BioWorld International Correspondent

LONDON - The idea that people with inflammatory bowel diseases could be treated by eating yogurt containing a particular variety of Lactobacillus is an appealing one - and new research by scientists in France, Belgium and Germany suggests that it soon might be possible.

Corinne Grangette, a senior scientist at the Institut Pasteur de Lille in France, and her colleagues have been investigating the nature of a mutant Lactobacillus that is able to bring about a calming effect on inflamed gut epithelium.

She told BioWorld International: "For the first time, we have shown that mutations in at least one component of the cell wall of lactic acid bacteria can influence whether the bacterium has a pro-inflammatory or an anti-inflammatory effect."

The work was reported in the June 20, 2005, issue of Proceedings of the National Academy of Sciences in a paper titled "Enhanced anti-inflammatory capacity of a Lactobacillus plantarum mutant synthesizing modified teichoic acids."

Grangette predicted that the results would be of great interest to companies developing probiotics - foods that contain live microorganisms that can be beneficial to human health.

"When we started this study, the aim was to carry out basic research and gain a better understanding of the role of cell wall components in determining which strains protect against gut inflammation," she said. "But clearly, some companies are interested in selecting strains with protective effects."

Rather than using genetically modified organisms that have had specific mutations engineered into their genomes, the way forward might be to select wild strains with the desired characteristics, once those have been fully elucidated.

The human gut is home to more than 400 different species of bacteria, many of them lactic acid bacteria or lactobacilli. The researchers already knew that lactobacilli could modulate components of the immune system, and that some strains were better at stimulating host cells to release pro-inflammatory cytokines - such as TNF-alpha, interleukin-12 and interferon-gamma - while others stimulated the release of anti-inflammatory cytokines, particularly IL-10.

Grangette and her colleagues wanted to analyze the factors that influenced how some lactobacilli could have beneficial anti-inflammatory effects, while others did not. They decided to investigate the role of components of the bacterial cell surface and constructed, in collaboration with a Belgium team, a range of lactobacilli that had mutations in the genes involved in cell wall biosynthesis.

"We observed an interesting result," Grangette said. "One of the mutants had a mutation in the gene encoding teichoic acid, one of the components of the Gram-positive bacterial cell wall. This mutation completely changed the immunomodulatory capacities of the bacteria."

Experiments carried out in collaboration with researchers at Konstantz University in Germany on purified teichoic acid showed that the wild-type molecule was able to induce pro-inflammatory mediators in an experimental system, while the modified mutant version was not.

In a mouse model of colitis, animals that received lactobacilli with mutant teichoic acid displayed fewer symptoms, lost less weight and developed milder colitis than those given a control strain of Lactobacillus. The anti-inflammatory effect on colitis was statistically significant.

The researchers were able to conclude that wild-type teichoic acid has a more pro-inflammatory effect than the mutant one. They also were able to show that the pro-inflammatory role of teichoic acid is dependent on its interaction with Toll-like receptor 2.

Grangette said, "We suggest that the modification of teichoic acid has changed the cellular surface of the lactobacilli, and unmasked one or more components that may have an anti-inflammatory role."

The team now wants to identify which component of the cell wall is responsible for the anti-inflammatory effect.

"We hypothesise that peptidoglycans, which are a main component of the bacterial cell wall, may be involved," Grangette said. "Peptidoglycans have been shown to preferentially induce signalling through the Nod2 receptor - and signalling through this receptor could mediate an inhibitory effect on the pro-inflammatory cascade. Furthermore, mutations in Card15, the gene encoding Nod2, have been associated with Crohn's disease. So we suggest that these types of components may be able to inhibit pro-inflammatory signals by interactions with the Nod2 receptor."

Their goal now is to identify precisely which component or components of the bacterial cell wall have an anti-inflammatory effect, and work out how those induce signalling to bring about that effect.