Scientists reveal the mechanism by which intestinal flora regulates the development and progression of colorectal cancer

Recently, the team of Professor Fang Jingyuan of Renji Hospital affiliated to Shanghai Jiao Tong University School of Medicine published an article in “Cell-Metabolism”, revealing for the first time that intestinal flora can mediate the host urea cycle metabolic pathway, form an immune-microbial metabolic axis with the host, and then regulate the host’s immune metabolism and function, affecting the occurrence of colorectal cancer. This achievement provides a potential diagnosis, early warning and therapeutic target for intervention in the process of colorectal adenoma-adenocarcinoma.

Intestinal flora mediates host urea cycle metabolism. Photo courtesy of the research team

According to data released by the World Health Organization’s International Agency for Research on Cancer (IARC), the incidence of colorectal cancer in China has shown a rapid growth trend, with 550,000 new cases occurring every year. For the mechanism of colorectal cancer, most scholars currently believe that about 85% of sporadic colorectal cancers progress from adenomas.

Colonoscopy is widely used for population screening and surveillance and is the gold standard for colorectal cancer and adenoma diagnosis. Endoscopic removal of adenoma can reduce the incidence of colorectal cancer by 76%~90%. However, there is still a fairly high probability of recurrence after polypectomy. Adenoma recurrence and carcinogenesis are currently largely based on anatomic and histologic features (including polyp size, number, and presence of dysplasia).

“However, these features are not specific, and more precise clinical indicators are urgently needed to determine the malignant transformation of adenoma-adenocarcinoma.” Fang Jingyuan said, “Colorectal cancer patients often show the characteristics of intestinal dysbacteriosis, and our recent studies have found that intestinal bacteria such as Fusobacterium nucleatum and Bacteroides enterotoxin fragilisis promote the occurrence and development of colorectal cancer by promoting inflammation, destroying the intestinal microenvironment, and aggravating metabolic disorders.” ”

However, the mechanism of action of the interaction between gut microbiota and host metabolism leading to colorectal adenoma-adenocarcinoma transition remains unclear. In this study, the researchers focused on the interaction mechanism between intestinal microbiome and host metabolism, and confirmed that during the progression of colorectal adenoma-adenocarcinoma, adenocarcinoma, the host urea cycle metabolic pathway was significantly activated, accompanied by the loss of intestinal commensal bacteria with urea degradation function represented by bifidobacteria. High urea loading can disrupt intestinal immune homeostasis by inhibiting the binding efficiency of the two promoters in macrophages and promoting macrophage differentiation towards immunosuppressive subtypes. Further animal intervention experiments suggested that inhibitors of urea cycle pathway and urease-rich probiotics may be effective intervention agents to prevent recurrence and carcinogenesis of intestinal adenomas.

This basic combined with clinical verification research determined the new mechanism of urea cycle pathway as a host-microbe co-metabolism pathway involved in colorectal cancer, and proposed for the first time a new view of “intestinal bacteria and host co-metabolism regulating the intestinal immune microenvironment”, which supplemented and improved the knowledge and conceptual system of intestinal bacteria affecting the progression of colorectal adenoma from a new theoretical level, and also provided potential diagnosis, early warning and potential treatment strategies for intervention in the process of colorectal adenoma-adenocarcinoma. (Source: China Science News, Zhang Shuanghu, Huang Xin)

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