Connecting gut bacteria and extra-intestinal cancer

During our investigations of colorectal cancer in 2005, we discovered that orogastric infection with an opportunistic microbial pathogen, Helicobacter hepaticus, rapidly promotes extra-intestinal tumors in mammary glands of mice. [7]. As a result, much of my ongoing research program now focuses on gut bacteria-induced systemic pathology as funded by an NIH-NCI grant entitled “GI tract dysbiosis and breast cancer” (PI= Erdman).

• Using Rag2-deficient mice lacking lymphocytes, we determined that mammary cancer arose from intestinal microbe–triggered innate immune systemic events requiring pro-inflammatory cytokines such as Tumor necrosis factor (TNF)-alpha. [5].
  
• Mammary tumors in this mouse model matched prior findings in women with elevated inflammatory cytokine levels and poor breast cancer outcome, and also correlated with the lower risk of breast cancer seen in women treated with anti-inflammatory drugs.
• We went on to show, using a widely applied adoptive cell transfer system in mice, that anti-inflammatory CD4+ regulatory T cells (T_REG) inhibited and suppressed this microbe-induced carcinoma while down-regulating systemic carcinogenic inflammatory responses. [6].
  
• Putting forth this systemic model linking bowel microbes and beneficial T_REG inhibiting distant cancers challenges the existing paradigm for roles of T_REG in cancer. [15], [13].
  
• On the surface, our findings on T_REG cells appear paradoxical, contrasting with widely held beliefs that T_REG cells function in cancer mainly to suppress protective anti-cancer T cell responses. In fact, recent evidence suggests that in vivo, as different T_REG cell subsets participate in a sophisticated systemic balancing act of beneficial host functions to maintain homeostasis. [17], [15], [7], [2].
  
• We have subsequently investigated larger questions of why breast cancer risk is increasing in developed countries with more rigorous hygiene practices, and how chronic use of prescribed antibiotics may enhance the risk for breast cancer in women.
  
• We demonstrated with lymphocyte titration experiments an increase in the anti-neoplastic potency of T_REG after prior exposures to H. hepaticus bacteria. [5]. Recent experimental evidence suggests that microbial infections in early life do indeed up-regulate functions that serve to inhibit deleterious disease processes later in life.
  
• Our data helps explain the apparent public health paradox in the context of the ‘‘hygiene hypothesis’’ theory: decades of data have shown that early-life infections reduce the incidence of inflammatory disorders such as asthma. Targeted stimulation with bacteria may protect against inflammation-associated pathology, and significantly reduce the risk of cancer later in life.
  
• Following this reasoning, even pathogenic bacterial infections may not be entirely adversarial and may impart some long-term health benefits by reducing risk for chronic debilitating diseases, such as autoimmunity and cancer.

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