Parabacteroides distasonis attenuates toll-like receptor 4 signaling and Akt activation and blocks colon tumor formation in high-fat diet-fed azoxymethane-treated mice

Authors: KOH, GAR YEE - Jean Mayer Human Nutrition Research Center On Aging At Tufts University; KANE, ANNE - Tufts Medical Center; LEE, KYONGBUM - Tufts University; XU, QIAOBING - Tufts University; WU, XIAN - Jean Mayer Human Nutrition Research Center On Aging At Tufts University; ROPER, JATIN - Tufts Medical Center; MASON, JOEL - Jean Mayer Human Nutrition Research Center On Aging At Tufts University; CROTT, JIMMY - Jean Mayer Human Nutrition Research Center On Aging At Tufts University

Submitted to: International Journal of Cancer
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 4/12/2018
Publication Date: 4/26/2018
Citation: Koh, G., Kane, A., Lee, K., Xu, Q., Wu, X., Roper, J., Mason, J.B., Crott, J.W. 2018. Parabacteroides distasonis attenuates toll-like receptor 4 signaling and Akt activation and blocks colon tumor formation in high-fat diet-fed azoxymethane-treated mice. International Journal of Cancer. https://doi.org/10.1002/ijc.31559.
DOI: https://doi.org/10.1002/ijc.31559

Interpretive Summary: Colorectal cancer is the third most common cancer in the U.S. We previously found that mice that developed colonic tumor showed decreased richness of a bacterium, Parabacteroides distasonis, in the stool. These mice also displayed a higher degree of inflammation in the colon that could trigger the development of colorectal cancer. In this study, we evaluated how Parabacteroides distasonis might alter colonic inflammation using both colon cancer cell lines and animal model of colorectal cancer. We reported that this bacterium can reduce inflammation and cancer-causing proteins in colorectal cancer cells. Similar results were also observed in an animal model of colorectal cancer, where feeding of Parabacteroides distasonis blocked the formation of colonic tumors in mice. These data suggest that Parabacteroides distasonis has anti-inflammatory and anti-cancer properties. Therefore, these results suggest that increasing the Parabacteroides distasonis abundance in the gut through diet interventions may be useful to prevent colorectal cancer development in at-risk individuals.

Technical Abstract: Gut dysbiosis may play an etiological role in colorectal tumorigenesis. We previously observed that the abundance of Parabacteroides distasonis (Pd) in stool was inversely associated with intestinal tumor burden and IL-1beta concentrations in mice. Here, we assessed the anti-inflammatory capacity of Pd membrane fraction (PdMb) in colon cancer cell lines. In addition, we tested whether Pd could suppress colon tumorigenesis in mice. Six-week old male A/J mice were fed a low-fat diet (LF), high-fat diet (HF), or HF+ whole freeze-dried Pd (HF+Pd, 0.04% w/w) for 24 weeks. After 1 week on diet, mice received 4 weekly injections of azoxymethane (AOM). PdMb robustly suppressed the production of pro-inflammatory cytokines and lowered the abundance of MyD88 and pAkt (ser473) induced by E. coli lipopolysaccharide in colon cancer cell lines. Moreover, PdMb induced apoptosis in colon cancer cell lines and blocked TLR4 activation in a reporter line. Colon tumors were observed in 0% of LF (0 of 19), 25% of HF (5 of 20) and 0% of HF+Pd mice (0 of 20) (P = 0.005). The latter group also displayed a lower abundance of MyD88 and pAkt (ser473) in colonic mucosa than HF mice. Taken together, these data suggest that Pd has anti-inflammatory and anti-cancer properties that are likely mediated by the suppression of TLR4 and Akt signaling, as well as promotion of apoptosis. Further work is needed to confirm these findings in additional models and fully elaborate the mechanism of action.