Lactobacillus delbrueckii CIDCA 133 Ameliorates Chemotherapy-Induced Mucositis by Modulating Epithelial Barrier and TLR2/4/Myd88/NF-κB Signaling Pathway

5-fluorouracil (5-FU) is widely used in the treatment of cancer. Over the past 20 years, increased understanding of the mechanism of action of 5-FU has led to the development of strategies that increase its anticancer activity. Despite these advances, drug resistance remains a significant limitation to the clinical use of 5-FU. Emerging technologies, such as DNA microarray profiling, have the potential to identify novel genes that are involved in mediating resistance to 5-FU. Such target genes might prove to be therapeutically valuable as new targets for chemotherapy, or as predictive biomarkers of response to 5-FU-based chemotherapy.

Innate immunity is the first line of defense against invading pathogens. A family of Toll-like receptors (TLRs) acts as primary sensors that detect a wide variety of microbial components and elicit innate immune responses. All TLR signaling pathways culminate in activation of the transcription factor nuclear factor-kappaB (NF-kappaB), which controls the expression of an array of inflammatory cytokine genes. NF-kappaB activation requires the phosphorylation and degradation of inhibitory kappaB (IkappaB) proteins, which is triggered by two kinases, IkappaB kinase alpha (IKKalpha) and IKKbeta. In addition, several TLRs activate alternative pathways involving the IKK-related kinases TBK1 [TRAF family member-associated NF-kappaB activator (TANK) binding kinase-1] and IKKi, which elicit antiviral innate immune responses. Here, we review recent progress in our understanding of the role of NF-kappaB in TLR signaling pathways and discuss potential implications for molecular medicine.

Probiotics are living microorganisms that confer health benefits to the host when administered in adequate amounts; however, dead bacteria and their components can also exhibit probiotic properties. Bifidobacterium and strains of lactic acid bacteria are the most widely used bacteria that exhibit probiotic properties and are included in many functional foods and dietary supplements. Probiotics have been shown to prevent and ameliorate the course of digestive disorders such as acute, nosocomial, and antibiotic-associated diarrhea; allergic disorders such as atopic dermatitis (eczema) and allergic rhinitis in infants; and Clostridium difficile-associated diarrhea and some inflammatory bowel disorders in adults. In addition, probiotics may be of interest as coadjuvants in the treatment of metabolic disorders, including obesity, metabolic syndrome, nonalcoholic fatty liver disease, and type 2 diabetes. However, the mechanisms of action of probiotics, which are diverse, heterogeneous, and strain specific, have received little attention. Thus, the aim of the present work was to review the main mechanisms of action of probiotics, including colonization and normalization of perturbed intestinal microbial communities in children and adults; competitive exclusion of pathogens and bacteriocin production; modulation of fecal enzymatic activities associated with the metabolization of biliary salts and inactivation of carcinogens and other xenobiotics; production of short-chain and branched-chain fatty acids, which, in turn, have wide effects not only in the intestine but also in peripheral tissues via interactions with short-chain fatty acid receptors, modulating mainly tissue insulin sensitivity; cell adhesion and mucin production; modulation of the immune system, which results mainly in the differentiation of T-regulatory cells and upregulation of anti-inflammatory cytokines and growth factors, i.e., interleukin-10 and transforming growth factor; and interaction with the brain-gut axis by regulation of endocrine and neurologic functions. Further research to elucidate the precise molecular mechanisms of action of probiotics is warranted.