Targeting aberrant colon cancer-specific DNA methylation with lipoteichoic acid-deficient Lactobacillus acidophilus

Abstract

Pathogenic autoinflammatory responses triggered by dysregulated microbial interactions may lead to intestinal disorders and malignancies. Previously, we demonstrated that a lipoteichoic acid (LTA)-deficient Lactobacillus acidophilus strain, NCK2025, ameliorated inflammation-induced colitis, significantly reduced the number of polyps in a colonic polyposis cancer model and restored physiological homeostasis in both cases. Nonetheless, the regulatory signals delivered by NCK2025 to reprogram the gastrointestinal microenvironment, and thus resist colonic cancer progression, remain unknown. Accumulating evidence suggest that epigenetic changes, in the presence and absence of pathogenic inflammation, can result in colorectal cancer (CRC). To test possible epigenetic modifications induced by NCK2025, the expression of epigenetically regulated, CRC-associated genes was measured with and without bacterial treatment. In vivo and in vitro, NCK2025 enhanced the expression of tumor suppressor genes that may regulate CRC development. Therefore, differential epigenetic regulation of CRC-related genes by NCK2025 represents a potential therapy against colitis-associated and sporadic CRC.

Keywords: DNA methylation; aberrant epigenetic alterations; colorectal cancer; inflammation; lipoteichoic acid.

Figure 1. LTA-deficient L. acidophilus induces the expression of genes commonly silenced through DNA methylation in CRC. (A) Healthy C57B/L6 mice were treated orally with wild-type L. acidophilus NCFM (NCK56), protective LTA-deficient L. acidophilus NCFM (NCK2025), or PBS, and colonic tissue samples were collected 24 h after treatment. Expression levels of epigenetically regulated, CRC-associated genes were measured by Real-time PCR and normalized to PBS-treated levels. (B) HT-29 colon carcinoma cells were treated for 48 h and analyzed as above. * denotes statistical significance p < 0.05.

Figure 2. Schematic summary of the potential role of LTA-deficient L. acidophilus in CRC mitigation. In sporadic CRC and CAC, tissue destruction and increased permeability lead to genetic instability and aberrant epigenetic alterations, thereby activating a deleterious cascade that culminates in colon cancer progression. Our previous studies demonstrate that NCK2025 dampens pathogenic inflammation in the gut and restores immunological homeostasis. As a result, proinflammatory mediators no longer promote oncogenesis. Data presented here suggest that in addition to its immunomodulatory role, NCK2025 may also be involved in the prevention of epigenetic modifications that are conducive to CRC development. Consequently, LTA-deficient L. acidophilus may not only be helpful in the treatment of CAC, but also in the prevention of sporadic CRC.