Infectious agents and Crohn's disease.

Bulois P, Desreumaux P, Neut C, Darfeuille-Michaud A, Cortot A, Colombel JF.
Clinique des Maladies de l'Appareil Digestif, Hôpital Claude Huriez, Centre Hospitalier Universitaire (ChetU), Lille.
Clin Microbiol Infect. 1999;5 (10):601-604.

Changes in the bacterial flora of the neoterminal ileum after ileocolonic resection for Crohn's disease.

Bacterial agents have been implicated in the early recurrence of Crohn's Disease after ileocolectomy. The aim of our study was to identify and quantify bacteria associated with the ileal mucosa in patients and controls, and to correlate specific bacteria with recurrence.

METHOD: The predominant bacterial microflora of the ileum were enumerated and identified, aerobically and anaerobically, in biopsies obtained at the time of surgery or by endoscopy from 61 patients with Crohn's disease and 10 ileocolectomy controls. The 61 specimens were comprised of 13 ileal biopsies taken from resection specimens, seven taken after ileostomy, and 41 taken after ileocolectomy.

RESULTS: Ileocolectomy induced a significant increase in bacterial counts and variety in the neoterminal ileum in both patients and controls that was not observed in ileostomy biopsies. Comparison between patients and controls revealed greater numbers of Escherichia coli and enterococci in Crohn's disease and of bifidobacteria and ruminococci in controls. Early recurrence was associated with high counts of E. coli and bacteroides and the frequent isolation of fusobacteria.

CONCLUSION: After ileocolectomy, colonization of the neoterminal ileum is increased. Our data suggest that increases in the populations of specific bacteria such as E. coli, enterococci, bacteroides, and fusobacteria may be important in postoperative recurrence of Crohn's disease.

Role of peroxisome proliferator-activated receptor gamma and retinoid X receptor heterodimer in hepatogastroenterological diseases.

The peroxisome proliferator-activated receptor gamma (PPAR gamma) and its partner, the retinoid X receptor (RXR), are two nuclear receptors that are expressed mainly in adipose tissue and which have a role in lipid metabolism and insulin sensitization. New sites of PPAR gamma/RXR expression have been described, especially in the intestinal tract, pancreas, and liver.

New functions have been attributed to this heterodimer in regulation of inflammation

Concomitantly, new functions have been attributed to this heterodimer in regulation of inflammation, by its inhibition of nuclear factor (NF)-kappaB and via stress-kinase pathways. These new sites and functions of PPAR gamma/RXR have led to novel ideas about pathophysiology of different inflammatory digestive diseases and to development of innovative treatment strategies with PPAR gamma activators.

Anti-inflammatory properties of the mu opioid receptor support its use in the treatment of colon inflammation.

The physiologic role of the mu opioid receptor (MOR) in gut nociception, motility, and secretion is well established. To evaluate whether MOR may also be involved in controlling gut inflammation, we first showed that subcutaneous administration of selective peripheral MOR agonists, named DALDA and DAMGO, significantly reduces inflammation in two experimental models of colitis induced by administration of 2,4,6-trinitrobenzene sulfonic acid (TNBS) or peripheral expansion of CD4 (+) T cells in mice.

MOR plays a role in the control of gut inflammation

This therapeutic effect was almost completely abolished by concomitant administration of the opioid antagonist naloxone. Evidence of a genetic role for MOR in the control of gut inflammation was provided by showing that MOR-deficient mice were highly susceptible to colon inflammation, with a 50% mortality rate occurring three days after TNBS administration. The mechanistic basis of these observations suggests that the anti-inflammatory effects of MOR in the colon are mediated through the regulation of cytokine production and T cell proliferation, two important immunologic events required for the development of colon inflammation in mice and patients with Inflammatory Bowel Disease (IBD). These data provide evidence that MOR plays a role in the control of gut inflammation and suggest that MOR agonists might be new therapeutic molecules in IBD.

Impaired expression of peroxisome proliferator-activated receptor gamma in ulcerative colitis.

The peroxisome proliferator-activated receptor gamma (PPAR gamma) has been proposed as a key inhibitor of colitis through attenuation of nuclear factor kappa B (NF-kappa B) activity. In Inflammatory Bowel Disease (IBD), activators of NF-kappa B, including the bacterial receptor toll-like receptor (TLR) 4, are elevated. We aimed to determine the role of bacteria and its signaling effects on PPAR gamma regulation during IBD.

METHOD: 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 PPAR gamma 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 Crohn's Disease (CD) and ulcerative colitis (UC), two 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 the PPAR gamma expression and a PPAR gamma-dependent reporter in an I kappa kappa beta dependent fashion. Murine and human intestinal flora induced PPAR gamma expression in colonic epithelial cells of control mice. PPAR gamma expression was significantly higher in the colon of control compared with Lps(d)/Lps(d) mice. Although PPAR gamma levels appeared normal in patients with CD and controls, UC patients displayed a reduced expression of PPAR gamma confined to colonic epithelial cells, without any mutation in the PPAR gamma gene.

CONCLUSIONS: These data showed that the commensal intestinal flora affects the expression of PPAR gamma and that PPAR gamma expression is considerably impaired in patients with UC