Introduction

In recent years, the global health community has been struggling with bowel cancer, also known as colorectal cancer (CRC). CRC ranks as the third most common cancer worldwide, impacting millions of people each year. In 2020, there were approximately 1.9 million new cases and unfortunately 935,000 deaths.¹ Mostly associated with countries that have Western diets - low fibre and high carbohydrate consumption.

Pathophysiology of colorectal cancer

Colorectal cancer (CRC) develops through a complex process that involves changes in our genes -mutations- and how they're controlled. This progression is known as the adenoma-carcinoma sequence.² It's important to understand what we eat daily or in other words how we fuel our body it’s important. It usually starts with normal colon cells growing unusually and excessively, which leads to the forming of small growths called adenomas or polyps. Over time, these adenomas may accumulate more changes, eventually transforming into cancer. 

How?

Changes in the APC gene -Adenomatous Polyposis Coli- which normally helps control cell growth [3]. A diet rich in fruits, vegetables, and whole grains helps protect this gene.

Alterations in the KRAS gene can cause cells to keep growing when they shouldn't.⁴ Some studies suggest that certain nutrients, like omega-3 fatty acids found in fish, may help to balance out KRAS mutations.

Later changes in genes like TP53, SMAD4, and PIK3CA, can lead to uncontrolled growth and spread of cancer cells.⁵ A balanced diet with perfect amounts of vitamins and minerals helps maintain the integrity of these genes.

Some nutrients, such as folate and other B vitamins, play crucial roles in maintaining proper epigenetic regulation. Epigenetic changes, affect how genes are controlled without altering the DNA itself.⁶

The western diet and colorectal cancer risk

Sugar and mitochondrial dysfunction

Dysfunctional mitochondria cause oxidative stress and DNA damage. This leads to abnormal cell growth, Which leads to tumour formation.

Eating sugar leads to high levels of glucose (a type of sugar) in our cells. This overwhelms the cell's energy-producing structures called mitochondria, specifically a process known as the electron transport chain. As a result, there's an increased production of harmful molecules called reactive oxygen species (ROS). 

These ROS can damage the genetic material (DNA) and proteins within mitochondria. Also, high glucose levels can cause a process called glycation, where glucose attaches to proteins in the mitochondria, impairing their normal function.⁷

Fibre

Not having enough fibre in our daily diet can cause constipation, which results in faecal staying in the colon for longer periods. This leads to irritation and inflammation of the colon which can cause changes in colon cells and leads to bowel cancer. 

Dietary fibre is crucial for our gut health as it’s food for beneficial gut bacteria. These bacteria break down fibre to produce substances called short-chain fatty acids (SCFAs), including butyrate, acetate, and propionate. 

Butyrate is particularly important as it's an energy source for the cells lining our colon (colonocytes). It also has anti-inflammatory properties and may help prevent cancer.

Butyrate works by inhibiting certain enzymes called histone deacetylases (HDACs), which promote the activation of genes that help stop cell division - excessive cell growth - and trigger a process of controlled cell death called apoptosis when necessary.⁸

Alcohol

Drinking alcohol can damage the cells lining the intestines. This damage can lead to inflammation and changes in the cells, making them more likely to become cancerous. Alcohol also kills good bacteria in our gut and impacts how the body processes other harmful substances, which can increase cancer risk. 

When we drink alcohol, our body breaks it down in two main steps. First, an enzyme called alcohol dehydrogenase (ADH) converts alcohol into a substance called acetaldehyde. Then, another enzyme, aldehyde dehydrogenase (ALDH), further breaks down acetaldehyde into acetate. 

The problem is that acetaldehyde is highly reactive and can attach to our DNA, potentially causing mutations that could lead to cancer. 

Moreover, the breakdown of alcohol produces a molecule called NADH, which can disrupt the balance of certain chemical reactions in our cells (cellular redox balance) and contribute to oxidative stress, a condition that can damage our cells.⁹

Biochemical mechanisms of sugar-induced carcinogenesis

High sugar intake leads to increased blood sugar levels, causing the pancreas to release more insulin. Insulin is a hormone that helps cells absorb sugar. Over time, this can lead to insulin resistance, where cells don't respond well to insulin, and an increase in insulin-like growth factor 1 (IGF-1). Both insulin and IGF-1 activate a cellular pathway called PI3K/Akt, which:

1. Inactivates proteins that normally cause cell death, like BAD and caspase-9
2. Activates mTOR, a protein that promotes cell growth and the production of new proteins
3. Modifies FOXO proteins, preventing them from entering the cell nucleus and turning on genes that stop cell growth and cause cell death¹⁰

These changes can contribute to colorectal cancer (CRC) by helping abnormal cells survive and multiply.

The Importance of Dietary Fiber: How It Works Soluble and insoluble fibres work together in the gut, forming a gel-like structure that aids digestion. This "fishnet" effect is lost when fibres are separated, as often happens in processed foods.

1. Soluble fibre forms a thick gel in the intestine, slowing digestion and sugar absorption, which helps control blood sugar and insulin levels after meals
2. Insoluble fibre increases stool bulk and speeds up digestion, diluting potential cancer-causing substances and reducing their contact with the colon lining
3. Gut bacteria ferment both types of fibre to produce short-chain fatty acids (SCFAs), which:
   • Provide energy for colon cells
   • Make the gut environment more acidic, inhibiting harmful bacteria
   • Influence which genes are active by affecting histone deacetylases (proteins that modify DNA packaging)
   • Activate specific receptors (GPR41, GPR43) involved in controlling inflammation and metabolism¹¹

Mitochondrial problems and CRC

Cancer cells often change how they produce energy, a shift known as the Warburg effect. They take in more glucose and convert it to lactate, even when oxygen is present. This change is supported by:

1. Increasing the number of glucose transporters (like GLUT1) and enzymes that break down glucose
2. Activating cellular pathways (like PI3K/Akt, HIF-1α) that promote glucose breakdown
3. Problems with mitochondria (the cell's energy-producing structures), can be worsened by high sugar intake and oxidative stress (damage from reactive molecules)¹²

Gut microbiome and CRC: how gut bacteria interact

The community of microorganisms in our gut (the microbiome) influences CRC development through:

1. Producing beneficial substances (like SCFAs) and harmful compounds (like secondary bile acids)
2. Affecting the body's immune response and inflammation
3. Influencing the gut's protective barrier and the growth of intestinal cells

Specific bacteria have been linked to CRC, such as Fusobacterium nucleatum, which can promote tumour growth by activating a cellular pathway (β-catenin signalling) and recruiting cells that suppress the immune system.¹³

Antioxidants and CRC prevention

Antioxidants neutralize harmful molecules called free radicals and reactive oxygen species (ROS) through,

1. Directly removing ROS (e.g., vitamins C and E)- Directly removing harmful molecules
2. Binding to metal ions that create ROS (e.g., flavonoids)- Binding to metal ions that create harmful molecules
3. Increasing the production of the body's own antioxidant enzymes (e.g., sulforaphane activates Nrf2, which turns on genes for detoxifying enzymes)-Increasing our body's own antioxidant production

These actions help maintain the balance of reactive molecules in cells, prevent DNA damage, and influence cellular processes involved in cell growth and survival.¹⁴

Antioxidant-rich foods

1. Berries (blueberries, strawberries, raspberries)
2. Dark leafy greens (spinach, kale)
3. Nuts (pecans, walnuts, almonds)
4. Dark chocolate
5. Artichokes
6. Beans (red, pinto, black)
7. Beets
8. Broccoli
9. Green tea
10. Sweet potatoes

Processed meat and cell energy

Processed meats contain compounds like nitrosamines and polycyclic aromatic hydrocarbons that can damage mitochondrial DNA which can lead to cellular damage. However, unprocessed meats provide essential nutrients like essential nutrients for mitochondria:

1. Coenzyme Q10: An important component in the cellular energy production process
2. L-carnitine: Helps transport fatty acids into mitochondria
3. Iron: A key part of proteins involved in cellular energy production for mitochondria. Balancing meat consumption and choosing high-quality, unprocessed sources can support cell health while minimising potential cancer-causing effects¹⁵

Conclusion

The link between diet and colorectal cancer involves complex biological processes. Understanding these helps us develop better ways to prevent and treat CRC. A diet rich in whole foods, antioxidants, and fibre, while low in added sugars, processed meats, and alcohol, can influence key processes involved in cancer development. Future research should focus on understanding exactly how what we eat interacts with our genes, how our genes are controlled, and how our gut bacteria influence cancer risk.