About 1 million Americans suffer from IBD and research around the world on new therapeutic strategies against IBD is being reported at a conference sponsored by the American Physiological Society.

On one thing most researchers agree on about IBD: it's very complex. And though it might seem obvious that treating a complex disease might take more than one agent, use of combination therapy hasn't been discussed much in relation to IBD.

Now separate groups working in Houston/Boston and Jerusalem have considered the implications of combination therapy in IBD. They are presenting their papers at the APS conference.

Intestinal Lactobacillus reuteri-based combination therapy directly modulates mucosal pro-inflammatory cytokine production in IL-10 deficient mice.

Probiotics and commensal bacteria represent likely sources for novel therapeutic strategies in inflammatory bowel diseases, and have become increasingly interesting to researchers. Indeed, some probiotic therapy agents are thought to be nearing the clinical trial stage. It is well-known that the human (and animal) gut is full of mostly beneficial bacteria. In IBD and other diseases researchers have taken an approach that reintroduces these positive bacteria, allow them to repopulate the gut and quite often they produce their own anti-inflammatory chemicals. One of the major such "bugs" is the genus Lactobacillus.

The research reported below was carried by James Versalovic and Jeremy Andrew Pena at the Baylor College of Medicine/Texas Children's Hospital, Houston, Texas, and by Arlin B. Rogers, Zhongming Ge and James G. Fox at the Division of Comparative Medicine at Massachusetts Institute of Technology, Cambridge, Mass.

Probiotics have demonstrated efficacy in treating patients with infectious colitis and pouchitis, the researchers noted. Lactobacillus reuteri is the only known commensal Lactobacillus common to mice and humans, and thus represents a probiotic model organism. L. reuteri clones with cytokine-inhibitory activity may have anti-inflammatory effects in the intestine, they reasoned. So they investigated the probiotic activities of TNF- inhibitory Lactobacillus clones in a pathogenic bacterium-induced murine colitis model. They selected L. reuteri and L. paracasei clones from the test tube for their anti-inflammatory activity.

Interleukin-10 deficient mice (IL-10) were pre-colonized with an L. reuteri/paracasei probiotic regimen and challenged with pathogenic Helicobacter hepaticus. After 10 weeks, intestinal colonization by the L. reuteri/paracasei clones diminished typhlocolitis in the mice, independent of the H. hepaticus levels. The researchers thus concluded that the probiotic regimen demonstrated direct mucosal anti-inflammatory effects independent of pathogen antagonism.

Treatment of IBD by membrane-anchored phospholipase A2 inhibitors linked to glycosaminoglycans: novel multi-functional anti-inflammatory drugs.

Researchers at Saul Yedgar's laboratory at the Department of Biochemistry, Hebrew University, Hebrew University-Hadassah Medical School, Jerusalem, Israel, include Marina Kleiman, Miron Krimsky, Larisa Aptekar, Ouri Schwob, Moshe Ligumsky and Saul Yedgar.

Hydrolysis of cell membrane phospholipids by phospholipase (PLA2) initiates production of inflammatory lipid mediators including arachidonic acid (AA)-derived eicosanoids, lysophospholipids and platelet-aggregating factor (PAF). Due to their role in IBD, eicosanoid suppression has been considered for treatment. However, inhibition of one production pathway (say, COX) diverts the AA to the other (LOX), often exacerbating the condition.

So they hypothesized that inclusive control of lipid mediators, by PLA2 inhibition, seems preferable for treating IBD. In addition, they said that denudation of intestinal epithelia from cell surface glycosaminoglycans (GAG) is believed to trigger IBD, and their enrichment has been proposed for treatment.

Yedgar's lab has designed and synthesized multi-functional anti-inflammatory drugs (MFAIDs) that address both these needs, by linking PLA2-inhibiting lipids to GAG. They report that MFAIDs, given IP, IV or orally, have been effective in treating animal inflammations including endotoxin-induced sepsis, and IBD induced by TNBS, indomethacin or DSS measured by survival, histological, and clinical parameters, and biochemical markers (cytokines, PLA2 and eicosanoids).

"While current IBD therapies usually address a single, presumably central, inflammatory mediator," the researchers said, "growing evidence shows that tissue injury involves the synergism of a number of mediators." They suggest that "MFAIDs control the production of a host of inflammatory mediators and thus introduce a novel therapeutic approach and drug prototype for treatment of IBD."