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  • Galactose 1-phosphate  To investigate a potential mecha

    2019-07-24

    To investigate a potential mechanism through which a HFD diet promotes intestinal inflammation in mice Gulhane et al., observed that a HFD increased endoplasmic reticulum (ER) and oxidative stress, and reduced mucosal barrier integrity as exemplified by reduced Muc2 and claudin-1, and increased serum endotoxin levels [89]. In cultured intestinal cells, non-esterified long-chain saturated fatty acids increased oxidative and ER stress, and the intracellular aggregation of Muc2, illustrating an UPR response. Previous studies by the same group showed that interleukin 22 (IL-22) can suppress oxidative and ER stress in pancreatic β cells, by activating the antioxidant pathway and repressing the pathways promoting reactive oxygen and nitrogen species, to restore insulin secretion [90]. They therefore treated epithelial Galactose 1-phosphate  and Winnie mice with palmitate or HFD respectively with IL-22, and observed that IL-22 reduced oxidative and ER stress, and inflammation. Importantly, IL-22 therapy in HFD mice, resulted in the dose-dependent reduction in the extent of Escherichia coli, and this was associated with decreased serum endotoxin levels [89]. Collectively, these experimental data illustrate that a HFD can promote inflammation, ER stress and reduced epithelial barrier integrity in rodents, similar to but independent of the genetic changes observed in IBD patients. It is plausible that rodents due to their evolution and normal dietary intake are more susceptible to the induction of IBD by a HFD, whereas in contrast in humans who are omnivores are more resistant to a HFD, and hence additionally require genetic alterations and dysbiosis to promote IBD. Nonetheless, another possible modulator of colon integrity and promoter of IBD in patients and in rodent models, is the indirect action of the expanded fat mass, this we will now consider.
    Adipocytes and their functional roles in IBD The adipose tissue is composed of white adipose tissue (WAT) and brown adipose tissue (BAT). The WAT chiefly contains adipocytes, which store fat molecules depending on the needs of the body through lipogenesis and lipolysis [91]. Under normal conditions of equal energy consumption and expenditure, lipogenesis and lipolysis are balanced and fat does not accumulate. During excess nutrition, adipocytes undergo hypertrophy until they reach a threshold size, and hyperplasia is then triggered and pre-adipocytes differentiate into mature adipocytes [92]. The rapid expansion of the adipose tissue results in poor vascularisation and cellular apoptosis, which promotes hypoxia to stimulate angiogenesis, and macrophages infiltrate the adipose and form crown-like structures around the dead cells, and release inflammatory cytokines, such as TNF-α and IL-6 [[93], [94], [95], [96]]. Additionally, inflammatory ligands like lipopolysaccharide (LPS), activate receptors such as the Toll-like receptor (TLR) and subsequently stimulate the NF-κB pathway to further reinforce inflammatory cytokine production [93]. Importantly, the WAT also has active endocrine activity, and as adiposity increases, the secretion of growth factors known as adipocytokines, the majors being leptin and adiponectin (APN), becomes dysregulated. Both these have defining roles in promoting insulin resistance, the metabolic syndrome, modulating inflammation, cardiovascular dysfunction and hepatic disease [97]. The mechanistic roles of leptin and adiponectin (APN) in IBD are only beginning to be understood, thus we will now consider the published evidence and what this may mean for the field.
    Conclusions and the future direction of research The adipose tissue is a very active organ and as it expands due to a disequilibrium between energy intake and energy expenditure, and the secretion of adipocytokines is disturbed. These differences correspond with several diseases, such as the metabolic syndrome, increased cardiovascular risk, insulin resistance and certain cancers. Population studies have not been convincing in providing direct linkages between IBD and obesity. However, in murine models, the incorporation of genetic mutations found in human IBD patients, and the digestion of a high fat diet can potentiate colonic inflammation, an unfolded protein response, colonic permeability, and promote dysbiosis (Table 2). Another avenue through which colonic inflammation can become dysregulated is through altered systemic levels of adipocytokines. How adipocytokines affect the colon and IBD progression in the presence of other mutations presented here remains to be determined. It is likely that adipokine interactions in IBD is patient specific, and therapeutic responses will have to be developed to incorporate this diversity.