A19

The mechanistic basis of the link between obesity and increased colorectal cancer risk is unclear. One hypothesis is that chronic inflammation associated with obesity drives colorectal carcinogenesis. Therefore, we studied the effect of weight loss secondary to RYGB on mucosal biomarkers of epithelial proliferation, as well as levels of mucosal pro-inflammatory cytokines and markers of the systemic inflammatory response. Serum and rectal mucosa were obtained pre and post (6 months)-RYGB from 25 morbidly obese patients and 22 individuals with a normal BMI (18.5-25 kg/m2) undergoing routine sigmoidoscopy (enema preparation). Patients with chronic inflammatory conditions were excluded. Crypt mitosis and bifurcation were measured in 40 micro-dissected Schiff's reagent-stained crypts, in a blinded manner. Changes in mucosal pro-inflammatory gene mRNA levels were quantified by real-time PCR using the ΔΔCt method with GAPDH as the control transcript. Serum CRP was measured by high-sensitivity immunoassay. Morbidly obese patients (mean BMI [SEM] 54.8 [2.0] kg/m2) had a significantly higher number of mitoses per crypt than individuals with a normal BMI (median 4.2 versus 2.7; p<0.001) and % number of crypts in fission (median 0.05 versus 0; p<0.01). There was a mean weight loss of 23.4% following RYGB. However, there was a significant (mean 2.1 [95%CI 1.6-2.6] fold) increase in the crypt mitosis count (median 9.0) after surgery. Although the mean serum CRP level fell from 8.9 [1.6] to 4.0 [0.9] mg/dl (p=0.0001), the mucosal levels of mRNAs for TNFα, MIF, IL-1, and IL-6 increased after RYGB (mean fold increase 3, 12, 2, 2 respectively) compared with pre-operative values. Mucosal biomarkers of colorectal carcinogenesis risk are increased in morbidly obese patients compared with normal weight individuals. Mucosal biomarkers and levels of pro-inflammatory cytokines are increased 6 months after RYGB, despite significant weight reduction and reduced systemic inflammatory indices. This may reflect changes in the colorectal luminal micro-environment following RYGB. Our findings have potentially important consequences for future colorectal cancer risk following weight reduction surgery.

[Fifth AACR International Conference on Frontiers in Cancer Prevention Research, Nov 12-15, 2006]