Inflammatory bowel disease, colorectal cancer and type 2 diabetes mellitus: the links

AbstractThe co-occurrence of the three disease entities, inflammatory bowel disease (IBD),colorectal cancer (CRC), type 2diabetes mellitus (T2DM) along with inflammation anddismicrobism has been frequently reported. Some authors have even suggested thatdysbiosis could be the link through a molecular crosstalk of multiple inflammatory loopsincluding TGFβ, NFKB, TNFα and ROS among others.This review focuses on the inflammatory process along with the role of microbiota in thepathophysiology of the three diseases.The etiology of IBD is multifactorial, and like CRC and T2DM, it is associated with awidespread and sustained GI inflammation and dismicrobism, whereby an array of proinflammatorymediators and other related biomolecules are up-regulated, both locally andsystematically. Such a persistent or an inadequately resolved chronic inflammation may be acausative agent, in the presence other factors, leading to several pathologies such as IBD,CRC and T2DM.TGFβ plays a crucial role in pancreatic β cell malfunctioning as glucotoxicity stimulates itssignaling cascade through smad 3, IL-6 and epithelial to mesenchymal transition. Such acascade could lead to macrophages and other cells recruitment, inflammation, then IBD andCRC.NFkB is also another key regulator in the crosstalk among the pathways leading to the threedisease entities. It plays a major role in linking inflammation to cancer development throughits ability to up regulate several inflammatory and tumor promoting cytokines like: IL-6, IL-1 αand TNF α, as well as genes like BCL2 and BCLXL. It activates JAK/STAT signalingnetwork via STAT3 transcription factors and promotes epithelial to mesenchymal transition.It also increases the risk for T2DM in obese people. In brief, NFKB is a matchmakerbetween inflammation, IBD, cancer and diabetes.In addition, TNFα plays a pivotal role in systemic inflammation. It is increased in the mucosaof IBD patients and has a central role in its pathogenesis. It also activates other signalingpathways like NFKB and MAPK leading to CRC. It is also overexpressed in the adiposetissues of obese patients thus linking it to T2DM, chronic inflammation and consequentlyCRC.On the other hand, increasing evidence suggests that dysbiosis plays a role in initiating,maintaining and determining the severity of IBD. Actually, among its functions, it modulatesgenotoxic metabolites which are able to induce CRC, a fact proven to be sustained by stooltransfer from patients with CRC. Probiotics, however, may actively prevent CRC as well asIBD and results in a significant decrease in fasting glycemia in T2DM patients.In conclusion, IBD, CRC and T2DM are commonly occurring interrelated clinical problems.