The two faces of reactive oxygen species (ROS) in adipocyte function and dysfunction.

White adipose tissue (WAT) is actively involved in the regulation of whole-body energy homeostasis via storage/release of lipids and adipokine secretion. Current research links WAT dysfunction to the development of metabolic syndrome (MetS) and type 2 diabetes (T2D). The expansion of WAT during oversupply of nutrients prevents ectopic fat accumulation and requires proper preadipocyte-to-adipocyte differentiation. An assumed link between excess levels of reactive oxygen species (ROS), WAT dysfunction and T2D has been discussed controversially. While oxidative stress conditions have conclusively been detected in WAT of T2D patients and related animal models, clinical trials with antioxidants failed to prevent T2D or to improve glucose homeostasis. Furthermore, animal studies yielded inconsistent results regarding the role of oxidative stress in the development of diabetes. Here, we discuss the contribution of ROS to the (patho)physiology of adipocyte function and differentiation, with particular emphasis on sources and nutritional modulators of adipocyte ROS and their functions in signaling mechanisms controlling adipogenesis and functions of mature fat cells. We propose a concept of ROS balance that is required for normal functioning of WAT. We explain how both excessive and diminished levels of ROS, e.g. resulting from over supplementation with antioxidants, contribute to WAT dysfunction and subsequently insulin resistance.

Selenoproteins: Antioxidant selenoenzymes and beyond.

Adequate intake of the essential trace element and micronutrient selenium is thought to be beneficial for maintaining human health. Selenium may modulate a broad spectrum of key biological processes, including the cellular response to oxidative stress, redox signalling, cellular differentiation, the immune response, and protein folding. Biochemical and cellular effects of selenium are achieved through activities of selenocysteine-containing selenoproteins. This small yet essential group comprises proteins encoded by 25 genes in humans, e.g. oxidoreductases such as glutathione peroxidases (GPx) and thioredoxin reductases (TrxR), as well as the iodothyronine deiodinases (DIO) and the plasma selenium transport protein, selenoprotein P (SePP1). Synthetic selenoorganic compounds, including the GPx mimetic ebselen, have also been applied in biological systems in vitro and in vivo; antioxidant and anti-inflammatory actions of ebselen and its history as a drug candidate are summarised here. Furthermore, we discuss several aspects of selenoprotein biochemistry, ranging from their well-known importance for cellular protection against oxidative damage to more recent data that link selenoprotein expression/activity to enterocyte and adipocyte differentiation and function and to (dys)regulation of insulin action and secretion.

Peroxynitrite: From interception to signaling.

Peroxynitrite is a strong oxidant and nitrating species that mediates certain biological effects of superoxide and nitrogen monoxide. These biological effects include oxidative damage to proteins as well as the formation of 3-nitrotyrosyl moieties in proteins. As a consequence, such proteins may lose their activity, gain altered function, or become prone to proteolytic degradation - resulting in modulation of cellular protein turnover and in the modulation of signaling cascades. In analogy to hydrogen peroxide, peroxynitrite may be scavenged by selenoproteins like glutathione peroxidase-1 (GPx-1) or by selenocompounds with a GPx-like activity, such as ebselen; in further analogy to H2O2, peroxiredoxins have also been established as contributors to peroxynitrite reduction. This review covers three aspects of peroxynitrite biochemistry, (i) the interaction of selenocompounds/-proteins with peroxynitrite, (ii) peroxynitrite-induced modulation of cellular proteolysis, and (iii) peroxynitrite-induced modulation of cellular signaling.

Intestinal selenoprotein P in epithelial cells and in plasma cells.

The micronutrient selenium and selenium-containing selenoproteins are involved in prevention of inflammation and carcinogenesis in the gut. Selenoprotein P (Sepp1), the plasma selenium transport protein, is secreted primarily from hepatocytes, but Sepp1 mRNA is also abundant in the intestine. By immunofluorescence analysis, we show that Sepp1 levels in epithelial cells of the rat jejunum increase along the crypt-to-villus axis. A different Sepp1 distribution pattern was observed in the rat colon, where the epithelial cells located at the base and at the top of the crypts were similarly positive for Sepp1. In addition, we found pronounced Sepp1 immunoreactivity in CD138-positive plasma cells scattered within the lamina propria of the colon. This hitherto unrecognized presence in terminally differentiated B-cells was corroborated by detection of Sepp1 in plasma cells residing in the rat spleen. Following supplementation with dietary selenium compounds, polarized intestinal epithelial Caco-2 cells secreted Sepp1 into the culture medium across the basolateral membrane. Our data suggest that Sepp1 secreted from epithelial cells may support the intestinal immune system by providing immune cells (including plasma cells) with selenium for the biosynthesis of endogenous selenoproteins.

Exploring substrate-microbe interactions: a metabiotic approach toward developing targeted synbiotic compositions.

Gut microbiota is an important modulator of human health and contributes to high inter-individual variation in response to food and pharmaceutical ingredients. The clinical outcomes of interventions with prebiotics, probiotics, and synbiotics have been mixed and often unpredictable, arguing for novel approaches for developing microbiome-targeted therapeutics. Here, we review how the gut microbiota determines the fate of and individual responses to dietary and xenobiotic compounds via its immense metabolic potential. We highlight that microbial metabolites play a crucial role as targetable mediators in the microbiota-host health relationship. With this in mind, we expand the concept of synbiotics beyond prebiotics' role in facilitating growth and engraftment of probiotics, by focusing on microbial metabolism as a vital mode of action thereof. Consequently, we discuss synbiotic compositions that enable the guided metabolism of dietary or co-formulated ingredients by specific microbes leading to target molecules with beneficial functions. A workflow to develop novel synbiotics is presented, including the selection of promising target metabolites (e.g. equol, urolithin A, spermidine, indole-3 derivatives), identification of suitable substrates and producer strains applying bioinformatic tools, gut models, and eventually human trials.In conclusion, we propose that discovering and enabling specific substrate-microbe interactions is a valuable strategy to rationally design synbiotics that could establish a new category of hybrid nutra-/pharmaceuticals.

Synbiotic Bacillus megaterium DSM 32963 and n-3 PUFA Salt Composition Elevates Pro-Resolving Lipid Mediator Levels in Healthy Subjects: A Randomized Controlled Study.

Beneficial health effects of omega-3 polyunsaturated fatty acids (n-3 PUFA) are partly attributed to specialized pro-resolving mediators (SPMs), which promote inflammation resolution. Strategies to improve n-3 PUFA conversion to SPMs may, therefore, be useful to treat or prevent chronic inflammatory disorders. Here, we explored a synbiotic strategy to increase circulating SPM precursor levels. Healthy participants (n = 72) received either SynΩ3 (250 mg eicosapentaenoic acid (EPA) plus docosahexaenoic acid (DHA) lysine salts; two billion CFU Bacillus megaterium; n = 23), placebo (n = 24), or fish oil (300 mg EPA plus DHA; N = 25) capsules daily for 28 days in a randomized, double-blind placebo-controlled parallel 3-group design. Biomarkers were assessed at baseline and after 2 and 28 days of intervention. The primary analysis involved the comparison between SynΩ3 and placebo. In addition, SynΩ3 was compared to fish oil. The synbiotic SynΩ3 comprising Bacillus megaterium DSM 32963 and n-3 PUFA salts significantly increased circulating SPM precursor levels, including 18-hydroxy-eicosapentaenoic acid (18-HEPE) plus 5-HEPE, which was not achieved to this extent by fish oil with a similar n-3 PUFA content. Omega-3 indices were increased slightly by both SynΩ3 and fish oil. These findings suggest reconsidering conventional n-3 PUFA supplementation and testing the effectiveness of SynΩ3 particularly in conditions related to inflammation.

Novel probiotic preparation with in vivo gluten-degrading activity and potential modulatory effects on the gut microbiota.

Gluten possesses unique properties that render it only partially digestible. Consequently, it exerts detrimental effects on a part of the worldwide population who are afflicted with celiac disease (1%) or related disorders (5%), particularly due to the potential for cross-contamination even when adhering to a gluten-free diet (GFD). Finding solutions to break down gluten during digestion has a high nutritional and social impact. Here, a randomized double-blind placebo-controlled in vivo challenge investigated the gluten-degrading activity of a novel probiotic preparation comprising lactobacilli and their cytoplasmic extracts, Bacillus sp., and bacterial protease. In our clinical trial, we collected feces from 70 healthy volunteers at specific time intervals. Probiotic/placebo administration lasted 32 days, followed by 10 days of wash-out. After preliminary GFD to eliminate residual gluten from feces, increasing amounts of gluten (50 mg-10 g) were administered, each one for 4 consecutive days. Compared to placebo, the feces of volunteers fed with probiotics showed much lower amounts of residual gluten, mainly with increased intakes. Probiotics also regulate the intestinal microbial communities, improving the abundance of genera pivotal to maintaining homeostasis. Quantitative PCR confirmed that all probiotics persisted during the intervention, some also during wash-out. Probiotics promoted a fecal metabolome with potential immunomodulating activity, mainly related to derivatives of branched-chain amino acids and short-chain fatty acids. IMPORTANCE: The untapped potential of gluten-degrading bacteria and their application in addressing the recognized limitations of gluten-related disorder management and the ongoing risk of cross-contamination even when people follow a gluten-free diet (GFD) emphasizes the significance of the work. Because gluten, a common protein found in many cereals, must be strictly avoided to stop autoimmune reactions and related health problems, celiac disease and gluten sensitivity present difficult hurdles. However, because of the hidden presence of gluten in many food products and the constant danger of cross-contamination during food preparation and processing, total avoidance is frequently challenging. Our study presents a novel probiotic preparation suitable for people suffering from gluten-related disorders during GFD and for healthy individuals because it enhances gluten digestion and promotes gut microbiota functionality.

Induction of glutathione peroxidase 4 expression during enterocytic cell differentiation.

Glutathione peroxidase 4 (GPx4), an abundant selenoenzyme, is ubiquitously expressed in a tissue-, cell- and differentiation-dependent manner, and it is localized in cytoplasmic, mitochondrial, and nuclear cellular compartments. Here, we report cytoplasmic and nuclear localization of GPx4 in Caco-2 intestinal epithelial cells. Enterocytic differentiation of Caco-2 cells triggers an increase in GPx4 mRNA and protein levels, mediated by enhanced promoter activity. We identified a combined cAMP response element (CREB) and CCAAT/enhancer binding protein (C/EBP) site as critical for the differentiation-triggered GPx4 promoter activity. Induction of GPx4 correlated with C/EBPα transcript levels during differentiation, suggesting a role of C/EBPα as regulator of enterocytic GPx4 expression. Consistent with the in vitro results, GPx4 protein was detected in cytoplasmic and nuclear compartments of enterocytes in human intestinal epithelia. GPx4 is uniformly expressed in colonic crypts and is differentially expressed along the crypt-to-villus axis in the small intestine with a more pronounced expression of GPx4 in the upper villi, which contain fully differentiated enterocytes. These data suggest that intestinal GPx4 expression is modulated by the enterocytic differentiation program, and the results support a direct role of nuclear GPx4 in the (selenium-dependent) prevention of oxidative damage in the gastrointestinal tract.

Synbiotic Compositions of Bacillus megaterium and Polyunsaturated Fatty Acid Salt Enable Self-Sufficient Production of Specialized Pro-Resolving Mediators.

Specialized pro-resolving mediators (SPM) have emerged as crucial lipid mediators that confer the inflammation-resolving effects of omega-3 polyunsaturated fatty acids (n-3 PUFA). Importantly, SPM biosynthesis is dysfunctional in various conditions, which may explain the inconclusive efficacy data from n-3 PUFA interventions. To overcome the limitations of conventional n-3 PUFA supplementation strategies, we devised a composition enabling the self-sufficient production of SPM in vivo. Bacillus megaterium strains were fed highly bioavailable n-3 PUFA, followed by metabololipidomics analysis and bioinformatic assessment of the microbial genomes. All 48 tested Bacillus megaterium strains fed with the n-3 PUFA formulation produced a broad range of SPM and precursors thereof in a strain-specific manner, which may be explained by the CYP102A1 gene polymorphisms that we detected. A pilot study was performed to test if a synbiotic Bacillus megaterium/n-3 PUFA formulation increases SPM levels in vivo. Supplementation with a synbiotic capsule product led to significantly increased plasma levels of hydroxy-eicosapentaenoic acids (5-HEPE, 15-HEPE, 18-HEPE) and hydroxy-docosahexaenoic acids (4-HDHA, 7-HDHA) as well as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) in healthy humans. To the best of our knowledge, we report here for the first time the development and in vivo application of a self-sufficient SPM-producing formulation. Further investigations are warranted to confirm and expand these findings, which may create a new class of n-3 PUFA interventions targeting inflammation resolution.

A nutritional supplement based on a synbiotic combination of Bacillus subtilis DSM 32315 and L-alanyl-L-glutamine improves glucose metabolism in healthy prediabetic subjects - A real-life post-marketing study.

Introduction: Impaired glucose homeostasis is a significant risk factor for cardiometabolic diseases, whereas the efficacy of available standard therapies is limited, mainly because of poor adherence. This post-marketing study assessed the glucose-lowering potential of a synbiotic-based formulation. Methods: One hundred ninety-two participants were enrolled in a digital nutrition program with continuous glucose monitoring (CGM) and received a study product comprising Bacillus subtilis DSM 32315 and L-alanyl-L-glutamine. Participants underwent a first sensor phase without supplementation, followed by a 14-day supplementation phase without sensor, and completed by a second sensor phase while continuing supplementation. Fasting glucose levels were determined before and after supplementation by CGM. In addition, the postprandial glycemic response to an oral glucose challenge, body weight, HbA1c concentrations, and BMI was analyzed. Subgroup analyses of subjects with elevated glucose and HbA1c levels vs. normoglycemic subjects were performed. Results: Supplementation with the study product resulted in significant improvements in glucose parameters (delta values: fasting glucose -2,13% ± 8.86; iAUC0-120 -4.91% ± 78.87; HbA1c: -1.20% ± 4.72) accompanied by a significant weight reduction (-1.07 kg ± 2.30) in the study population. Subgroup analyses revealed that the improvements were mainly attributed to a prediabetic subgroup with elevated fasting glucose and HbA1c values before supplementation (delta values: fasting glucose -6.10% 4± 7.89; iAUC0-120 -6.28% ± 115.85; HbA1c -3.31% ± 4.36; weight: -1.47 kg ± 2.82). Conclusion: This study indicates that the synbiotic composition is an effective and convenient approach to counteract hyperglycemia. Further placebo-controlled studies are warranted to test its efficacy in the treatment of cardiometabolic diseases.

A Synbiotic Formulation Comprising Bacillus subtilis DSM 32315 and L-Alanyl-L-Glutamine Improves Intestinal Butyrate Levels and Lipid Metabolism in Healthy Humans.

The gut microbiota is a crucial modulator of health effects elicited by food components, with SCFA (short chain fatty acids), especially butyrate, acting as important mediators thereof. We therefore developed a nutritional synbiotic composition targeted at shifting microbiome composition and activity towards butyrate production. An intestinal screening model was applied to identify probiotic Bacillus strains plus various amino acids and peptides with suitable effects on microbial butyrate producers and levels. A pilot study was performed to test if the synbiotic formulation could improve fecal butyrate levels in healthy humans. A combination of Bacillus subtilis DSM (Number of German Collection of Microorganisms and Cell Cultures) 32315 plus L-alanyl-L-glutamine resulted in distinctly increased levels of butyrate and butyrate-producing taxa (Clostridium group XIVa, e.g., Faecalibacterium prausnitzii), both in vitro and in humans. Moreover, circulating lipid parameters (LDL-, and total cholesterol and LDL/HDL cholesterol ratio) were significantly decreased and further metabolic effects such as glucose-modulation were observed. Fasting levels of PYY (Peptide YY) and GLP-1 (Glucagon-like Peptide 1) were significantly reduced. In conclusion, our study indicates that this synbiotic composition may provide an effective and safe tool for stimulation of intestinal butyrate production with effects on e.g., lipid and glucose homeostasis. Further investigations in larger cohorts are warranted to confirm and expand these findings.

Selection of Gut-Resistant Bacteria and Construction of Microbial Consortia for Improving Gluten Digestion under Simulated Gastrointestinal Conditions.

This work aimed to define the microbial consortia that are able to digest gluten into non-toxic and non-immunogenic peptides in the human gastrointestinal tract. METHODS: 131 out of 504 tested Bacillus and lactic acid bacteria, specifically Bacillus (64), lactobacilli (63), Pediococcus (1), and Weissella (3), showed strong gastrointestinal resistance and were selected for their PepN, PepI, PepX, PepO, and PepP activities toward synthetic substrates. Based on multivariate analysis, 24 strains were clearly distinct from the other tested strains based on having the highest enzymatic activities. As estimated by RP-HPLC and nano-ESI-MS/MS, 6 cytoplasmic extracts out of 24 selected strains showed the ability to hydrolyze immunogenic epitopes, specifically 57-68 of α9-gliadin, 62-75 of A-gliadin, 134-153 of γ-gliadin, and 57-89 (33-mer) of α2-gliadin. Live and lysed cells of selected strains were combined into different microbial consortia for hydrolyzing gluten under gastrointestinal conditions. Commercial proteolytic enzymes (Aspergillusoryzae E1, Aspergillusniger E2, Bacillussubtilis Veron HPP, and Veron PS proteases) were also added to each microbial consortium. Consortium activity was evaluated by ELISA tests, RP-HPLC-nano-ESI-MS/MS, and duodenal explants from celiac disease patients. RESULTS: two microbial consortia (Consortium 4: Lactiplantibacillus (Lp.) plantarum DSM33363 and DSM33364, Lacticaseibacillus (Lc.) paracasei DSM33373, Bacillussubtilis DSM33298, and Bacilluspumilus DSM33301; and Consortium 16: Lp. plantarum DSM33363 and DSM33364, Lc. paracasei DSM33373, Limosilactobacillusreuteri DSM33374, Bacillusmegaterium DSM33300, B.pumilus DSM33297 and DSM33355), containing commercial enzymes, were able to hydrolyze gluten to non-toxic and non-immunogenic peptides under gastrointestinal conditions. CONCLUSIONS: the results of this study provide evidence that selected microbial consortia could potentially improve the digestion of gluten in gluten-sensitive patients by hydrolyzing the immunogenic peptides during gastrointestinal digestion.

8-Oxoguanine DNA glycosylase (Ogg1) causes a transcriptional inactivation of damaged DNA in the absence of functional Cockayne syndrome B (Csb) protein.

We have analysed the effect of oxidative guanine lesions on the expression of a transfected reporter gene in mouse embryonic fibroblasts deficient in Cockayne syndrome B protein (Csb) and/or the 8-oxoguanine DNA glycosylase (Ogg1). We used a highly sensitive flow cytometry-based approach and quantitative real-time PCR to measure the changes in gene expression caused by the presence of oxidised guanine residues generated by photosensitisation in the vector DNA. In wild-type cells, small numbers (one or three) of oxidised guanines did not affect gene expression at short times after transfections, whereas progressive reduction of the transgene expression was observed at later time points. Although Ogg1 has a major contribution to the repair of oxidised guanine bases, its absence did not have a strong effect on the gene expression. In contrast, the lack of functional Csb protein caused a pronounced inactivation of the damaged reporter gene. Most strikingly, an additional Ogg1 deficiency significantly attenuated this effect. The results indicate that the processing of oxidative guanine modifications by Ogg1 can mediate host cell inactivation rather than reactivation of the damaged genes and that this effect is strongly enhanced in the absence of Csb.

Attenuation of hepatic expression and secretion of selenoprotein P by metformin.

High serum selenium levels have been associated epidemiologically with increased incidence of type 2 diabetes. The major fraction of total selenium in serum is represented by liver-derived selenoprotein P (SeP). This study was undertaken to test for a hypothesized effect of hyperglycemia and the antihyperglycemic drug metformin on hepatic selenoprotein P biosynthesis. Cultivation of rat hepatocytes in the presence of high glucose concentrations (25 mmol/l) resulted in increased selenoprotein P mRNA expression and secretion. Treatment with metformin dose-dependently downregulated SeP mRNA expression and secretion, and suppressed glucocorticoid-stimulated production of SeP. Moreover, metformin strongly decreased mRNA levels of selenophosphate synthetase 2 (SPS-2), an enzyme essential for selenoprotein biosynthesis. Taken together, these results indicate an influence of metformin on selenium metabolism in hepatocytes. As selenoprotein P is the major transport form of selenium, metformin treatment may thereby diminish selenium supply to extrahepatic tissues.

Selenoprotein P expression is controlled through interaction of the coactivator PGC-1alpha with FoxO1a and hepatocyte nuclear factor 4alpha transcription factors.

UNLABELLED: Selenoprotein P (SeP), the major selenoprotein in plasma, is produced mainly by the liver, although SeP expression is detected in many organs. Recently, we reported stimulation of SeP promoter activity by the forkhead box transcription factor FoxO1a in hepatoma cells and its attenuation by insulin. Here, we demonstrate that this translates into fine-tuning of SeP production and secretion by insulin. Overexpression of peroxisomal proliferator activated receptor-gamma coactivator 1alpha (PGC-1alpha) enhanced the stimulatory effect of FoxO1a on SeP promoter activity. We identified a novel functional binding site for hepatocyte nuclear factor (HNF)-4alpha, termed hepatocyte nuclear factor binding element 1, in the human SeP promoter directly upstream of the FoxO-responsive element daf16-binding element 2 (DBE2). Point mutations in hepatocyte nuclear factor binding element 1 alone or together with DBE2 decreased basal activity and responsiveness of the SeP promoter to PGC-1alpha. Moreover, the PGC-1alpha-inducing glucocorticoid dexamethasone strongly enhanced SeP messenger RNA levels and protein secretion in cultured rat hepatocytes, whereas insulin suppressed the stimulation of both PGC-1alpha and SeP caused by dexamethasone treatment. In a brain-derived neuroblastoma cell line with low basal SeP expression, SeP transcription was stimulated by PGC-1alpha together with FoxO1a, and overexpression of HNF-4alpha potentiated this effect. CONCLUSION: High-level expression of SeP in liver is ensured by concerted action of the coactivator PGC-1alpha and the transcription factors FoxO1a and HNF-4alpha. Hence, the production of SeP is regulated similarly to that of the gluconeogenic enzyme glucose-6-phosphatase. As hepatic SeP production is crucial for selenium distribution throughout the body, the present study establishes PGC-1alpha as a key regulator of selenium homeostasis.

Selenium increases hepatic DNA methylation and modulates one-carbon metabolism in the liver of mice.

The average intake of the essential trace element selenium (Se) is below the recommendation in most European countries, possibly causing sub-optimal expression of selenoproteins. It is still unclear how a suboptimal Se status may affect health. To mimic this situation, mice were fed one of three physiologically relevant amounts of Se. We focused on the liver, the organ most sensitive to changes in the Se supply indicated by hepatic glutathione peroxidase activity. In addition, liver is the main organ for synthesis of methyl groups and glutathione via one-carbon metabolism. Accordingly, the impact of Se on global DNA methylation, methylation capacity, and gene expression was assessed. We observed higher global DNA methylation indicated by LINE1 methylation, and an increase of the methylation potential as indicated by higher S-adenosylmethionine (SAM)/S-adenosylhomocysteine (SAH) ratio and by elevated mRNA expression of serine hydroxymethyltransferase in both or either of the Se groups. Furthermore, increasing the Se supply resulted in higher plasma concentrations of triglycerides. Hepatic expression of glycolytic and lipogenic genes revealed consistent Se-dependent up-regulation of glucokinase. The sterol regulatory element-binding transcription factor 1 (Srebf1) was also up-regulated by Se. Both effects were confirmed in primary hepatocytes. In contrast to the overall Se-dependent increase of methylation capacity, the up-regulation of Srebf1 expression was paralleled by reduced local methylation of a specific CpG site within the Srebf1 gene. Thus, we provided evidence that Se-dependent effects on lipogenesis involve epigenetic mechanisms.

Epigenetic effects of selenium and their implications for health.

Alterations of epigenetic marks are linked to normal development and cellular differentiation as well as to the progression of common chronic diseases. The plasticity of these marks provides potential for disease therapies and prevention strategies. Macro- and micro-nutrients have been shown to modulate disease risk in part via effects on the epigenome. The essential micronutrient selenium affects human health outcomes, e.g., cancers, cardiovascular and autoimmune diseases, via selenoproteins and through a range of biologically active dietary selenocompounds and metabolism products thereof. This review provides an assessment of the current literature regarding epigenetic effects of dietary and synthetic selenocompounds, which include the modulation of marks and editors of epigenetic information and interference with one-carbon metabolism, which provides the methyl donor for DNA methylation. The relevance of a selenium-epigenome interaction for human health is discussed, and we also indicate where future studies will be helpful to gain a deeper understanding of epigenetic effects elicited by selenium.

Selenium and selenoproteins in inflammatory bowel diseases and experimental colitis.

Inadequate dietary intake of the essential trace element selenium (Se) is thought to be a risk factor for several chronic diseases associated with oxidative stress and inflammation. Biological actions of Se occur through low-molecular weight metabolites and through selenoproteins. Several key selenoproteins including glutathione peroxidases; selenoproteins M, P, and S; and selenium-binding protein 1 have been detected in the intestine. Interestingly, Se and antioxidant selenoproteins are known to modulate differentiation and function of immune cells and contribute to avoid excessive immune responses. This review discusses the role of Se and intestinal selenoproteins in inflammatory bowel diseases, based on data from human, animal, and in vitro studies. In humans, Se deficiency is commonly observed in patients with Crohn's disease. In animal models of experimental colitis, the Se status was negatively correlated with the severity of the disease. While the cause-effect relationship of these observations remains to be clarified, the beneficial outcome of dietary Se supplementation and an optimization of selenoprotein biosynthesis in murine inflammatory bowel disease models have led to investigations of targets and actions of Se in the gastrointestinal tract. The Se status affects gene expression, signaling pathways, and cellular functions in the small and large intestine as well as the gut microbiome composition. This data, particularly from animal experiments, hold promise that adequate dietary Se supply may counteract chronic intestinal inflammation in humans.

Selenoprotein S is a marker but not a regulator of endoplasmic reticulum stress in intestinal epithelial cells.

Selenoproteins are candidate mediators of selenium-dependent protection against tumorigenesis and inflammation in the gut. Expression and roles of only a limited number of intestinal selenoproteins have been described so far. Selenoprotein S (SelS) has been linked to various inflammatory diseases and is suggested to be involved in endoplasmic reticulum (ER) homeostasis regulation and antioxidative protection in a cell-type-dependent manner, but its protein expression, regulation, and function in the gut are not known. We here analyzed the expression and localization of SelS in the healthy and inflamed gut and studied its regulation and function in intestinal epithelial cell lines. SelS was expressed in the intestinal epithelium of the small and large intestine and colocalized with markers of Paneth cells and macrophages. It was upregulated in inflamed ileal tissue from Crohn's disease patients and in two models of experimental colitis in mice. We detected SelS in colorectal cell lines, where it colocalized with the ER marker calnexin. SelS protein expression was unaffected by enterocytic differentiation but increased in response to selenium supplementation and after treatment with the ER stress inducer tunicamycin. On the other hand, depletion of SelS in LS174T, HT29, and Caco-2 cells by RNA interference did not cause or modulate ER stress and had no effect on hydrogen peroxide-induced cell death. In summary, we introduce SelS as a novel marker of Paneth cells and intestinal ER stress. Although it is upregulated in Crohn's disease, its role in disease etiology remains to be established.

Toward understanding success and failures in the use of selenium for cancer prevention.

SIGNIFICANCE: Adequate and supranutritional selenium (Se) intake, maintaining full expression of selenoproteins, has been assumed to be beneficial for human health with respect to prevention of cancer. Strikingly, the effectiveness of dietary Se supplementation depends on many factors: baseline Se status, age, gender, and genetic background of an individual; type of cancer; and time point of intervention in addition to metabolic conversion and dose of applied Se compounds. RECENT ADVANCES: Se intake levels for optimization of plasma selenoproteins in humans have been delineated. Regulation, function, and genetic variants of several selenoproteins have been characterized in the intestine, where Se-mediated prevention of colorectal cancer appears to be particularly promising. CRITICAL ISSUES: Numerous cell culture and animal studies indicate anticarcinogenic capacity of various Se compounds but, at present, the outcome of human studies is inconsistent and, in large part, disappointing. Moreover, supranutritional Se intake may even trigger adverse health effects, possibly increasing the risk for Type 2 diabetes in Se-replete populations. FUTURE DIRECTIONS: To improve protocols for the use of Se in cancer prevention, knowledge on cellular and systemic actions of Se compounds needs to be broadened and linked to individual-related determinants such as the occurrence of variants in selenoprotein genes and the Se status. Based on better mechanistic insight, populations and individuals that may benefit most from dietary Se supplementation need to be defined and studied in suitably planned intervention trials.