Progress Reports

It has been clear for many years that the bacteria play a very important part in the development and perpetuation of IBD. This has been more evident for Crohn’s disease than ulcerative colitis, but both are affected. In the last few years, there has been an explosion of new information regarding the role of bacteria, both in our external and internal environments. The work of the two groups reviewed below are excellent examples of this exciting new information.

Intestinal microbiota and the increased sensitivity to colitis in depression

Premysl Bercik & Stephen M. Collins

These authors have provided a brief review of five of their studies. They have previously shown that mice with pre-existing depression develop more severe experimental colitis compared to control. The thinking was that depression/anxiety results in abnormal gut function and a change in the bacterial population (known as the microbiota), and these changes create an environment in the intestine which favors the development of inflammation. In a mouse colitis model, they have also shown that mice with mild to moderate gut inflammation show anxiety/depression-like behavior. The abnormal behavior can be eliminated by either a drug which reduces inflammation or by administration of the specific probiotic bacterium known as B. longum. This research has also shown a chemical known as kynurenine is increased as a result of inflammation; this is very interesting, as kynurenine nine has been shown to induce depression-like behavior.

A second study has focused on the role of intestinal bacteria on behavior. The authors have found that using antibiotics to change the normal gut bacteria in mice changes their behavior and brain biochemistry. The antibiotics had no effect if they were not given directly into the gut. Combined with other data in the studies, they have shown that the normal intestinal bacteria play a role in host behavior.
Maternal separation has been established by others as a model of depression in mice. In a third study, these authors have investigated the effect of maternal separation on behavior, the intestinal microbiota, and gut function. They have shown that adult mice previously separated from their mothers display anxiety-like behavior, have an abnormal composition of gut bacteria, and altered function of the gut nervous system.

A fourth study looked at the mechanisms by which the probiotic bacterium B. longum normalizes the anxiety-like behavior caused by inflammation. They have shown that this bacterium normalizes behavior in at least one other commonly-used animal model of colitis. These studies indicate that these effects are not related to the immune system, but clearly have something to do with the nervous system of the animal.

Lastly, using another model of depression (eliminating the ability of a mouse to smell things), these authors found that mice in this model have a changed and unstable gut bacterial composition. They have evidence that this altered microbiota promotes inflammation, as well as abnormal gastrointestinal activity.

Taken together, these studies contribute significantly to putting together the pieces of the puzzle that is IBD, and particularly its relationship to psychological factors.

Bacterial DNA and gut homeostasis

Eric Albert, Jody Backer, Halley Bell, Saad Salim, Naomi Hotte and Karen Madsen

The objectives in this group of studies were: to determine the effects of bacterial DNA on interactions between intestinal lining cells and cells within the lining, known as dendritic cells, and the effects of these interactions on differentiation of immune cells known as T cells; and, to characterize the effects of bacterial DNA on increased T cell numbers and microbial colonization of the gut. We know that the inner lining cells of the intestine (known as intestinal epithelial cells, or IECs, for short) are instrumental in organizing immune responses to foreign substances within the gastrointestinal tract. Colonic lining cells are constantly exposed to high levels of bacteria and bacterial DNA. We know that intestinal cells must recognize and respond appropriately to invaders while, at the same time, maintaining a tolerance to the commensal bacteria.

This group has demonstrated that the type of bacterial DNA that interacts with IEC’s has an effect on the responses of both dendritic cells and T cells. These responses are further modulated by various inflammatory cytokines (chemicals that may either promote or suppress inflammation). An interesting and unexpected finding that came out of the studies was a gender influence on the host response to probiotics (friendly bacteria) and TLR-9 agonists. TLR stands for “toll-like receptors”; these are cell receptors that have been shown to be very important in various immune responses. An agonist is a hormone, neurotransmitter, or drug that triggers a response by binding to specific cell receptors. TLR9 agonists directly induce activation and maturation of plasmacytoid dendritic cells and enhance differentiation of B cells into antibody-secreting plasma cells. (If you’re thinking this is hard to understand, this is pretty complicated stuff, for advanced amateur immunologists only!) The unexpected finding is that estrogen has a significant effect on IEC responses to TLR-9; if this occurs in humans, it obviously has important implications for the use of probiotics in the treatment of IBD.

In another part of this project, the authors are also examining the response of biopsies from patients with IBD to bacterial DNA. Genetic effects of both probiotic and pathogenic (disease-causing) bacterial DNA are being analyzed. These studies are helping clarify how isolated bacterial DNA can affect immune responses in the gut, and how DNA itself may possibly be used to treat IBD.