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Our findings suggest that activation of the IL-23/IL-17 axis is fundamentally connected to the etiology of CD and may represent the basis for the relapsing nature of the disease by increasing the sensitivity of epithelium to microbial LPS.

Background and Aims: Several factors support the view of inflammatory bowel disease [IBD] origin in the host responsiveness to intestinal bacteria, although no single bacterial species has been shown as a causative agent in the pathogenesis. Our aim was to analyse the fecal microbiota of paediatric IBD patients at different stages of the disease. In addition, the characteristics of immune response to the bacterial isolates showing very low abundance in IBD were studied. Methods: Fecal samples [1-3 samples/child] were collected from 10 paediatric patients with crohn's disease [CD],] and 12 with ulcerative colitis [UC] and from 8 healthy children, for polyphasic microbiological analysis (culture, real-time polymerase chain reaction [PCR], and denaturing gradient gel electrophoresis). In addition, in vitro cytokine responses of peripheral blood mononuclear cells to the bacterial isolates, which showed very low abundance in IBD, were studied. Results: Although predominant bacterial diversity was higher in IBD, the numbers of Lachnospiraceae and Coriobacteriaceae bacteria were lower in IBD patients as compared with control children [p < 0.05]. In addition, Ruminococcaceae population diversity was lower in IBD [p < 0.05] and correlated negatively with fecal calprotectin levels. Both abundance and diversity of bifidobacterial populations were lower in children with IBD [p < 0.05], and particularly low numbers of certain bifidobacterial isolates were detected. In CD, we found enhanced up-regulation of interleukin-6 transcripts and impaired RAR-related orphan receptor C response to bifidobacteria, whereas decreased interferon-gamma response was observed in both CD and UC. Conclusion: We demonstrate altered fecal microbiota in paediatric IBD, particularly low numbers and diversity of bifidobacterial populations. Interestingly, immunological response to bifidobacteria differed between paediatric CD patients and control children.

Dietary wheat gluten has been associated with the risk of diabetes in animal models of human insulin-dependent diabetes mellitus (IDDM). To evaluate the role of wheat gluten as a T cell antigen in human IDDM, we studied the cell-mediated immune response to wheat gluten in patients with IDDM and in control subjects. The cellular response to gluten was measured by the peripheral blood mononuclear cell (PBMC) proliferation test, and the results were expressed as a stimulation index (SI). We observed an enhanced cellular immune response to gluten (SI > or = 3) in seven of 29 patients with newly diagnosed IDDM (24.1%), in six of 39 patients with a longer duration of IDDM (15.4%), and in two of 37 non-diabetic controls (5.4%). Reactivity of T cells to gluten was associated with IDDM at diagnosis (P = 0.03), whereas patients with longer duration of IDDM did not differ from controls (P = 0.16). Responses of T cells to gluten were low in general: the median SI (range) was 2.0 (1-8.6) in patients with newly diagnosed IDDM and 1.5 (1-5.8) in control subjects (P = 0.03). Cellular responsiveness to gluten was not associated with HLA-DQB1 risk alleles for IDDM in patients. Although T cell responses to gluten were slightly increased in newly diagnosed patients the responsiveness was rare, and thus our results do not support a major role of gluten in the pathogenesis of human IDDM.

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Elevated levels of antibodies to cow's milk proteins, i.e., beta-lactoglobulin (BLG) and bovine serum albumin (BSA), have been associated with IDDM. We observed enhanced cellular immune response by a proliferation test of peripheral blood mononuclear cells to BLG in 22 of 40 (55%) patients with newly diagnosed IDDM compared with 7 of 32 healthy children (22%) (P = 0.004, chi 2 test). The median stimulation index to BLG was 3.3 in patients and 1.5 in healthy children (P = 0.003, Mann-Whitney U test). No difference was found in cellular reactivity to other cow's milk proteins, such as BSA or alpha-casein, or to a dietary immunogenic protein, ovalbumin. Cellular responsiveness to BLG was not associated with HLA-DQB1* risk alleles of IDDM, which suggests that immune response to the protein does not only reflect the accumulation of these HLA alleles in the patients with IDDM. We suggest that enhanced cellular immune response to dietary BLG may reflect a disturbance in the regulation of immune response to oral antigens in IDDM. This kind of defect may play a fundamental role in the development of beta-cell autoimmunity in IDDM.

Early feeding with cows' milk (CM) may cause cows' milk allergy (CMA). Breast milk contains many immune factors which compensate for the undeveloped defence mechanisms of the gut of the newborn infant. We studied the effect of supplementary CM feeding at the maternity hospital on the subsequent incidence of CMA, the effects of formula and breast feeding on the subsequent immunologic types of CMA, and the importance of immune factors present in colostrum in the immune responses of infants with CMA. In a cohort of 6209 infants, 824 were exclusively breast-fed and 87% required supplementary milk while in the maternity hospital: 1789 received CM formula, 1859 pasteurized human milk, and 1737 whey hydrolysate formula. The cumulative incidence of CMA, verified by a CM elimination-challenge test, was 2.4% in the CM, 1.7% in the pasteurized human milk and 1.5% in the whey hydrolysate group. Among these infants, exposure to CM at hospital and a positive atopic heredity increased the risk of CMA. Of the exclusively breast-fed infants, 2.1% had CMA. Risk factors for the development of IgE-mediated CMA were: exposure to CM at hospital, breast-feeding during the first 8 weeks at home either exclusively or combined with infrequent exposure to small amounts of CM and long breast-feeding. The content of transforming growth factor-beta1 (TGF-beta1) in colostrum from mothers of infants with IgE-mediated CMA was lower than from mothers of infants with non-IgE-mediated CMA. In infants with CMA, TGF-beta1 in colostrum negatively correlated with the result of skin prick test and the stimulation of peripheral blood mononuclear cells to CM, but positively with infants' IgA and IgG antibodies to CM proteins. Feeding of CM formula at maternity hospital increases the risk of CMA, but exclusive breast-feeding does not eliminate the risk. Prolonged breast-feeding exclusively or combined with infrequent exposure to small amounts of CM during the first 8 weeks induces the development of IgE-mediated CMA. Colostral TGF-beta1 may inhibit IgE- and cell mediated reactions and promote IgG-IgA antibody production to CM in infants prone to developing CMA.

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