Pierre Desreumaux

Activation of the peroxisome proliferator-activated receptor gamma promotes the development of colon tumors in C57BL/6J-APCMin/+ mice.

The development of colorectal cancer, one of the most frequent cancers, is influenced by prostaglandins and fatty acids. Decreased prostaglandin production, seen in mice with mutations in the cyclooxygenase 2 gene or in animals and humans treated with cyclooxygenase inhibitors, prevents or attenuates colon cancer development. There is also a strong correlation between the intake of fatty acids from animal origin and colon cancer. Therefore, the peroxisome proliferator-activated receptor γ (PPARγ; ref. 7), a downstream transcriptional mediator for prostaglandins and fatty acids which is highly expressed in the colon, may be involved in this process. Activation of PPARγ by two different synthetic agonists increased the frequency and size of colon tumors in C57BL/6J-APCMin /+ mice, an animal model susceptible to intestinal neoplasia. Tumor frequency was only increased in the colon, and did not change in the small intestine, coinciding with the colon-restricted expression of PPARγ. Treatment with PPARγ agonists increased β-catenin levels both in the colon of C57BL/6J-APCMin/+ mice and in HT-29 colon carcinoma cells. Genetic abnormalities in the Wnt/wingless/APC pathway, which enhance the transcriptional activity of the β-catenin-T-cell factor/lymphoid enhancer factor 1 transcription complex, often underly the development of colon tumors. Our data indicate that PPARγ activation modifies the development of colon tumors in C57BL/6J-APCMin/+ mice.

Presence of adherent Escherichia coli strains in ileal mucosa of patients with Crohn's disease

BACKGROUND & AIMS Infectious agents are suspected of being involved in the pathogenesis of Crohns disease. This study was designed to look for the presence of virulent Escherichia coli strains associated with the ileal mucosa of patients with Crohns disease. METHODS E. coli strains were recovered from resected chronic ileal lesions (n = 20), neoterminal ileum after surgery from patients with (n = 19) and without (n = 11) endoscopic recurrence, and controls (n = 13). Bacterial adhesion was determined in vitro using intestinal cell lines; other associated virulence factors were assessed by DNA hybridization and polymerase chain reaction experiments. RESULTS None of the strains harbored any of the virulence factor-encoding genes of E. coli involved in acute enteric diseases. However, mannose-resistant adhesion to differentiated Caco-2 cells was found for 84.6% and 78.9% of the E. coli strains isolated from chronic and early recurrent lesions, respectively, compared with 33% of controls (P < 0.02). In addition, 21.8% of the strains induced a cytolytic effect by synthesis of an alpha-hemolysin. CONCLUSIONS E. coli strains isolated from the ileal mucosa of patients with Crohns disease adhere to differentiated intestinal cells and may disrupt the intestinal barrier by synthesizing an alpha-hemolysin.

Lactobacillus acidophilus modulates intestinal pain and induces opioid and cannabinoid receptors

Abdominal pain is common in the general population and, in patients with irritable bowel syndrome, is attributed to visceral hypersensitivity. We found that oral administration of specific Lactobacillus strains induced the expression of μ-opioid and cannabinoid receptors in intestinal epithelial cells, and mediated analgesic functions in the gut—similar to the effects of morphine. These results suggest that the microbiology of the intestinal tract influences our visceral perception, and suggest new approaches for the treament of abdominal pain and irritable bowel syndrome.

Dysbiosis in inflammatory bowel disease

Abundant data have incriminated intestinal bacteria in the initiation and amplification stages of inflammatory bowel diseases. However, the precise role of intestinal bacteria remains elusive. One theory has suggested a breakdown in the balance between putative species of “protective” versus “harmful” intestinal bacteria—this concept has been termed “dysbiosis”. Arguments in support of this concept are discussed.

CEACAM6 acts as a receptor for adherent-invasive E. coli, supporting ileal mucosa colonization in Crohn disease

The ileal mucosa of Crohn disease (CD) patients is abnormally colonized by adherent-invasive E. coli (AIEC) that are able to adhere to and invade intestinal epithelial cells. Here, we show that CD-associated AIEC strains adhere to the brush border of primary ileal enterocytes isolated from CD patients but not controls without inflammatory bowel disease. AIEC adhesion is dependent on type 1 pili expression on the bacterial surface and on carcinoembryonic antigen-related cell adhesion molecule 6 (CEACAM6) expression on the apical surface of ileal epithelial cells. We report also that CEACAM6 acts as a receptor for AIEC adhesion and is abnormally expressed by ileal epithelial cells in CD patients. In addition, our in vitro studies show that there is increased CEACAM6 expression in cultured intestinal epithelial cells after IFN-gamma or TNF-alpha stimulation and after infection with AIEC bacteria, indicating that AIEC can promote its own colonization in CD patients.

Intestinal antiinflammatory effect of 5-aminosalicylic acid is dependent on peroxisome proliferator-activated receptor-gamma.

5-aminosalicylic acid (5-ASA) is an antiinflammatory drug widely used in the treatment of inflammatory bowel diseases. It is known to inhibit the production of cytokines and inflammatory mediators, but the mechanism underlying the intestinal effects of 5-ASA remains unknown. Based on the common activities of peroxisome proliferator–activated receptor-γ (PPAR-γ) ligands and 5-ASA, we hypothesized that this nuclear receptor mediates 5-ASA therapeutic action. To test this possibility, colitis was induced in heterozygous PPAR-γ+/− mice and their wild-type littermates, which were then treated with 5-ASA. 5-ASA treatment had a beneficial effect on colitis only in wild-type and not in heterozygous mice. In epithelial cells, 5-ASA increased PPAR-γ expression, promoted its translocation from the cytoplasm to the nucleus, and induced a modification of its conformation permitting the recruitment of coactivators and the activation of a peroxisome-proliferator response element–driven gene. Validation of these results was obtained with organ cultures of human colonic biopsies. These data identify PPAR-γ as a target of 5-ASA underlying antiinflammatory effects in the colon.

Impaired expression of peroxisome proliferator-activated receptor γ in ulcerative colitis

Abstract Background & Aims: The peroxisome proliferator-activated receptor γ (PPARγ) has been proposed as a key inhibitor of colitis through attenuation of nuclear factor κB (NF-κB) activity. In inflammatory bowel disease, activators of NF-κB, including the bacterial receptor toll-like receptor (TLR)4, are elevated. We aimed to determine the role of bacteria and their signaling effects on PPARγ regulation during inflammatory bowel disease (IBD). Methods: TLR4-transfected Caco-2 cells, germ-free mice, and mice devoid of functional TLR4 ( Lps d /Lps d mice) were assessed for their expression of PPARγ in colonic tissues in the presence or absence of bacteria. This nuclear receptor expression and the polymorphisms of gene also were assessed in patients with Crohns disease (CD) and ulcerative colitis (UC), 2 inflammatory bowel diseases resulting from an abnormal immune response to bacterial antigens. Results: TLR4-transfected Caco-2 cells showed that the TLR4 signaling pathway elevated PPARγ expression and a PPARγ-dependent reporter in an Iκκβ dependent fashion. Murine and human intestinal flora induced PPARγ expression in colonic epithelial cells of control mice. PPARγ expression was significantly higher in the colon of control compared with Lps d /Lps d mice. Although PPARγ levels appeared normal in patients with CD and controls, UC patients displayed a reduced expression of PPARγ confined to colonic epithelial cells, without any mutation in the PPARγ gene. Conclusions: These data showed that the commensal intestinal flora affects the expression of PPARγ and that PPARγ expression is considerably impaired in patients with UC.

PPARγ as a new therapeutic target in inflammatory bowel diseases

The peroxisome proliferator activated receptor γ (PPARγ) is a nuclear receptor highly expressed in the colon and playing a key role in bacterial induced inflammation. Regulation of colon inflammation by this receptor has been well demonstrated in many experimental models of colitis but also in patients with ulcerative colitis, characterised by impaired expression of PPARγ confined to their colon epithelial cells. Recent data showing that PPARγ was the major functional receptor mediating the common aminosalicylate activities in inflammatory bowel diseases (IBD) have also reinforced the roles of this receptor in the control of intestinal inflammation. The aims of this review are to discuss the potential roles of PPARγ in the physiopathology of IBD, as well as the emerging therapeutic strategies targeting this receptor. Current evidence suggests that Crohn’s disease (CD) and ulcerative colitis (UC) result from a complex interplay between genetic and environmental factors, leading to an abnormal innate and adaptive immune response of the gut directed against luminal constituents in genetically determined patients. Identification of cytoplasmic receptors of bacterial peptidoglycan, namely nucleotide oligomerisation domain (NOD)2/caspase recruitment domain (CARD)15 and NOD1/CARD4, as CD susceptibility genes reinforced the pivotal role of the interactions between enteric microbes and the intestinal immune system in the physiopathology of IBD.1–3 Furthermore, recent advances in our laboratory and others also indicate the involvement of another key receptor, PPARγ, which regulates colon inflammation. This represents a new target in the development of therapeutic molecules in IBD. PPARγ is a nuclear receptor discovered in mammals in 1993 as an orphan receptor.4 Until recently, PPARγ was known as a receptor mainly expressed by adipose tissue and involved in the regulation of insulin resistance. PPARγ is activated by antidiabetic thiazolidinedione drugs.5 In 1998, the first studies were published reporting a potential link between this receptor and …

A Unique PPARγ Ligand with Potent Insulin-Sensitizing yet Weak Adipogenic Activity

FMOC-L-Leucine (F-L-Leu) is a chemically distinct PPARgamma ligand. Two molecules of F-L-Leu bind to the ligand binding domain of a single PPARgamma molecule, making its mode of receptor interaction distinct from that of other nuclear receptor ligands. F-L-Leu induces a particular allosteric configuration of PPARgamma, resulting in differential cofactor recruitment and translating in distinct pharmacological properties. F-L-Leu activates PPARgamma with a lower potency, but a similar maximal efficacy, than rosiglitazone. The particular PPARgamma configuration induced by F-L-Leu leads to a modified pattern of target gene activation. F-L-Leu improves insulin sensitivity in normal, diet-induced glucose-intolerant, and in diabetic db/db mice, yet it has a lower adipogenic activity. These biological effects suggest that F-L-Leu is a selective PPARgamma modulator that activates some (insulin sensitization), but not all (adipogenesis), PPARgamma-signaling pathways.

Inflammatory alterations in mesenteric adipose tissue in Crohn's disease

BACKGROUND & AIMS Abnormalities of fat in the mesentery including adipose tissue hypertrophy and fat wrapping have been long recognized on surgical specimens as characteristic features of Crohns disease. However, the importance, origin, and significance of the mesenteric fat hypertrophy in this chronic inflammatory disease are unknown. Peroxisome proliferator-activated receptor gamma (PPARgamma) is a crucial factor involved in the homeostasis of adipose tissue, a major source of biologically active mediators. METHODS Intra-abdominal fat accumulation was quantified using a magnetic resonance imaging method in patients with Crohns disease and controls. PPARgamma and inflammatory cytokines synthesized by mesenteric adipose tissues were assessed by quantitative polymerase chain reaction, in situ hybridization, and immunohistochemistry. RESULTS In vivo, patients with Crohns disease have an important accumulation of intra-abdominal fat. This mesenteric obesity, present from the onset of the disease, is associated with overexpression of PPARgamma and tumor necrosis factor (TNF)-alpha, synthesized, at least in part, by adipocytes. CONCLUSIONS These results suggest that confined increased PPARgamma mesenteric concentrations could lead to the mesenteric fat hypertrophy, which could actively participate through the synthesis of TNF-alpha in the inflammatory response.