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Re: Chronic sub-clinical bowel inflammation may explain increased risk of colorectal cancer in the obese

Dear Editor,

We read with interest the recent articles on obesity, inflammation and Colorectal cancer (CRC).1,2,3 Although insulin resistance is the most widely accepted underlying mechanism explaining the association between obesity and CRC, recent evidence suggests that the effects of obesity on the immune system in general and specifically on the gut may play a role. We propose that obesity predisposes to CRC through its effects on innate immune activation (IIA) and a consequent sub-clinical bowel inflammation. We further propose that the role of insulin resistance is either complementary or might merely represent an epiphenomenon. Explained below is the justification of our argument.

We recently studied the determinants of whole gut inflammation in a normal middle-aged population by determining levels of calprotectin in faeces. Calprotectin is a calcium binding protein found only in neutrophils and monocytes. Levels in faeces correlate well with faecal levels of indium labelled white cells and inflammatory bowel disease activity. It is well established that many risk factors for CRC influence levels of IIA in the healthy individual. Lack of physical exercise for instance is associated with increased serum levels of C-reactive protein, as are body mass index, smoking and increasing age.4 We confirmed that faecal levels of calprotectin also correlated directly with increasing age, obesity and, lack of physical activity and fibre intake, demonstrating that these same environmental risk factors are also associated with bowel inflammation.5, (fig 1)

The link between chronic inflammation and CRC is well documented in patients with Ulcerative colitis. In our late middle aged population 25% of subjects had elevated faecal levels of calprotectin similar to those found in inflammatory bowel disease. Although these cancers follow a different histological course as compared to sporadic CRC, similar genetic mutations tend to occur with similar frequencies in both the groups suggesting that sporadic CRC could arise or be promoted on a background of chronic sub-clinical inflammation.6 Many other common cancers are associated with chronic inflammation including oesophageal, gastric, pancreatic and lung cancer. Furthermore, epidemiological studies have demonstrated the chemoprophylactic benefits of non-steroidal anti- inflammatory agents in colorectal and oesophageal cancers supporting the role of chronic inflammation in their pathogenesis.

The association between obesity, chronic sub-clinical bowel inflammation and ultimately CRC could result from the effects of obesity to promote generalised innate immune activation or through paracrine effects of mesenteric or serosal adipose tissue. The enlarged adipocytes of the obese synthesise increased amounts of various pro-inflammatory adipokines such as TNFα and IL-6, as well as other adipokines known to modulate immune function such as leptin (pro-inflammatory) and adiponectin (anti-inflammatory).7 Adipokines exert autocrine, paracrine or endocrine effects influencing various metabolic and immune processes. Many of these cytokines and adipokines contribute strongly to insulin resistance, which may merely be an epiphenomenon of this activation rather than playing a direct role in CRC pathogenesis. Elevated levels of pro- inflammatory cytokines and reduced levels of adiponectin have been noted in the serum of asymptomatic obese individual; levels corresponding to the degree of obesity. 7 Circulating mononuclear cells from the obese have been shown to exhibit increased NFκB nuclear binding with decreased levels of NFκB inhibitor, together with increased mRNA expression of IL-6, TNFα and migration inhibition factor. Furthermore there is a good correlation between the markers of macrophage activation and plasma levels of free fatty acids which represents an additional mechanism whereby adipose tissue could influence systemic inflammatory activity.8 Central or abdominal obesity more strongly correlates with the risk of colorectal cancer suggesting that the paracrine effects of mesenteric or serosal fat may be important. The association between lack of physical exercise and colorectal cancer can also be explained by an activated immune state secondary to a decreased vagal tone in the physically unfit.9 IIA and chronic inflammation are characterized by chronic NFκB activation which in turn promotes tumourogenesis by inhibiting apoptosis.3 These findings suggest that environmental factors could influence CRC development through activation of the innate immune system and its effect on promoting gut inflammation.

Pro-inflammatory mediators have been shown to increase gut permeability and consequently exposure to luminal antigens. For example, patients with histologically proven quiescent CD have increase gut permeability, attributable to the heightened local expression of TNFα.10 Treatment with infliximab (anti-TNFα agent) is associated with decrease in gut permeability in patients with active CD.11 Although most of the evidence emerges from studies in disease groups, similar mechanisms, albeit at a sub-clinical level may operate in normal obese subjects. Besides the increased circulating levels of pro- inflammatory mediators and free fatty acids associated with innate immune activation the paracrine effects of adipokines secreted by mesenteric or serosal fat could directly influence gut barrier function. Increased exposure to luminal antigens will induce a local immune response resulting in mucosal inflammation.

Epidemiological and cell culture studies have shown a correlation between CRC, hyperinsulinemia and increased IGF-1 levels. Although insulin has been shown to directly stimulate growth of colon cancer lines in vitro, its role in initiating tumourogenesis is doubtful as it is known to have anti-inflammatory properties. The role of IGF-1 as a pro-carcinogen is much better established, acting by promoting cell growth and inhibiting apoptosis. However, as mentioned by Freeza et al. recent studies have not shown a significant correlation between CRC and IGF-1 levels when a Bonferroni adjustment was applied.1 Insulin resistance furthermore may be the result of the IIA associated with obesity. This calls for a need to reconsider 'insulin resistance' as the underlying mechanism.

In conclusion, IIA could be the link between environmental risk factors and CRC. Processes secondary to IIA such as chronic gut inflammation and insulin resistance promote tumourogenesis. We propose that gut inflammation is the dominant mechanism responsible for the increased incidence of CRC in the obese and believe that the role of insulin resistance could represent an epiphenomenon. Further research in this direction is warranted.

References

1. Frezza EE, Wachtel MS, Chiriva-Internati M. Influence of obesity on the risk of developing colon cancer. Gut 2006;55(2): 285-91.

2. Hall NR. Survival in colorectal cancer: impact of body mass and exercise. Gut 2006; 55(1):8-10.

3. Boland CR, Luciani MG, Gasche C, Goel A. Infection, inflammation, and gastrointestinal cancer. Gut 2005;54(9):1321-31.

4. Mendall MA, Strachan DP, Butland BK, Ballam L, Morris J, Sweetnam PM, Elwood PC. C-reactive protein: relation to total mortality, cardiovascular mortality and cardiovascular risk factors in men. Eur Heart J. 2000;21(19):1584-90.

5. Poullis A, Foster R, Shetty A, Fagerhol MK, Mendall MA. Bowel inflammation as measured by fecal calprotectin: a link between lifestyle factors and colorectal cancer risk. Cancer Epidemiol Biomarkers Prev. 2004;13(2):279-84.

6. Clevers H. At the crossroads of inflammation and cancer. Cell 2004;118:671-674.

7. Kershaw EE, Flier JS. Adipose Tissue as an Endocrine Organ. The J Clin Endoc & Metab 2004;89(6):2548-2556.

8. Ghanim H, Aljada A, Hofmeyer D, Syed T, Mohanty P, Dandona P. Circulating mononuclear cells in the obese are in a proinflammatory state. Circulation 2004;110(12):1564-71.

9. Pavlov VA, Tracey KJ. The cholinergic anti-inflammatory pathway. Brain Behav Immun 2005;19(6):493-9.

10. Soderholm JD, Streutker C, Yang PC, Paterson C, Singh PK, McKay DM, Sherman PM, Croitoru K, Perdue MH. Increased epithelial uptake of protein antigens in the ileum of Crohn's disease mediated by tumour necrosis factor alpha. Gut 2004;53(12):1817-24.

11. Suenaert P, Bulteel V, Lemmens L, Noman M, Geypens B, Van Assche G, Geboes K, Ceuppens JL, Rutgeerts P. Anti-tumor necrosis factor treatment restores the gut barrier in Crohn's disease. Am J Gastroenterol 2002;97(8):2000-4.

Fig.1 Relationships between age, body mass index, physical activity, and fiber intake with fecal calprotectin geometric mean; bars, ±1 SE (Y axis logarithmic scale). Age quartiles 1 = 50–54, 2 = 55–59, 3 = 60–64, and 4 = 65–70. Body mass index quartiles 1 = 17.6–23.5, 2 = 23.6–25.6, 3 = 25.7–28.1, and 4 = 28.2–41.2. Fiber quartiles (%) 1 < 9.8, 2 = 10–13.9, 3 = 14–16.7, and 4 = 17–38.8. ⁵