Why does a high-fat diet promote cancer? It turns out that they are "covering" cancer cells

Colorectal cancer (CRC) refers to cancers that begin in the tissues of the colon or rectum. After breast cancer and lung cancer, it is the commonly occurring malignant tumor. The proportion of patients can reach 9.4 %.

Diet is a significant component that has a direct impact on health and disease states. Long-term dietary patterns (e.g., high-fat diets) have been related to various types of cancer, including colon cancer, in a rising number of important epidemiological and preclinical studies. However, it is unknown how intestinal epithelial cell adaptation to a high-fat diet affects cancer risk.

Lgr5+ intestinal stem cells (ISC) found at the base of the crypt maintain the intestinal epithelium and create a number of unique cell types in the intestine's inner wall. These rapidly renewing ISCs coordinate intestinal adaptation by balancing stem cell self-renewal and differentiation in response to dietary changes. Intestine stem cells are related to dietary nutrients, symbiotic bacteria, and immune cells, and are the origin cells of many early intestinal cancers. Understanding how nutrition affects intestinal stem cells and their surrounding components can assist clarify the early stages of colorectal cancer development.

A team of researchers from Cold Spring Harbor Laboratory, Harvard Medical School, and MIT discovered through mouse experiments that a high-fat diet disrupts the interactions between the gut microbiome, intestinal stem cells, and the immune system, causing immune cells to "turn a blind eye" to cancer-like cells. This led immune cells to become "blind" to cancer-like cells, creating a breeding ground for tumor growth. It is believed that cancer immunotherapy will be improved through diet, drugs, or modifying the composition of the gut microbiome.

Although several strategies employed by cancer to avoid detection by the immune system have been thoroughly researched. However, scientists aren't sure how diet affects tumor immune recognition by intestinal stem cells.

Under normal circumstances, immune cells patrol the tissues, looking for and removing health hazards. Some immune cells search for labels that differentiate normal cells from abnormal cells. The major histocompatibility complex class II, or MHC class II, is one of these.

The fundamental mechanism for inducing antitumor immunity is T cell identification of antigens via the antigen presentation pathway. While activation of cytotoxic CD8+ T cells mediated by the major histocompatibility complex class I (MHC class I) antigen presentation pathway plays a major role in the antitumor immune response, activation of CD4+ T cells via MHC class II is also critical for tumor immunity.

Researchers evaluated mRNA sequencing data from Lgr5+ intestinal stem cells isolated from control and high-fat diet-fed mice to investigate how a high-fat diet interferes with immunomodulatory gene expression in intestinal stem cells.

They discovered that a high-fat diet decreased MHC class II gene expression in intestinal epithelial cells, particularly ISC, and that decreased epithelial MHC class II expression was linked to decreased intestinal microbiome diversity. This means that the immune system does not recognize these markers, allowing aberrant cells to elude detection and proliferate into tumor cells in the background.

Researchers sequenced fecal DNA obtained from high-fat-fed mice and controls for comparison to acquire insight into the microbiome members capable of triggering epithelial MHC class II expression. Consistent with earlier findings, obesity caused by a high-fat diet resulted in a dysregulated intestinal microbiome with lower bacterial diversity in the feces. Helicobacter spp. were among the bacteria that were considerably reduced under high-fat diet conditions.

The researchers used a "messy roommate" experiment to see if Helicobacter colonization in mice is connected with MHC class II expression in the intestinal epithelium. They housed bacteria-free mice alongside regular mice. As a result, the "clean" mice became infected with H. pylori and produced an increased number of MHC-II tags.

The researchers subsequently performed fecal transplants on germ-free mice and found that Helicobacter colonization linked with MHC class II expression in intestinal epithelial tissues.

These findings demonstrate that MHC class II expression in epithelial tissue is regulated by intestinal commensal bacteria, particularly Helicobacter, and is inhibited in response to a high-fat diet.

This study also suggests a novel method to enhance current cancer immunotherapy by increasing MHC-II label synthesis via diet, drugs, or altering the gut microbial composition to aid the immune system in recognizing and destroying cancer cells.

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