Effects of Probiotics at the Interface of Metabolism and Immunity to Prevent Colorectal Cancer-Associated Gut Inflammation: A Systematic Network and Meta-Analysis With Molecular Docking Studies

Abstract

BackgroundDysbiosis/imbalance in the gut microbial composition triggers chronic inflammation and promotes colorectal cancer (CRC). Modulation of the gut microbiome by the administration of probiotics is a promising strategy to reduce carcinogenic inflammation. However, the mechanism remains unclear.MethodsIn this study, we presented a systematic network, meta-analysis, and molecular docking studies to determine the plausible mechanism of probiotic intervention in diminishing CRC-causing inflammations.ResultsWe selected 77 clinical, preclinical, in vitro, and in vivo articles (PRISMA guidelines) and identified 36 probiotics and 135 training genes connected to patients with CRC with probiotic application. The meta-analysis rationalizes the application of probiotics in the prevention and treatment of CRC. An association network is generated with 540 nodes and 1,423 edges. MCODE cluster analysis identifies 43 densely interconnected modules from the network. Gene ontology (GO) and pathway enrichment analysis of the top scoring and functionally significant modules reveal stress-induced metabolic pathways (JNK, MAPK), immunomodulatory pathways, intrinsic apoptotic pathways, and autophagy as contributors for CRC where probiotics could offer major benefits. Based on the enrichment analyses, 23 CRC-associated proteins and 7 probiotic-derived bacteriocins were selected for molecular docking studies. Results indicate that the key CRC-associated proteins (e.g., COX-2, CASP9, PI3K, and IL18R) significantly interact with the probiotic-derived bacteriocins (e.g., plantaricin JLA-9, lactococcin A, and lactococcin mmfii). Finally, a model for probiotic intervention to reduce CRC-associated inflammation has been proposed.ConclusionProbiotics and/or probiotic-derived bacteriocins could directly interact with CRC-promoting COX2. They could modulate inflammatory NLRP3 and NFkB pathways to reduce CRC-associated inflammation. Probiotics could also activate autophagy and apoptosis by regulating PI3K/AKT and caspase pathways in CRC. In summary, the potential mechanisms of probiotic-mediated CRC prevention include multiple signaling cascades, yet pathways related to metabolism and immunity are the crucial ones.

Bioactive Feed Additive for the Prevention of Clostridial Disease in High-Yielding Dairy Cattle

“…Probiotics, used for prevention or treatment of clostridia, act through multiple possible mechanisms, including the restoration of normobiotic resistance, antagonistic activity, and synthesis of a wide range of metabolites, which have a protective effect on the main targets of Clostridia [61][62][63]. They protect cells from damage and reduce the level of expression (activity) of apoptosis (cell death) and inflammation genes [64,65].…”

Beneficial insights into postbiotics against colorectal cancer

“…Probioticsderived bacteriocins, including plantaricin JLA-9, plantaricin W, lactococcin A, and lactococcin MMFII directly interact with CRC-promoting protein COX2 and modulate inflammasome complex NLRP3 and NF-kB pathways to reduce CRC-associated inflammation. They also have the potential of activating autophagy and apoptosis by regulating PI3K/AKT and caspase pathways in CRC (140).…”

Das intestinale Mikrobiom bei gastroenterologischen Krankheitsbildern

“…B. β-Galaktosidase oder Exopolysaccharide. In vielen Fällen führen sie aber auch zu einer immunregulatorischen Wirkung und hemmen so die entzündungsvermittelte Karzinogenese [7].…”