BioWorld International Correspondent

LONDON - Just how the millions of commensal bacteria that inhabit our guts manage to exist there without harming us is a question that immunologists have been studying for many years. Now new research has discovered the immunological mechanisms that keep gut bacteria under control.

That could be good news for people with inflammatory bowel diseases such as Crohn's disease and ulcerative colitis, because the conditions almost certainly are caused by abnormal inflammatory responses to commensal bacteria. Once scientists know how the healthy gut deals with those bacteria, it might allow them to identify how the system goes wrong in the unlucky individuals who suffer the pain and other symptoms of inflammatory bowel diseases.

Andrew Macpherson, group leader for mucosal immunology at the Institute of Experimental Immunology in Zurich, Switzerland, told BioWorld International: "With almost no exceptions, all the drugs for inflammatory bowel disease manipulate the final common pathway of inflammation. What we clearly need to do is to have drug targets that are much closer to the fault that causes the inflammation to occur."

The work by Macpherson, with his colleague Therese Uhr, shows how different cells of the immune system deal with commensal bacteria that breach the lining of the intestine. An account of their experiments appears in the March 12, 2004, issue of Science, in a paper titled "Induction of Protective IgA by Intestinal Dendritic Cells Carrying Commensal Bacteria."

The intestines of the average human being contain about 10¹² nonpathogenic bacteria - that is more than the number of cells in the body. When a baby is born, its gut is sterile but quickly becomes colonized by many bacteria.

It has been suggested that the reason commensal bacteria do not cause infections and trigger a full-scale immune response is because they do not interact with the body, other than inhabiting the lumen of the gut. However, that is unlikely, because the lining of the gut is only one cell thick, and known to be "leaky" in some circumstances.

Further evidence that the bacteria are more than just harmless passengers comes from animal experiments. Mice born by Caesarean section and raised in a sterile environment have fewer immune cells in their guts and they secrete fewer antibodies than normal mice. In addition, the collections of lymphocytes in the gut known as Peyer's patches, which have the role of inducing immune responses, do not develop properly in those animals. So the bacteria play an important role in developing the immune system in the gut.

But why don't they do any harm? Macpherson and Uhr set out to try to answer that question. They infected sections of gut in mice with a particular species of bacterium and then looked to see where the bacteria ended up. The researchers knew that macrophages were capable of phagocytosing and killing the bacteria, but when they isolated macrophages from different tissues adjacent to the gut, they failed to find any bacteria within them.

Macpherson said: "We were puzzled by this, but after a while it dawned on us that the cells were able, during the course of these quite long experiments, to kill the bacteria they had engulfed. We showed that they were very efficient at killing them."

Having sorted several different types of cell, they also noticed that dendritic cells were not able to kill the bacteria so easily. "This struck us as very interesting," Macpherson said. "We decided to investigate what effect these live bacteria in dendritic cells had and were able to show that they induced the mucosal immune system to secrete antibodies. This in turn prevented the bacteria from penetrating the very thin single-cell layer of the intestinal mucosa."

Their experiments showed that the resulting immune response specifically generated IgA antibodies. "This means that we have found a way of selectively inducing IgA in vivo." Macpherson said.

Further studies demonstrated that the dendritic cells that encountered the bacteria from the gut did not move around the body, triggering a generalized immune response, but went only as far as the mesenteric lymph nodes.

Pathogenic bacteria behave differently, evading death by macrophages to allow their numbers to multiply in the gut.

Macpherson and Uhr now plan to study in more detail the mechanism that leads to a selective increase in IgA antibodies. They also want to examine how the antibodies in murine milk help to shape the development of the immune system in newborn mice.