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  • An important protein involved in cell cell adhesion is


    An important protein involved in cell-cell adhesion is epithelial-cadherin (E-cadherin; CDH1). E-cadherin is involved in key morphogenetic processes such as cell growth, epithelial differentiation, and proliferation [75]. Genetic studies have shown that truncated forms of E-cadherin are associated with Crohn's disease, and intestinal biopsies from patients with Crohn's disease carrying these mutant BYL-719 show inappropriate protein localization and cytosolic accumulation of E-cadherin [76]. The nuclear transcription factor, hepatocyte nuclear factor 4α (HNF4α), modulates the expression of several genes involved in metabolism, cell junctions, differentiation and proliferation in the liver and intestinal epithelial cells. HNF4α is down-regulated in patients with IBD and mice with specific intestinal epithelial cell removal of Hnf4α are more susceptible to chemically induced colitis, indicating HNF4α is necessary for intestinal barrier function [[77], [78], [79]]. Taken together genetic polymorphisms and subsequent murine studies have linked genes involved with inflammation, autophagy, endoplasmic reticulum stress, barrier function and cell adhesion with IBD. Nonetheless, as discussed in the aforementioned sections, the correlation between increased body weight and human IBD risk is poor. However, IBD can progress to colitis-associated colorectal cancer (CRC), and is responsible for 10–15% of all deaths among IBD patients [80]. Additionally, overweight and obese individuals have an increased risk of developing CRC, and the number of patients diagnosed with CRC is increasing [[81], [82], [83], [84]]. However, the genetic changes that have been described as causative factors for increased IBD risk have been in humans for millennia. Therefore, apart from genetic change and bacterial type being associated with IBD, there must be other causative effectors that a western diet and obesity dysregulate. The evidence for this we will now consider.
    Experimental evidence for a western diet as a risk factor in IBD Since the data concerning links with adiposity and IBD in humans is inconclusive, mouse models have been developed to explore this relationship. Ma and colleagues fed C57BL/6 mice either a high-fat diet (HFD) or a normal chow, and then exposed them to DSS to induce colonic inflammation. The HFD fed mice had shorter colons, more inflammation and greater weight loss than their normal chow counterparts. In addition, they observed that HFD mice had greater numbers of non-CD1d-restricted natural killer (NK) cells, and they expressed more tumour necrosis factor (TNF-α) and interferon (IFN-γ). HFD mice also had decreased levels of colonic immunosuppressive T regulatory cells (Treg), and the depletion of colonic NK T cells or the adoptive transfer of Treg cells reduced DSS colitis in HFD mice, and TNF-α and IFN-γ expression [85]. Similarly, Cheng et al., fed mice a low fat (LFD) or HFD diet and then treated them with 2% DSS for 7 days. They observed that HFD/DSS mice developed more severe colitis as shown by shorter and more damaged colons, epithelial loss, and an increased inflammatory response, compared to LFD/DSS mice [86]. An additional study, showed alike pathology findings with an increased inflammatory infiltrate consisting of macrophages, neutrophils and lymphocytes in both the colon and visceral adipose tissue (VAT) of the DSS HFD group. They found as well in the adipose tissues increased levels of Toll like receptor 4 (TLR4), IL-6 and TNF-α, showing that a HFD promoted inflammation in the fat deposits and colon [87]. In contrast, to illustrate the favourable aspects of a high fibre diet on colitis outcome, a Korean group fed mice a HFD in combination with a normal raw diet (NRM), consisting of dried fruits, vegetables and brown rice. They showed that the NRM, was protective against colitis, reducing colonic shortening, damage and the infiltration of inflammatory, and the serum levels of IL-6, TNF-α and IL-1β [88].