The co-occurrence of the three disease entities, inflammatory bowel disease (IBD), colorectal cancer (CRC), type 2diabetes mellitus (T2DM) along with inflammation and dismicrobism has been frequently reported. Some authors have even suggested that dysbiosis could be the link through a molecular crosstalk of multiple inflammatory loops including TGFβ, NFKB, TNFα and ROS among others.

This review focuses on the inflammatory process along with the role of microbiota in the pathophysiology of the three diseases.

The etiology of IBD is multifactorial, and like CRC and T2DM, it is associated with a widespread and sustained GI inflammation and dismicrobism, whereby an array of pro-inflammatory mediators and other related biomolecules are up-regulated, both locally and systematically. Such a persistent or an inadequately resolved chronic inflammation may be a causative 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 its signaling cascade through smad 3, IL-6 and epithelial to mesenchymal transition. Such a cascade could lead to macrophages and other cells recruitment, inflammation, then IBD and CRC.

NFkB is also another key regulator in the crosstalk among the pathways leading to the three disease entities. It plays a major role in linking inflammation to cancer development through its ability to up regulate several inflammatory and tumor promoting cytokines like: IL-6, IL-1 α and TNF α, as well as genes like BCL2 and BCLXL. It activates JAK/STAT signaling network 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 matchmaker between inflammation, IBD, cancer and diabetes.

In addition, TNFα plays a pivotal role in systemic inflammation. It is increased in the mucosa of IBD patients and has a central role in its pathogenesis. It also activates other signaling pathways like NFKB and MAPK leading to CRC. It is also overexpressed in the adipose tissues of obese patients thus linking it to T2DM, chronic inflammation and consequently CRC.

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 modulates genotoxic metabolites which are able to induce CRC, a fact proven to be sustained by stool transfer from patients with CRC. Probiotics, however, may actively prevent CRC as well as IBD and results in a significant decrease in fasting glycemia in T2DM patients.

In conclusion, IBD, CRC and T2DM are commonly occurring interrelated clinical problems. They share a common basis influenced by an inflammatory process, an imbalance in intestinal microbiota, and a crosstalk between various signaling pathways. Would probiotics interrupt the crosstalk or orient it in the physiological direction?

The medical literature is depleting in publications reporting the co-occurrence of the three disease entities: inflammatory bowel disease (IBD), colorectal cancer (CRC) and type 2 diabetes mellitus (T2DM), along with inflammation and dismicrobism [8] , [17] , [21] , [41] and [51] . Actually, the body microbiota represents a complex ecosystem with enormous microbial diversity. Trillions of bacterial cells colonize the GI surface within the human body and can reach 10 times the number of the cells forming the whole organism. In addition; the genes of these microorganisms are 150 times higher in number than those in the human body. Most of the commensal bacteria are symbiotic; however, they could cause pathology after their translocation to the mucosa or under specific conditions. The largest number of bacterial cells is found in the large intestine (10¹¹ per gram of intestinal content), the main geography of IBD and CRC [19] and [41] .

In general, intestinal dysbiosis is associated with an undesirable qualitative and quantitative alteration in the balance between beneficial and harmful bacteria in the gut [17] . It is also well documented that changes in the homeostasis of the intestinal microbiota have far-reaching effects on local and systemic immunity and contribute to the pathogenesis of gastrointestinal diseases like inflammatory bowel disease, irritable bowel syndrome and colorectal cancer, as well as extra intestinal systemic diseases like obesity, diabetes and atherosclerosis among others [57] . Some authors have even suggested that dysbiosis could be the link between chronic inflammation, IBD, CRC and T2DM trough a crosstalk between several molecular pathways, in particular, TGFβ, NFKB, TNFα and ROS among others [20] . The mechanisms forming the basis of such a phenomenon were referred to a series of complex interactions between the intestinal epithelium, microbiota, genetic factors, and the host immune system, which modulate the intestinal equilibrium.

Normally, the intestinal epithelium has a critical function as a protective barrier against luminal antigens. It is covered by a single layer of intestinal epithelial cells (IECs) distinguished by a fast renewal rate. They are circumferentially tied by intracellular tight junctions and coated by a thick adherent mucus gel, thus forming a dynamic physical interface between the host and its environment [35] and [62] . Despite its robust and multi-faced nature, this barrier can be breached, hence disrupting the intestinal homeostasis, and thus promoting a state of chronic inflammation in all these three disease entities: IBD, T2DM and CRC [29] .

Normally, inflammation is basically a beneficial activity that rejuvenates injured tissue and removes the foreign agents disturbing homeostasis, thus leading to recovery of the equilibrium state. This task is achieved through a complex inflammatory response which may involve a balance between a huge panel of bioactive molecules, pro and anti-inflammatory (IL-6, NFKB, TNFα and TGFβ, among others …), provided from resident or infiltrating inflammatory cells. However, a persistent or an inadequately resolved chronic inflammation, due to the tilting of the balance in favor of pro-inflammatory agents, may increase the risk of several pathologies such as IBD, CRC and T2DM. How inflammation lies on the causative pathway mechanistically linking these three chronic clinical problems remains unclear [43] and [13] .

In this review, the focus is on the inflammation process as constituting the basis in the development of CRC, IBD and T2DM. Several molecular signaling pathways involved in such inflammation like TGFβ, JAK/STAT, TNFα, NFkB and ROS production mechanisms will be discussed, along with the role of microbiota in the physiopathology of these three diseases. Collectively, the molecular crosstalk between all of these pathways could probably define the nature of the link or links between all three disease entities.