Parabacteroides distasonis attenuates colonic inflammation and prevents tumor formation in azoxymethane-treated high-fat diet-fed mice

Authors: KOH, GAR YEE - Jean Mayer Human Nutrition Research Center On Aging At Tufts University; KANE, ANNE - Tufts University; LEE, KYONGBUM - Tufts University; XU, QIAOBING - Tufts University; WU, XIAN - Jean Mayer Human Nutrition Research Center On Aging At Tufts University; 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: Federation of American Societies for Experimental Biology Conference
Publication Type: Abstract Only
Publication Acceptance Date: 4/1/2017
Publication Date: 4/1/2017
Citation: Koh, G., Kane, A.V., Lee, K., Xu, Q., Wu, X., Mason, J.B., Crott, J.W. 2017. Parabacteroides distasonis attenuates colonic inflammation and prevents tumor formation in azoxymethane-treated high-fat diet-fed mice [abstract]. Federation of American Societies for Experimental Biology Conference. 31(1):435.2.

Interpretive Summary:

Technical Abstract: Obesity is a major risk factor for colorectal cancer (CRC) and inflammation is thought to constitute one of the underlying mechanisms. We previously observed a depletion of Parabacteroides distasonis (PD) in the stool of tumor-bearing mice that was inversely related to the abundance of the pro-inflammatory cytokine IL-1beta in the colon. Here, we aimed to determine whether the administration of PD can suppress obesity-driven colonic inflammation and tumorigenesis in mice. Six-week old male A/J mice were randomly assigned to receive one of the 3 diets: 1) low fat diet with 10% calories from fat (LF), 2) high fat diet with 60% calories from fat (HF), and 3) HF+0.04% w/w of freeze-dried P.distasonis (HF+PD). After 1 week, mice were given 4 weekly injections of the colon carcinogen azoxymethane and were maintained on their respective diet for 20 weeks after the final injection. Histologically-confirmed colonic tumors were observed in 0% (0 of 19), 25% (5 of 20) and 0% (0 of 20) of LF, HF, and HF+PD mice, respectively (Fisher's exact test = 0.0049). Compared to HF mice, HF+PD mice tended to have reduced colonic TNF-alpha concentrations (30% lower; P = 0.08). Activations of both MyD88-dependent innate immune signaling and Akt signaling have been implicated in inflammation and tumorigenesis. Compared to HF mice, colonic MyD88 and phosphorylated Akt protein expression were reduced by 39% (P < 0.01) and 47% (P = 0.03), respectively, in HF+PD mice. Our results indicate, for the first time, that administration of P. distasonis can prevent HF diet-driven tumorigenesis and attenuate colonic inflammation in azoxymethane-treated mice. Associated with PD administration was a reduction in pAkt and Myd88, suggesting that PD, to a certain extent, blunts inflammatory signaling. Further work is required to fully elucidate the mechanism and confirm our findings in alternate animal models of CRC.