Abstract
Purpose: Probiotics have been advocated for use in a variety of gastrointestinal disorders yet their mode of action remains unclear. We hypothesized that interactions between probiotics and dendritic cells, which sample microbes and provide polarization signals to lymphocytes following pattern-recognition receptor activation, might be critical to their beneficial activity. The aim of this study was to elucidate in man the molecular mechanisms which are involved in the induction of Foxp3+ T cells by myeloid (mDC) and plasmacytoid (pDC) dendritic cells following interaction with a parobiotic. Methods: Both mDCs and pDCs were isolated from peripheral blood from human volunteers and incubated in vitro with the probiotic strain Bifidobacterium longum subsp. infantis 35624 (B. infantis) and autologous lymphocytes. Transcription factor expression, co-stimulatory molecule expression, cytokine secretion, retinoic acid and tryptophan metabolism were assessed. Cytokine secretion and Foxp3 expression were then studied in human volunteers following B. infantis feeding. Results: mDCs and pDCs expressed indoleamine 2,3 dioxygenase (IDO) and secreted IL-10, but not IL-12p70, in response to B. infantis. mDC IL-10 secretion was TLR-2 dependent, while pDC IL-10 secretion was TLR-9 dependent. In addition, mDCs expressed retinaldehyde dehydrogenase 2 (RALDH2) resulting in retinoic acid secretion, which was TLR-2 and DC-SIGN dependent. B. infantis-stimulated mDCs and pDCs induced T cell Foxp3 expression and IL-10 secretion. TLR-2, DC-SIGN and retinoic acid were required for mDC induction of Foxp3+ T cells, while pDCs required IDO. Human volunteers fed B. infantis displayed increased secretion of IL-10 and enhanced expression of Foxp3. Conclusion: Cross-talk between TLR-2, DC-SIGN and TLR-9 determines the innate and subsequent T regulatory cell response to B. infantis. In addition, DC subsets utilize different metabolic pathways, which enhance Foxp3 expression. These findings link nutrition, microbiota and the induction of tolerance within the gastrointestinal mucosa in the response to a probiotic. Disclosure: Dr. Liam O'Mahony - Consultant Alimentary Health Ltd. Prof. Fergus Shanahan - Consultant Alimentary Health Ltd. Prof. Eamonn M Quigley - Consultant Alimentary Health Ltd. Mr. David Groeger - Employee Alimentary Health Ltd. Dr. Barry Kiely - Employee Alimentary Health Ltd.
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