Abating colon cancer polyposis by Lactobacillus acidophilus deficient in lipoteichoic acid

Abstract

An imbalance of commensal bacteria and their gene products underlies mucosal and, in particular, gastrointestinal inflammation and a predisposition to cancer. Lactobacillus species have received considerable attention as examples of beneficial microbiota. We have reported previously that deletion of the phosphoglycerol transferase gene that is responsible for lipoteichoic acid (LTA) biosynthesis in Lactobacillus acidophilus (NCK2025) rendered this bacterium able to significantly protect mice against induced colitis when delivered orally. Here we report that oral treatment with LTA-deficient NCK2025 normalizes innate and adaptive pathogenic immune responses and causes regression of established colonic polyps. This study reveals the proinflammatory role of LTA and the ability of LTA-deficient L. acidophilus to regulate inflammation and protect against colonic polyposis in a unique mouse model. dendritic cells | regulatory T cells | anti-inflammatory I dentifying bacterial gene products that enhance protective versus pathogenic inflammation in the gut is critical to rebalance homeostasis in gastrointestinal (GI) chronic inflammatory diseases and malignancies. Commensal Lactobacillus species (i.e., Lactobacillus acidophilus) are normal inhabitants of the natural microbiota in the human GI tract (1, 2). L. acidophilus stimulates innate cells to produce inflammatory and regulatory cytokines through interaction of their surface layer proteins and other cell surface components (3-7). To investigate the potential role of lipoteichoic acid (LTA) of L. acidophilus in the induction of inflammatory signals, we deleted the phosphoglycerol transferase gene (LBA0447) that synthesizes LTA. LTA is a zwitterionic glycolipid found in the cell wall of several Gram-positive bacterial strains, including L. acidophilus, which stimulates dendritic cells (DCs) through Toll-like receptor 2, resulting in cytokine release (8, 9). Disruption of LTA synthesis generated a L. acidophilus derivative (NCK2025) that mitigates colitis in mice (10). Based on these observations and those of others (11,12), it was proposed that LTA induces inflammation and that its absence significantly attenuates overt intestinal inflammation.Inflammation has a tumor-promoting role in mice with polyposis and in human colon cancer (13)(14)(15)(16)(17). T regulatory cells (Tregs) critically regulate inflammation and play a protective role in polyposis (15, 18) and colon cancer (19-21). However, chronic interaction of Tregs with proinflammatory cells and their cytokines can reverse the anti-inflammatory properties of these cells and render them proinflammatory (15,16,22,23). Consensus suggests that interactions between lymphocytes and myeloid cells regulate pro-vs. antitumor immunity (17, 24), and we hypothesized that the gut microbiota plays an essential role in control of this balance. We used L. acidophilus NCK2025, deficient in LTA, to investigate the moderation of pathogenic inflammation within the tumor microenvironment in a unique mouse model of colonic polyposis...

Gut microbiome and anticancer immune response: really hot Sh*t!

“…A L. acidophilus strain harboring a deletion in the phosphoglycerol transferase gene and unable to synthetize LTA prevented the progression of colonic polyps in Apc Dflox mice. 90 Elafin-overexpressing L. casei and L. lactis reduced colitis in mice and ex vivo in inflamed epithelial cells from human colitis. 91 L. gasseri genetically modified to overexpress superoxide dismutase decreased colitis in IL-10-deficient hosts.…”

Advancing the use ofLactobacillus acidophilussurface layer protein A for the treatment of intestinal disorders in humans

“…can have devastating consequences, resulting in autoinflammatory diseases, including IBD. These uncontrolled immune signals (e.g., IL-1b) are generated by highly activated innate cells, including dendritic cells (DCs), during microbial dysbiosis 4 and create an unbalanced microenvironment, wherein released soluble mediators activate intestine-infiltrating pathogenic T lymphocyte subsets (e.g., Th1, Th17), and even proinflammatory regulatory T cells (Tregs), [7][8][9] resulting in tissue damage and gut barrier dysfunction. 22 The cellular and molecular mechanisms induced by gut microbes, their gene products, and their metabolites, as well as how these relevant factors potentially interact Keywords: bacterial protein isolation, colonic inflammation, gut microbiota, intestinal immune regulation, surface layer protein A to determine the activation and differentiation of innate cells and T cell subsets at distal sites, require further scientific investigation.…”

“…[10][11][12][13][14] Furthermore, this L. acidophilus strain lacking LTA significantly diminished inflammation-promoting colonic polyposis in the Apc lox468 x TS4-Cre mouse model via the regulation of proinflammatory innate and T cell subsets. 9 Thus, we theorized that the cross-talk between a specific surface molecule expressed by the LTAdeficient L. acidophilus, called SlpA, with intestinal innate cells (e.g., DCs) not only suppresses pathogenic inflammation, but also potentially modulates the expression of epigenetically-regulated, colorectal cancer (CRC)-associated genes, 15 and restores gut homeostasis to ablate colonic polyps. 9,16,17 These data galvanized our laboratory to more thoroughly define this protective role of bacterial SlpA in a murine colitis model.…”

Chemopreventive Potential of Probiotics and Prebiotics

“…Rather a secreted factor mediated this effect by suppressing the TNFα-induced IL-8 transactivation by a mechanism independent of NF-κB inhibition [54]. An oral administration of engineered Lactobacillus acidophilus strain, which was unable to synthesize lipoteichoic acid, to mice, resulted in reduction of developed colonic polyps [55].…”