Fermented functional foods present biogenic properties related to the microbial production of bioactive metabolites produced during the fermentation process.4Lactobacillus helveticus have been used to generate bioactive peptides that exhibit antihypertensive, antimicrobial, and immunomodulatory properties during milk fermentation47,48 and increase osteoblastic bone formation in vitro.49L. paracasei CBA L74-fermented milk preparations for infant formula present a strong anti-inflammatory activity both in vitro, reducing S. typhimurium-induced damage of dendritic cells, and in vivo. In murine dextran sodium sulphate colitis models, these preparations reduce severity of colitis and favor a better recovery.24 These activities were not dependent on the inactivated bacteria but on the metabolic products released during the fermentation process. Finally, L. rhamnosus also has recently been shown to produce exopolysaccharides in skim milk with potential immunomodulatory activity.50 These products suppress cytokines-induced apoptosis and attenuate hydrogen peroxide-induced disruption in intestinal cells in murine models of colitis.40
To date, p40 and p75 are the first identified probiotic bacterial soluble proteins regulating intestinal epithelial homeostasis through specific cellular signal transduction pathways. The antiapoptotic effects of soluble factors are likely associated to a phosphatidylinositol-3′-kinase (PI3K)-dependent Akt activation, subsequent to activation of EGF receptor (EGFR).52 Previous studies have underlined both the importance of EGF in maintaining intestinal health and inducing restitution of the damaged epithelium53 and the crucial regulatory role played by the serine/threonine kinase Akt in different physiological cellular processes (cell differentiation, cell cycle, transcription, translation, metabolism, and apoptosis).54 Akt is able to promote cell survival through a 2-fold way: the inactivation of proapoptotic signals and activation of antiapoptotic signals.55
In particular, on epithelial cells, p40 stimulates the activity of the nonreceptor tyrosine kinase, Src that activates EGFR directly or indirectly through activation of matrix metalloproteinases, which are proteotytic enzymes that induce release of EGFR ligands for transactivation of EGFR and its downstream target, Akt46,56 (Fig. 2A). p40 has also relevant immunoregulatory functions acting on macrophages and lymphocytes to directly downregulate proinflammatory cytokine production.46
The available experimental data indicate that probiotic-derived factors, whose presently suggested definition is “postbiotics,” have beneficial properties against pathogen-induced inflammation and related alteration of cytokine release. Several distinct cellular and molecular mechanisms have been proposed and described such the enhancement of the innate immunity, as well as the promotion of intestinal epithelial cell survival and barrier function. The identification of soluble factors mediating the beneficial effects of probiotics may present an opportunity not only to understand their fine mechanisms of action, but also to develop effective pharmacological strategies apted to integrate the action of treatments with live bacteria. Future in vivo studies in animal models will help to determine the feasibility of their use to regulate intestinal inflammatory responses and to promote maintenance of intestinal epithelial integrity.
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