Emerging roles of lactic acid bacteria in protection against colorectal cancer

Abstract

Colorectal cancer (CRC) is the third leading cause of cancer deaths worldwide and the fourth most common cancer diagnosed among men and women in the United States. Considering the risk factors of CRC, dietary therapy has become one of the most effective approaches in reducing CRC morbidity and mortality. The use of probiotics is increasing in popularity for both the prevention and treatment of a variety of diseases. As the most common types of microbes used as probiotics, lactic acid bacteria (LAB) are comprised of an ecologically diverse group of microorganisms united by formation of lactic acid as the primary metabolite of sugar metabolism. LAB have been successfully used in managing diarrhea, food allergies, and inflammatory bowel disease. LAB also demonstrated a host of properties in preventing colorectal cancer development by inhibiting initiation or progression through multiple pathways. In this review, we discuss recent insights into cellular and molecular mechanisms of LAB in CRC prevention including apoptosis, antioxidant DNA damages, immune responses, and epigenetics. The emerging experimental findings from clinical trials as well as the proposed mechanisms of gut microbiota in carcinogenesis will also be briefly discussed.

Keywords: Carcinogenesis; Gastrointestinal; Gut bacteria; Microbiota; Probiotics.

Figure 1

Potential mechanisms of action of lactic acid bacteria via extrinsic and intrinsic pathways of apoptosis[19,20]. The apoptosis signaling pathways can be activated by lactic acid bacteria (LAB) through the extrinsic and intrinsic pathways. The extrinsic pathway engages Fas/tumor necrosis factor receptors or other factors to induce caspase related pathway. The intrinsic pathway requires mitochondrial localization and activation of Bax and Bak that can be prevented by anti-apoptotic Bcl-2 family proteins or pharmacologic inhibitors. LAB enhanced the apoptosis induction capacity of 5-fluorouracil (5-FU) and induced the activation of autophagic cell death promoted directly by the induction of Beclin-1 and GRP78, as well as indirectly through the induction of Bcl-2 and Bak. LAB may act to prevent cancer via downregulating nuclear factor-kappaB (NF-κB)-dependent gene products which regulate cell proliferation (Cox-2, cyclin D1) and survival (Bcl-2, Bcl-xL).

Figure 2

Immune responses induced by lactic acid bacteria. Lactic acid bacteria (LAB) can provoke immune responses via two main pathways: inflammation and anticancer immune response. The inflammation pathways involve lipoteichoic acid (LTA) which can stimulate T cells to release interleukin (IL)-10, IL-12 and increase effectors Foxp3⁺RORγt^- Tregs. In the anticancer immune response pathway, LAB stimulate the immune cells, such as T cells, dendritic cell (DC), natural killer (NK) and MHC class II cells to induce IL-10, tumor necrosis factor (TNF)-α, interferon (IFN)-γ and IL-1β to inhibit tumor growth.