To maintain immunological homeostasis, the intestinal immune system is equipped with unique innate and acquired immunocompetent cells operated by crosstalk between the host and environmental factors such as nutrition and intestinal microbiota. A lipid mediator, sphingosine 1-phosphate (S1P), has recently been identified as a functional molecule in the regulation of lymphocyte trafficking, especially at the step of emigration from secondary lymphoid organs. Our recent findings revealed that S1P uniquely regulates the innate and acquired phase of intestinal immunity. When the S1P-mediated pathway was disrupted, the trafficking of both peritoneal B1 and Peyer's patch B2 cells into the intestine was inhibited, leading to impaired intestinal IgA responses to T-independent and -dependent antigens. In contrast, intraepithelial T lymphocytes (IELs), unique lymphocytes observed in the intestinal epithelium, showed a distinct dependence upon S1P. Conventional single-positive thymocytes use S1P for their trafficking into the intestine, where they differentiate to CD4 or CD8αβ IELs expressing TCRαβ. However, S1P did not play a role in the trafficking of unconventional thymic precursors of CD8αα IELs. In addition, we found that S1P contributed to the development of allergic diarrhea, particularly in the trafficking of pathogenic T and mast cells into the large intestine. These findings collectively suggest that S1P plays a pivotal role in the regulation of both immunosurveillance and immunological homeostasis in the intestine. The fact that lipids are abundantly provided by intestinal microbiota and nutrition raises the possibility that these environmental factors may uniquely participate in the regulation of intestinal immunity through lipid mediators such as S1P.

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P.acnes is the only microorganism that has been isolated from sarcoid lesions. Many P.acnes genomes have been detected in sarcoid lymph nodes using quantitative PCR and in sarcoid granulomas by in situ hybridization. These suggest an etiologic link between P.acnes and some cases of sarcoidosis. A recombinant trigger-factor protein from P.acnes causes a cellular immune response in some patients with sarcoidosis, but not in subjects without sarcoidosis. The P.acnes trigger-factor protein causes pulmonary granulomas in some 25-50% of mice sensitized with the protein and adjuvant. The results of animal experiments suggest that sensitization with P.acnes trigger-factor protein induces granulomas only in mice infected by P.acnes, whereas mice without granulomas may be free of P.acnes in their lungs. This pathogenesis has been confirmed by further experiments involving mice and rabbits, in which the eradication of P.acnes by antibiotics prevented granulomas in these experimental models. P.acnes can cause latent infection in peripheral lung tissue and the mediastinal lymph nodes and persist intracellularly in a cell-wall-deficient form. This dormant form of P.acnes can be activated endogenously under certain environmental conditions (hormones, stress, living habits, etc.) and proliferate in cells at the sites of latent infection. Granulomatous inflammation occurs in sarcoidosis patients with hypersensitivity to intracellular proliferation of the cell-wall-deficient bacteria, which can infect other cells or organs when spread via the lymphatic system or blood stream. The timely use of antibiotics may not only kill the bacteria proliferating at the sites of disease activity, but also prevent endogenous activation of P.acnes. If long term administration of antibiotics eradicates dormant forms of the bacteria persistent in organs, it may lead to complete remission of sarcoidosis.

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The effectiveness of probiotics in preventing and treating allergic diseases has recently been reported. Effects such as alleviation of pollen allergy symptoms and improvement of serum markers have been reported in human clinical trials using Bifidobacterium longum BB536, which was isolated from the human intestinal tract and is widely used in fermented dairy products. However, the mechanisms of these effects have yet to be fully elucidated, and the bacterial components of probiotics that exert anti-allergic effects must be identified to obtain basic knowledge for determining relationships with intestinal immunity. The objective of the present study was to investigate the immunomodulatory effects of BB536 with a focus on its genomic DNA, a component of microorganisms that has gained attention in the study of natural immunity in recent years.

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