Gut microbiota linked to psychological stress-induced breast cancer growth

Gut Microbiota Linked to Psychological Stress-Induced Breast Cancer Growth

Psychological stress may accelerate the progression of breast cancer by altering the composition of the gut microbiome. According to research published in Nature and PubMed, stress induces a state of microbial dysbiosis that promotes tumor growth and "cancer stemness," a process dependent on the presence of gut microbiota.

The study utilized germ-free and antibiotic-treated mice to demonstrate that the impact of psychological stress on breast tumor growth is tied to these microorganisms. Metagenomic and metabolomic analyses revealed that stress markedly alters the abundance of gut microbiota, specifically affecting the species Akkermansia muciniphila (A. Muciniphila) and decreasing the levels of the short-chain fatty acid butyrate.

This reduction in butyrate serves as a mechanical trigger for cancer progression. Researchers found that butyrate typically acts as an HDAC inhibitor, elevating histone H3K9 acetylation levels. This process transcriptionally activates ZFP36, which then accelerates the decay of LRP5 mRNA by binding to adenine uridine-rich (AU-rich) elements of the LRP5 transcript.

When butyrate levels drop due to stress, the blockage of the Wnt/β-catenin signaling pathway is lifted. Specifically, butyrate is required to decrease LRP5 expression; without it, the activation of this pathway dampens the controls on breast cancer stemness, allowing the tumor to grow more aggressively.

The research suggests that these effects can be reversed. In murine spontaneous and orthotopic tumor models, the oncogenic properties and anxiety-like behaviors induced by psychological stress were dramatically reversed through three specific interventions:

• Supplementation of active A. Muciniphila.
• Administration of butyrate.
• A high-fiber diet capable of producing butyrate.

These findings extend to human clinical observations. In breast cancer patients, researchers found that fecal A. Muciniphila and serum butyrate were inversely correlated with negative mood, poor prognosis, and the expression of tumoral LRP5/β-catenin.

The broader context of this discovery aligns with a wider understanding of the microbiome's role in oncology. As noted in a review by Md. Wasim Khan of the University of Illinois at Chicago, the gut microbiome is localized in the gastrointestinal mucosa and interacts with host tissues via metabolites like short-chain fatty acids (SCFAs). While the relationship between the microbiome and cancers physically close to the gut — such as colorectal, gastric, and pancreatic cancers — is well-documented, the connection to distant cancers like breast cancer is often less apparent without the use of transcriptome and metabolomic analyses.

Other research indicates that dysbiosis, a shift in the microbiome profile and a reduction in diversity, is a major characteristic of multiple cancers. In breast cancer specifically, some cohorts show an increased Firmicutes to Bacteroidetes ratio and elevated levels of Escherichia.

The ability of the microbiome to influence cancer is linked to several metabolic and epigenetic pathways. For instance, SCFAs are known modulators of whole-body glucose metabolism, and their reduction is frequently observed in various cancers. Additionally, the microbiome can influence epigenetic modifications, such as DNA methylation at CpG islands and histone post-translational modification, which can alter oncogene expression.

Current efforts in the field are moving toward the clinical translation of this science. This includes the development of the ONCOBIOME initiative, which seeks to integrate microbiome science into oncology workflows. Potential therapeutic avenues now being explored include bacterial consortia, fecal microbiota transplantation, and dietary modifications to correct microbiome dysfunction and potentially enhance the efficacy of traditional treatments like immunotherapy and chemotherapy.