br Mechanism of action of probiotics The actual mechanism of

Mechanism of action of probiotics The actual mechanism of action of probiotics has not been clearly understood, however, documented results are those obtained from animal models and in vitro experiments. One mode of action of probiotics may be an improvement of the barrier functions of the gut mucosa (Fig. 1). Several strains of Lactobacillus and Bifidobacterium as well as structural components, and microbial-produced metabolites are able to stimulate epithelial cell signaling pathways [53]. The Nuclear Factor Kappa-Light-Chain-Enhancer of activated thymidylate synthase (NF-kB) pathway is modulated by probiotics at many different levels with effects seen on I Kappa B protein (IKB) degradation and ubiquitination [123], proteosome function [122] and nuclear-cytoplasmic movement of RelA through a PPAR-gamma dependent pathway. Some probiotics such as S. thermophilus and L. acidophilus alter the expression of tight junction proteins and/or their localization in both in vivo and in vitro models [54]. Lactobacillus plantarum MB452 has been shown to alter expression levels of genes coding for occludin, tubulin, proteasome and certain cytoskeleton anchoring proteins [55]. Other probiotics boost gut barrier function through increased production of cytoprotective molecules such as heat-shock proteins. In addition, probiotics are able to prevent cytokine and oxidant-induced epithelial damage thereby promoting cell survival [121]. Probiotics may also modulate the immune system functions. For instance, L. acidophilus has been found to modulate toll-like receptors and the proteoglycan recognition proteins of enterocytes, leading to activation of dendric cells and lymphocytes T-helper 1 responds. The resulting stimulation of lymphocytes T-helper 1 cytokines can suppress lymphocyte T-helper 2 responses which provoke the atopic issues [120]. By this mechanism, the probiotics such as L. acidophilus, and Rhamnococcus GG decrease skin sensitivity in children and can reduce disorders like eczema [56,57]. Another possible mechanism of action of probiotics may be their ability to suppress the growth of pathogenic bacteria by producing broad spectrum bacteriocins [58]. Probiotics such as B. infantis Y1, L. acidophilus MB 443, L. plantarum MB 452, L. paracasei MB 451, L. bulgaricus MB453 inhibit pathogens from binding to gut cell walls and also produce short chain fatty acids (SCFA) which decrease the pH of the gut to selectively favor the growth of desirable microbes [118,119]. Some strains of lactobacilli express human mucus-binding pili, which would enhance their ability for colonization [117].
Health effects of probiotics Though many human and animal studies have proved the health effects of probiotic consumption [59–61,103], health authorities have only approved claims on (a) lactose intolerance and lactose digestion and (b) cholesterol reduction mostly because of biomarker deficiency. Probiotics research is still in the early stages, and far more studies need to be conducted to determine the health benefits and safety of probiotics.
Future perspectives From general gut health, to immune support, skin health, cholesterol control, maybe even sensorimotor behaviors, the research thus continues to build. Over the past decade, there has been extensive work in animal models on how probiotics and prebiotics modulate host metabolism. Studies with animal models have shown that the gut microbiota can regulate inflammation, adiposity, satiety, energy expenditure and glucose metabolism. As more knowledge on the mechanisms from in vivo experiments is unraveling, there is a growing need to translate the results into humans. However, there are very few good, double-blind, placebo-controlled clinical trials that can prove causality of pro- and prebiotics on modulating human metabolism [62]. At present, high-quality human trials have demonstrated the potential for gut microbiota in manipulating and preventing or treating disease such as hypercholesterolemia and obesity [12,85,86]. Cholesterol lowering effects of fermented dairy products and encapsulated bile salt hydrolase (BSH) were reported in animal trials, with a reduction of 58% serum cholesterol level in rats by oral feeding of encapsulated BSH [87]. Though cholesterol reducing probiotic L. reuteri NCIMB 30242 (Micropharma, Canada) has been on the market as the first recognized biomaker of disease, in human trials, however, there are mixed outcomes [88,89]. This therefore calls for more work to carry out to identify strains with excellent activities as well as their mechanism of action. Lebeer et al. [90] have reported an increase in anti-inflammatory activity when lipoteichoic acid is removed from lactobacilli cell walls and this opens a new door to unraveling the mechanism by which probiotics work. Specific bacterial strains can therefore be genetically modified to study their mechanisms of action. Some animal studies have revealed that probiotics produce bioactive compounds which significantly contribute to functionality within the gastrointestinal tract [91]. Bifidobacterium breve, B. bifidum, B. pseudolongum and Lactobacillus convert linoleic acid (LA) into conjugated linoleic acid, CLA [92,93] which suppresses multistage carcinogenesis at different sites [94]. Lactobacillus helveticus and Bifidobacterium longum have also been reported to produce and respond to mammalian serotonin [95] and affect behavior modulation [96,97]. The ability of these bacteria to produce as well as respond to neurochemicals substantiates the potential of probiotics to influence psychological health and general behavior as observed by Hsiao et al. [98] and Tillisch et al. [99]. It is therefore probable that modulating the gut microbiota with such biotherapeutics may target stress-related CNS disorders, including stress-induced cognitive deficits [100]. However, elucidation of mechanisms and substantiation of animal studies in humans remain essential research goals.