Abstract
Probiotics, such as lactic acid bacteria (LAB) and Bacillus subtilis var. natto, have been shown to modulate immune responses. It is important to understand how probiotic bacteria impact intestinal epithelial cells (IECs), because IECs are the first line of defense at the mucosal surface barrier and their activities substantially affect the gut microenvironment and immunity. However, to date, their precise mechanism remains unknown due to a lack of analytical systems available for live animal models. Recently, we generated a conditional Ca2+ biosensor Yellow Cameleon (YC3.60) transgenic mouse line and established 5D (x, y, z, time, and Ca2+) intravital imaging systems of lymphoid tissues including those in Peyer’s patches and bone marrow. In the present study, we further advance our intravital imaging system for intestinal tracts to visualize IEC responses against orally administrated food compounds in real time. Using this system, heat-killed B. subtilis natto, a probiotic TTCC012 strain, is shown to directly induce Ca2+ signaling in IECs in mice housed under specific pathogen-free conditions. In contrast, this activation is not observed in the Lactococcus lactis strain C60; however, when we generate germ-free YC3.60 mice and observe the LAB stimulation of IECs in the absence of gut microbiota, C60 is capable of inducing Ca2+ signaling. This is the first study to successfully visualize the direct effect of probiotics on IECs in live animals. These data strongly suggest that probiotic strains stimulate IECs under physiological conditions and that their activity is affected by the microenvironment of the small intestine, such as commensal bacteria.
Highlights
Food compounds are digested and absorbed through the gastrointestinal tract for nutrition, and probiotic bacteria and polysaccharides affect immunological homeostasis in the gut [1,2,3,4,5,6]
We previously established an intravital imaging system of Ca2+ signaling in lymphoid tissues, such as in Peyer’s patches, spleen, and bone marrow [25]
We establish a real-time visualization system of Ca2+ signaling in small intestinal epithelial cells (IECs) in vivo to monitor food signals
Summary
Food compounds are digested and absorbed through the gastrointestinal tract for nutrition, and probiotic bacteria and polysaccharides affect immunological homeostasis in the gut [1,2,3,4,5,6]. Oral administration of some LAB strains has been shown to stimulate innate immunity at mucosal sites and to potentiate systemic immune responses against pathogenic bacteria or viruses [13,14,15,16,17]. Most LAB strains contain large amounts of doublestranded RNA and are sensed by the endosomal toll-like receptor (TLR) 3 on intestinal dendritic cells to produce interferon-β. This innate sensing procedure contributes to anti-inflammatory and protective immune responses both locally and systemically; both live and inactive LAB can be utilized as effective probiotics [12]. We have not determined the mechanism of interaction between LAB and intestinal epithelial cells (IECs)
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