Probiotics and inflammatory bowel diseases

Abstract

The pathogenesis of inflammatory bowel diseases remains elusive. However, the resident luminal bacteria seem to be an important factor in their development and chronicity. There is evidence to suggest that inflammatory bowel diseases may represent an aggressive immunological response to the resident luminal flora, rather than an alteration in the normal flora. In prior research, probiotic bacteria were effective in managing certain acute diarrheal diseases, and investigators reported that certain Lactobacilli strains seem to have protective immunomodulating and bowel flora manipulating properties. We report the results of recent studies with probiotics in animal models, in which promising effects for the treatment of chronic inflammatory bowel disease, pouchitis, and ulcerative colitis were observed. Future research may clarify a precise role for probiotic bacteria in managing chronic inflammatory bowel diseases.

Introduction

Despite many years of extensive research, the pathogenesis of inflammatory bowel diseases (IBD) remains unclear. Genetic factors as well as environmental triggers seem to play a substantial role, as the incidence of Crohn’s disease is increasing, at least in the Western world. Among those environmental triggers, bacterial and viral organisms have been studied the most (1), but the dramatic changes regarding food production and consumption habits during the last century should be taken into account (2). The most recent studies in IBD and experimental colitis indicate that normal resident luminal bacteria are a significant factor in the onset and chronicity of inflammation. However, a fundamental question remains: Is the intestinal flora aberrant in diseased patients, or are we dealing with an overly aggressive immune response toward the normal resident flora? Crohn’s disease is known to occur in sites with the highest concentration of luminal bacteria, such as the colon and terminal ileum (3). Giaffer et al. showed that the intestinal flora of patients with active Crohn’s disease is considerably different from that of patients with quiescent disease, ulcerative colitis, or normal controls (3). In these individuals, the concentration of aerobic bacteria was elevated, especially Escherichia coli, and within the fraction of anaerobic bacteria, Bacteroides fragilis and Bacteroides vulgatus were increased. Additionally, in all patients with Crohn’s disease, Bifidobacteria were decreased (3). Although the search for clearly defined triggering factors in IBD continues, the protective qualities of probiotic bacteria may provide an innovative approach to treatment.

Research in animal models further supports the involvement of resident luminal bacteria in experimental colitis. Rats that were transgenic for the human HLA-B₂₇ gene and raised in a specific pathogen-free (SPF) environment developed gastritis, colitis, and arthritis; in a sterile environment, HLA- B₂₇ transgenic rats were free of colitis, gastritis, and arthritis (4). In addition, when SPF transgenic rats were treated with metronidazole, or a combination of vancomycin and imipenem, attenuation occurred (5). Gnotobiotic experiments demonstrated that Bacteriodes vulgatus provided a dominant antigen stimulus, whereas E. coli had no effect on colitis (4). Similarly, normal luminal bacteria are essential contributors to colitis in interleukin-10 knockout mice (IL-10^-/-). Targeted deletion of IL-10, an antiinflammatory cytokine, induced colitis in the SPF environment and no inflammation in germ-free animals (6). SPF IL-10^-/- mice also exhibited disease attenuation with metronidazole or the combination vancomycin/imipenem (5). IL-2^-/- mice yielded an unexpected finding. Because IL-2 is one of the proinflammatory cytokines, it was believed that colitis would not develop (7). However, IL-2^-/- mice not only developed very aggressive colitis in the SPF environment, leading to death by about 28 wk; another surprising outcome was that germ-free animals were not completely disease-free, but had mild, nonfatal colitis, gastritis, and periportal hepatitis (8). These studies indicate that normal luminal bacteria are essential to the development of chronic intestinal inflammation in genetically susceptible hosts and that all intestinal bacterial species do not exhibit equal abilities to induce colitis.