Molecular Effects of Aspirin & Metformin on Colonic Epithelium

Bowel cancer, a significant problem in the United Kingdom (UK) with \~ 41,000 diagnoses and \~ 16,000 deaths annually, has a large preventable component (\~54%). It is, in part, due to energy imbalance within bowel cells as suggested by associated risk factors: high-fat diet, obesity, physical inactivity and type 2 diabetes mellitus. Drugs that decrease bowel cancer risk, like aspirin and metformin, may prevent the disease by mimicking the molecular effects of dietary restriction and exercise. Energy imbalance, through obesity, expands stem cells which may increase bowel cancer. We have shown that aspirin activates an energy molecule, which increases when we exercise, and blocks signalling associated with obesity in bowel cancer. Indeed aspirin in combination with metformin (commonly used in diabetes) has a greater effect on this pathway than either drug alone. To predict which patients may benefit from aspirin and metformin, we need to discover if these drugs may mimic healthy lifestyle changes at a cellular level and which cells are being targeted. This project investigates how aspirin and metformin influence energy molecules in bowel cells to mimic beneficial effects of exercise or dietary restriction. Participants, recruited from Western General Hospital (Edinburgh) colorectal clinics, will have bowel lining and blood samples take initially and then depending on their assigned cohort, after; 24 hours, 7 days, 28 days or a 6-week course of aspirin, metformin or both tablets. Samples will be analysed for energy genes (main outcome). Secondary outcomes will measure effects on quantitative faecal immunochemical tests (qFIT), used to detect blood in the stool, and on gut bacteria. This critical research will inform how aspirin and metformin can be used in specific populations to decrease bowel cancer risk and to develop new drugs to target abnormal energy pathways.

Sex

All

Minimum age

16 Years

Inclusion Criteria:

All participants who are capable of giving informed consent. All participants aged 16 years or over. All participants must have no known contraindications to rectal biopsy procedures.

All participants must be resident in the United Kingdom. All participants must have no known contraindications to aspirin and metformin.

Exclusion Criteria:

Unable to give informed consent. Under the age of 16 years. Individuals who are taking anti-coagulation medication. Individuals with platelet disease or other bleeding issues. Individuals with a history of a significant rectal bleed. History of diabetes mellitus or impaired glucose tolerance. Any contraindication to either aspirin or metformin. Female subjects of child bearing age who are not taking effective contraception during the period of the trial