientific fields, "nutrigenetics" and "nutrigenomics" have been established. "Nutrigenetics," studying the effect of genetic variations on nutrient-gene interactions and "Nutrigenomics," describing the impact of nutrition on physiology and health status on the level of gene transcription, protein expression, and metabolism. It is hoped that the integration of both research areas will promote the understanding of the complex gene-environment interaction in IBD etiology and in the long-term will lead to personalized nutrition for disease prevention and treatment. This review briefly summarizes data on the impact of nutrients on intestinal inflammation, highlights nutrient-gene interactions, and addresses the potential of applying "omic" technologies in the context of IBD.

Metabolic phenotyping of the Crohn's disease-like IBD etiopathology in the TNF(ΔARE/WT) mouse model.

The underlying biochemical consequences of inflammatory bowel disease (IBD) on the systemic and gastrointestinal metabolism have not yet been fully elucidated but could help to better understand the disease pathogenesis and to identify tissue-specific markers associated with the different disease stages. Here, we applied a metabonomic approach to monitor metabolic events associated with the gradual development of Crohn's disease (CD)-like ileitis in the TNF(ΔARE/WT) mouse model. Metabolic profiles of different intestinal compartments from the age of 4 up to 24 weeks were generated by combining proton nuclear magnetic resonance ((1)H NMR) spectroscopy and liquid chromatography-mass spectrometry (LC-MS). From 8 weeks onward, mice developed CD similar to the immune and tissue-related phenotype of human CD with ileal involvement, including ileal histological abnormalities, reduced fat mass and body weight, as well as hallmarks of malabsorption with higher energy wasting. The metabonomic approach highlighted shifts in the intestinal lipid metabolism concomitant to the histological onset of inflammation. Moreover, the advanced disease status was characterized by a significantly altered metabolism of cholesterol, triglycerides, phospholipids, plasmalogens, and sphingomyelins in the inflamed tissue (ileum) and the adjacent intestinal parts (proximal colon). These results describe different biological processes associated with the disease onset, including modifications of the general cell membrane composition, alteration of energy homeostasis, and finally the generation of inflammatory lipid mediators. Taken together, this provides novel insights into IBD-related alterations of specific lipid-dependant processes during inflammatory states.