Genetic and environmental factors are important in the pathogenesis of clinical and experimental chronic intestinal inflammation. We investigated the influence of normal luminal bacteria and several groups of selected bacterial strains on spontaneous gastrointestinal and systemic inflammation in HLA-B27 transgenic rats. Rats maintained germfree for 3-9 mo were compared with littermates conventionalized with specific pathogen-free bacteria. Subsequently, germfree transgenic rats were colonized with groups of five to eight bacteria that were either facultative or strictly anaerobic. Transgenic germfree rats had no gastroduodenitis, colitis, or arthritis, but developed epididymitis and dermatitis to the same degree as conventionalized rats. Colonic proinflammatory cytokine expression was increased in transgenic conventionalized rats but was undetectable in germfree and nontransgenic rats.

A number of inflammatory disease states occur with greatly increased frequency in individuals inheriting the human major histocompatibility complex class I allele HLA-B27. In a minority of cases, namely those with B27-associated reactive arthritis, there is good evidence that the disease state is triggered by infection with an enteric or genitourinary bacterial pathogen. For the majority of B27-associated disease, no definite pathogenetic role for bacteria has been established. However, in these latter cases intestinal inflammation can often be demonstrated, and it sometimes occupies a major part of the clinical picture. Rats transgenic for B27 are known to develop a disorder resembling B27-associated human disease, with prominent intestinal, joint, skin, and male genital inflammatory lesions. We report here that B27 transgenic rats raised in a germfree environment do not develop inflammatory intestinal or peripheral joint disease, whereas the skin and genital inflammatory lesions are unaffected by the germfree state. These findings support the concept that gut and joint inflammation are pathogenetically closely related, and they provide direct evidence that the commensal gut flora play an important role in the pathogenesis of B27-associated gut and joint inflammation.

Different commensal bacterial species selectively initiate immune-mediated intestinal inflammation with distinctly different kinetics and anatomic distribution in the same host.

Germ-free interleukin-10 knockout (IL-10 KO) mice developed inflammatory bowel disease (IBD) after they were colonized with a pure culture of Enterococcus faecalis. E. faecalis not only induced IBD (primarily in colon and rectum) but rectal dysplasia and adenocarcinoma was also found in the IL-10 KO mice. Conventional (complex-intestinal flora) IL-10 KO mice developed IBD within 10 to 15 weeks of age and showed more pathology in the cecum (typhlitis) than we observed with E. faecalis-induced IBD in gnotobiotic IL-10 KO mice. Conversely, neither germ-free IL-10 mice nor IL-10 KO mice colonized as adults, with a pure culture of Candida albicans, Escherichia coli, Lactobacillus casei, L. reuteri, L. acidophilus, a Bifidobacterium sp., Lactococcus lactis, or a Bacillus sp. developed IBD during the 25-to 30-week study. E. faecalis is a common intestinal microbe of man and animals that can trigger IBD, dysplasia, and carcinoma in a genetically susceptible murine host. Inflammatory bowel diseases (IBD), which affects several million patients, 1 has two main clinical manifestations: 1) ulcerative colitis, an inflammatory disease that occurs in the colonic and rectal mucosa; and 2) Crohn's disease that affects both the small and large intestine and is associated with transmural granulomatous inflammation of the bowel.Genetic, autoimmune, infectious, and epithelial cell function(s) and metabolism have all been proposed as factors involved in the etiology and pathogenesis of IBD. Spontaneous and genetically engineered animal models of IBD have been described.2,4,5 IBD can also be induced in experimental animals with chemicals.6 -9 IBD occurs in conventional flora and specific pathogen-free rodents that have been genetically altered [knockout (KO) or transgenic] to impair their capacity to control T-cell-mediated immune responses to intestinal antigens. 10 -16 Recent studies have demonstrated the induction of IBD in genetically susceptible, conventional flora mice by adoptive transfer of specific T cells suggesting that dysfunctional, unregulated, T-cell-mediated immune responses play an important role in IBD pathogenesis. 15,17,18 Several recent studies have focused attention on an important role for intestinal microbes in the etiology of IBD. For example, antibiotics can ameliorate IBD. 2,19Also, IBD-susceptible, genetically engineered rodents are protected from IBD by maintaining them under germfree conditions. 10 -16,20 Certain rodents (Tg⑀ 26 mice) when treated with bone marrow develop IBD if they have a complex intestinal flora. However, germ-free Tg⑀ 26 mice are protected from IBD by maintaining them germfree after treatment with bone marrow. 21Several studies have attempted to induce IBD in genetically susceptible germ-free rodents by colonizing them with a pure culture of an intestinal microbe 22 or with various combinations of intestinal microbes; 20,23 however, to date no common intestinal microbe in pure culture has been able to induce IBD in a genetically susceptible germ-free host.In this study, we demonstr...