Abstract
Host intestinal epithelial cells (IEC) present at the gastrointestinal interface are exposed to pathogenic and non-pathogenic bacteria and their products. Certain probiotic lactic acid bacteria (LAB) have been associated with a range of host-immune modulatory activities including down-regulation of pro-inflammatory gene expression and cytokine production by IEC, with growing evidence suggesting that these bacteria secrete bioactive molecules with immunomodulatory activity. The aim of this study was to determine whether two lactobacilli with immunomodulatory activity [Lactobacillus rhamnosus R0011 (Lr) and Lactobacillus helveticus R0389 (Lh)], produce soluble mediators able to influence IEC responses to Pattern Recognition Receptor (PRR) ligands and pro-inflammatory cytokines [Tumor Necrosis Factor α (TNFα), Interleukin-1β (IL-1β)], signals inducing IEC chemokine production during infection. To this end, the effects of cell-free supernatants (CFS) from Lr and Lh on IEC production of the pro-inflammatory chemokines interleukin (IL)-8 and cytokine-induced neutrophil chemoattractant 1 (CINC-1) induced by a range of host- or pathogen-derived pro-inflammatory stimuli were determined, and the impact on human HT-29 IEC and a primary IEC line (rat IEC-6) was compared. The Lr-CFS and Lh-CFS did not significantly modulate basal IL-8 production from HT-29 IECs or CINC-1 production from IEC-6 cells. However, both Lr-CFS and Lh-CFS significantly down-regulated IL-8 production from HT-29 IECs challenged with varied PRR ligands. Lr-CFS and Lh-CFS had differential effects on PRR-induced CINC-1 production by rat IEC-6 IECs, with no significant down-regulation of CINC-1 observed from IEC-6 IECs cultured with Lh-CFS. Further analysis of the Lr-CFS revealed down-regulation of IL-8 production induced by the pro-inflammatory cytokines IL-1β and TNFα Preliminary characterization of the bioactive constituent(s) of the Lr-CFS indicates that it is resistant to treatment with DNase, RNase, and an acidic protease, but is sensitive to alterations in pH. Taken together, these results indicate that these lactobacilli secrete bioactive molecules of low molecular weight that may modulate host innate immune activity through interactions with IEC.
Highlights
Lactic acid bacteria (LAB) have been associated with a wide array of host-immune modulatory effects, some of which are mediated through direct interactions with host IECs
In order to determine whether secreted products from L. rhamnosus R0011 and L. helveticus R0389 could increase or down-regulate constitutive IL-8 production from HT-29 IECs or CINC-1 production from IEC-6 IECs, concentrations of these chemokines were measured after IEC culture with 40% v/v of the L. rhamnosus R0011 cell-free supernatant (Lr-CFS) or L. helveticus R0389 cell-free supernatant (Lh-CFS) for 6 h
Varied strain-dependent host defense-associated activities have been reported for LAB, including stimulation of the immune system, modulation of host immune responses to pro-inflammatory challenges, and the ability to antagonize the attachment of known-gut pathogens to IECs [41]
Summary
Lactic acid bacteria (LAB) have been associated with a wide array of host-immune modulatory effects, some of which are mediated through direct interactions with host IECs. Several species of lactobacilli and bifidobacteria have been characterized for their ability to modulate immune activity and to antagonize gut pathogen attachment to IECs [reviewed in [9, 10]], and the ability of certain strains to down-regulate proinflammatory cytokine production by human IECs challenged with innate immune stimulants via direct contact with host cells has been characterized extensively [reviewed in [7, 11, 12]]. L. reuteri 6475 produces histamine which has been associated with inhibiting TNFα production in human monocytes via inhibition of the MAPK signaling pathway [22] Taken together, these studies emphasize the need to examine secreted products of immunomodulatory LAB to further interrogate their dynamic cross-talk with host immune cells
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