Gut: An underestimated target organ for Aluminum.

Since World War II, several factors such as an impressive industrial growth, an enhanced environmental bioavailability and intensified food consumption have contributed to a significant amplification of human exposure to aluminum. Aluminum is particularly present in food, beverages, some drugs and airbone dust. In our food, aluminum is superimposed via additives and cooking utensils. Therefore, the tolerable intake of aluminum is exceeded for a significant part of the world population, especially in children who are more vulnerable to toxic effects of pollutants than adults. Faced with this oral aluminum influx, intestinal tract is an essential barrier, especially as 38% of ingested aluminum accumulates at the intestinal mucosa. Although still poorly documented to date, the impact of oral exposure to aluminum in conditions relevant to real human exposure appears to be deleterious for gut homeostasis. Aluminum ingestion affects the regulation of the permeability, the microflora and the immune function of intestine. Nowadays, several arguments are consistent with an involvement of aluminum as an environmental risk factor for inflammatory bowel diseases.

The RAGE signaling pathway is involved in intestinal inflammation and represents a promising therapeutic target for Inflammatory Bowel Diseases.

Inflammatory Bowel Diseases (IBD) are chronic inflammatory conditions of the intestinal tract. IBD are believed to result from an inappropriate immune response against the intestinal flora in genetically predisposed patients. The precise etiology of these diseases is not fully understood, therefore treatments rely on the dampening of symptoms, essentially inflammation, rather than on the cure of the disease. Despite the availability of biologics, such as anti-TNF antibodies, some patients remain in therapeutic failure and new treatments are thus needed. The multiligand receptor for advanced glycation end-products (RAGE) is a pattern recognition receptor implicated in inflammatory reactions and immune system activation. Here, we investigated the role of RAGE in intestinal inflammation and its potential as a therapeutic target in IBD. We showed that RAGE was upregulated in inflamed tissues from IBD patients compared to controls. Rage-/- mice were less susceptible to intestinal and colonic inflammation development than WT mice. WT mice treated with the RAGE-specific inhibitor FPS-ZM1 experienced less severe enteritis and colitis. We demonstrated that RAGE could induce intestinal inflammation by promoting oxidative stress and endothelial activation which were diminished by FPS-ZM1 treatment. Our results revealed the RAGE signaling pathway as a promising therapeutic target for IBD patients.

Toxicological consequences of experimental exposure to aluminum in human intestinal epithelial cells.

Aluminum (Al), a non-essential element, is ubiquitous in industrialized societies. Whereas adult intake is estimated between 3 and 12 mg/day according to dietary aluminum studies conducted in many countries, it is not known if aluminum may have a toxic effect on intestinal epithelium. The aim of this work was to evaluate the cytotoxicity and RNA expression patterns induced in HT-29 cells by aluminum. Both classical toxicological methods and a global transcriptomic approach were used. Cytotoxicity determined by MTT assay showed a time and dose dependent decrease of cell viability in aluminum treated cells compared to control cells. Cell cycle analysis by flow cytometry revealed that aluminum induced accumulation of cells in phase G0/G1, associated with a decrease in the proportion of cells in S and G2/M phases. Aluminum led to apoptosis as evidenced by nuclear morphology changes and mitochondrial membrane perturbations, and induced reactive oxygen species generation. Transcriptomic pattern argued in favor of pro-tumorigenic and pro-inflammatory effects of aluminum in intestinal epithelial cells. These results highlight several pathways by which aluminum has a disturbing impact on intestinal epithelial cells, supporting that the effects of aluminum on intestine warrants further investigation.

Aluminum enhances inflammation and decreases mucosal healing in experimental colitis in mice.

The increasing incidence of inflammatory bowel diseases (IBDs) in developing countries has highlighted the critical role of environmental pollutants as causative factors in their pathophysiology. Despite its ubiquity and immune toxicity, the impact of aluminum in the gut is not known. This study aimed to evaluate the effects of environmentally relevant intoxication with aluminum in murine models of colitis and to explore the underlying mechanisms. Oral administration of aluminum worsened intestinal inflammation in mice with 2,4,6-trinitrobenzene sulfonic acid- and dextran sodium sulfate-induced colitis and chronic colitis in interleukin 10-negative (IL10(-/-)) mice. Aluminum increased the intensity and duration of macroscopic and histologic inflammation, colonic myeloperoxidase activity, inflammatory cytokines expression, and decreased the epithelial cell renewal compared with control animals. Under basal conditions, aluminum impaired intestinal barrier function. In vitro, aluminum induced granuloma formation and synergized with lipopolysaccharide to stimulate inflammatory cytokines expression by epithelial cells. Deleterious effects of aluminum on intestinal inflammation and mucosal repair strongly suggest that aluminum might be an environmental IBD risk factor.

Recent advances in the development of selective CB(2) agonists as promising anti-inflammatory agents.

The high distribution of CB(2) receptors in immune cells suggests their important role in the control of inflammation. Growing evidence offers this receptor as an attractive therapeutic target: CB(2) selective agonists are able to modulate inflammation without triggering psychotropic effects. This review will summarize the literature on the implication of CB(2) in inflammation and CB(2) selective agonists with anti-inflammatory activity.

Protein hydrolysates stimulate proglucagon gene transcription in intestinal endocrine cells via two elements related to cyclic AMP response element.

AIMS/HYPOTHESIS: Protein hydrolysates (peptones) increase not only glucagon-like peptide-1 (GLP-1) secretion but also transcription of the proglucagon ( PG) gene in the intestine. The critical physiological roles of gut-derived GLPs raised hope for their therapeutic use in several disorders, especially GLP-1 in diabetes. We aimed to investigate the molecular mechanisms involved in this nutrient- PG gene interaction. METHODS: Wild-type and mutated PG promoter fragments fused to the luciferase reporter gene were transfected into enteroendocrine STC-1 cells, which were then either treated or not with peptones. Co-transfection with expression vectors of dominant-negative forms of cAMP response element binding protein (CREB) and protein kinase A (PKA) proteins were performed, as well as electrophoresis mobility shift assays. RESULTS: Deletion analysis showed that the promoter region spanning between -350 and -292 bp was crucial for the transcriptional stimulation induced by peptones. Site-directed mutagenesis of the canonical cAMP response element (CRE(PG)) and of the adjacent putative CRE site (CRE-like1) led to a dramatic inhibition of the promoter responsiveness to peptones. Over expression of a dominant-negative mutant of CREB or of PKA produced a comparable and selective inhibitory effect on the activity of transfected promoter fragment containing the -350/-292 sequence. EMSA showed that CREB and fra2 transcription factors bound to CRE(PG) and CRE-like1 elements respectively, independently of peptone treatment. CONCLUSIONS/INTERPRETATION: Our report identified cis- and trans-regulatory elements implicated in the transcriptional control of PG gene by nutrients in enteroendocrine cells. It highlights the role of a previously unsuspected CRE-like1 element, and emphasises the importance of CRE-related sequences in the regulation of PG gene transcription in the intestine.