The Link Between Bacterial Inflammagens, Leaky Gut Syndrome and Colorectal Cancer.

There is a causal relationship between cancer (including colorectal cancer), chronic systemic inflammation and persistent infections, and the presence of dysregulated circulating inflammatory markers. It is known that aberrant clot formation and coagulopathies occur in systemic inflammation. In colorectal cancer, there is a close link between gut dysbiosis and an inflammatory profile. In this review, we present evidence of the connection between gut dysbiosis, the entry of bacteria into the internal environment, and the presence of their highly potent inflammagenic molecules, such as lipopolysaccharide and lipoteichoic acid, in circulation. These bacterial components may act as one of the main drivers of the inflammatory process (including hypercoagulation) in colorectal cancer. We review literature that points to the role of these bacterial inflammagens and how they contribute to colorectal carcinogenesis. Insight into the factors that promote carcinogenesis is crucial to effectively prevent and screen for colorectal cancer. Early diagnosis of an activated coagulation system and the detection of bacterial components in circulation and also in the tumour microenvironment, could therefore be important, and may also, together with modulation of the gut microbiota, serve as potential therapeutic targets.

Bile Acids Activate NLRP3 Inflammasome, Promoting Murine Liver Inflammation or Fibrosis in a Cell Type-Specific Manner.

Bile acids (BA) as important signaling molecules are considered crucial in development of cholestatic liver injury, but there is limited understanding on the involved cell types and signaling pathways. The aim of this study was to evaluate the inflammatory and fibrotic potential of key BA and the role of distinct liver cell subsets focusing on the NLRP3 inflammasome. C57BL/6 wild-type (WT) and Nlrp3-/- mice were fed with a diet supplemented with cholic (CA), deoxycholic (DCA) or lithocholic acid (LCA) for 7 days. Additionally, primary hepatocytes, Kupffer cells (KC) and hepatic stellate cells (HSC) from WT and Nlrp3-/- mice were stimulated with aforementioned BA ex vivo. LCA feeding led to strong liver damage and activation of NLRP3 inflammasome. Ex vivo KC were the most affected cells by LCA, resulting in a pro-inflammatory phenotype. Liver damage and primary KC activation was both ameliorated in Nlrp3-deficient mice or cells. DCA feeding induced fibrotic alterations. Primary HSC upregulated the NLRP3 inflammasome and early fibrotic markers when stimulated with DCA, but not LCA. Pro-fibrogenic signals in liver and primary HSC were attenuated in Nlrp3-/- mice or cells. The data shows that distinct BA induce NLRP3 inflammasome activation in HSC or KC, promoting fibrosis or inflammation.