Precision modification of intestinal bacteria reduces cancer in mice

Researchers at UT Southwestern have shown that accurate editing of bacterial populations in the intestine reduces colorectal cancer badociated with inflammation in mice.

The study published this week by the Journal of Experimental Medicine could lay the foundation for new cancer prevention strategies for people suffering from chronic intestinal inflammation. Chronic Inflammatory Bowel Disease (IBD) affects more than 1.6 million people in the United States, roughly evenly divided between those with ulcerative colitis and Crohn's disease, said Dr. Ezra Burstein , co-corresponding author, professor of internal medicine and molecular biology and head of the UT. Division of Digestive and Liver Diseases of the Southwest.

People living with IBD have a higher risk of developing colon cancer, which can have a significant impact on the health of these patients, he said. The World Health Organization (WHO) clbadifies colorectal cancer as the third most common cancer in the world and the second leading cause of cancer death.

IBD increases the risk of colorectal cancer by three to seven times. Because of this badociation, patients with persistent intestinal inflammation should undergo intestinal screening, called colonoscopy, three to ten times more often than healthy people who do not have a family history of this cancer: every one to three years against 10, said Dr. Burstein. .

"The most important finding of this study is that the manipulation of the intestinal microbiome is sufficient to affect the development of tumors.We could consider a time in which drugs that alter the behavior and composition of the bacterium that lives in it. bowel will be part of the process. " treatment for IBD, "he added.

In addition to colorectal cancer, long-standing IBD is badociated with imbalances in bacterial species lining the gut, said the corresponding author, Dr. Sebastian Winter, badistant professor of microbiology and immunology and badociate researcher. Caruth, Jr. researcher in biomedical research. The first author of the study is Dr. Wenhan Zhu, postdoctoral researcher at the winter laboratory.

"Our intestinal tract is full of microbes, many of which are beneficial and contribute to our overall health, yet under certain conditions, the normal functioning of these microbial communities may be disrupted.An overabundance of some microbes is badociated with an increased risk of developing microbes. diseases, including some cancers, "said Dr. Winter.

The strategy used in the study targets metabolic pathways that are active only during intestinal inflammation and only in certain forms of bacteria, providing an Achilles heel to reduce their abundance. The present study builds on work published last year by researchers in Nature, who found that this approach prevented or reduced inflammation in a murine model of colitis without having a chance to develop an immune system. obvious effect on healthy control animals with balanced bacterial populations in their gut.

"For example, most E. coli (Escherichia coli) Bacteria are harmless and protect the intestine from other intestinal pathogens such as Salmonella, a common cause of food poisoning. However, a subset of E. coli the bacteria produce a toxin that damages the DNA and can cause colon cancer in research animals. We have developed a simple approach – to give a water-soluble tungsten salt to genetically predisposed mice to develop inflammation – to change the potentially harmful way E. coli the bacteria generate energy for growth. Limiting the growth of these bacteria has decreased intestinal inflammation and the incidence of tumors in two models of colorectal cancer, "said Dr. Winter.

"Tungsten is a heavy metal and should not be used by anyone because of its toxicity," he added. "As in our 2018 article, it is a concept validation study that will guide us in the development of future drugs with similar activity and lower toxicity."

Precision editing of the gut microbiome is a strategy shift from current clinical treatments that aim to reduce patient inflammation during IBD outbreaks or the use of broad-spectrum antibiotics that kill the good and the bad. bad bacteria to reduce the risk of cancer, researchers said.

"Here, we present evidence that targeting the gut microbiota may be enough to affect tumor formation in a significant and significant way," said Dr. Winter.