New research, published in the journal Nature Communications, shows how our diet affects bacteria in our gut, which, in turn, can alter the behavior of our genes and the risk of cancer. The good bacteria in our gut offer a protective barrier against harmful viruses, but they can also influence the behavior of our genes. The link between intestinal bacteria and the risk of colorectal cancer has received increasing attention in recent years. Last year, the NCI estimated more than 135,000 new cases of this cancer, with over 50,000 people dying from the disease. According to the National Cancer Institute (NCI), colorectal cancer is the fourth most common type of cancer, after breast, lung and prostate. About a year ago, there has been reported a study showing how different diets alter the bacteria in our gut which, in turn, affects the risk of developing colorectal cancer. Now, new research deepens our understanding of the connection between intestinal bacteria and the risk of developing colorectal cancer and various infections. The new study, led by dr. Patrick Varga-Weisz, of the Babraham Institute of Cambridge, England, shows how intestinal bacteria can influence genes, which therefore influence the risk of disease. Dr. Varga-Weisz and the team conducted experiments with mice and cultures of human cells, focusing on the role of molecules called short-chain fatty acids (SCFA) in disease prevention.
SCFAs are produced by intestinal bacteria during the digestion of fruits, vegetables and generally plant fibers. They can be used as a source of energy from our intestine lining cells, influencing their genes. Researchers used antibiotics to reduce intestinal bacteria in mice, analyzed their fecal samples and cells from their intestinal epithelium, i.e. the mucosa. A link between cellular metabolism, SCFAs, and transcriptional regulation is particularly relevant in the intestine where microorganisms break down complex carbohydrates to SCFAs such as acetate, propionate, and butyrate. SCFAs are an important component of normal gut physiology by providing a major energy source for the colon epithelial cells. They also affect cellular functions and modulate immune responses, in part by affecting gene expression and the epigenome Dr. Varga-Weisz and his team added SCFAs to human colon cancer cells and found that crotonylations increased, which are protein modifications that can activate or deactivate genes. These crotonylations were produced by inhibiting a protein called HDAC2. Previous studies have shown that a high number of HDAC2 proteins can increase the risk of colorectal cancer. Furthermore, bacteria-free mice showed a high number of HDAC2 proteins. Fruits and vegetables are essential for producing SCFA and these acids help regulate crotonylations.
So the results, the researchers explain, suggest that the regulation of crotonylation in the genome of intestinal cells can prevent cancer, and that a healthy diet of fruit and vegetables is essential for this prevention. A surprising finding of our work is that depletion of the microbiota of mice with antibiotics not only led to a drop in luminal and serum SCFAs, but also an increased expression of HDAC2 in colon. A reduction in histone crotonylation is consistent with both changes. A loss of SCFAs upon microbiota depletion may lead to stabilization or increased expression of HDAC2. In this context, it is interesting to note that a previous study has shown that the stability of HDAC2 is selectively reduced by the HDAC inhibitor valproic acid (a branched SCFA). Dr. Rachel Fellows explains: “SCFAs are a key energy source for cells in the gut, but we have also shown that they influence the genome’s crotonilation. Crotonilation is found in many cells but is particularly common in the gut. Our study reveals why this is the case by identifying a new role for HDAC2, which in turn is implicated in cancer and offers a new interesting drug target to be studied further. There is no need to remember how our gut is the home of countless bacteria, which produce certain vitamins, or that aid in the digestion of foods, elimination of harmful bacteria and educate our immune system to tolerance, a fundamental part of these processes”.
- a cura del Dr. Gianfrancesco Cormaci, Medico specialista in Biochimica Clinica.
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