Parabacteroides distasonis attenuates tumorigenesis, modulates inflammatory markers and promotes intestinal barrier integrity in azoxymethane-treated A/J mice

Authors: KOH, GAR YEE - University Of Florida; KANE, ANNE - Tufts Medical Center; WU, XIAN - Miami University - Ohio; CROTT, JIMMY - Jean Mayer Human Nutrition Research Center On Aging At Tufts University

Submitted to: Carcinogenesis
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 2/25/2020
Publication Date: 3/2/2020
Citation: Koh, G., Kane, A.V., Wu, X., Crott, J.W. 2020. Parabacteroides distasonis attenuates tumorigenesis, modulates inflammatory markers and promotes intestinal barrier integrity in azoxymethane-treated A/J mice. Carcinogenesis. https://doi.org/10.1093/carcin/bgaa018.
DOI: https://doi.org/10.1093/carcin/bgaa018

Interpretive Summary: We fed freeze-dried Parabacteroides distasonis (Pd), a normal gut bacterium, to mice. It reduced the number of colon tumors induced by a chemical carcinogen. Pd also increase the integrity of the gut barrier.

Technical Abstract: Imbalance of the gut microbial community promotes inflammation and colorectal cancer (CRC). Previously, we demonstrated that freeze-dried Parabacteroides distasonis (Pd) suppressed obesity-driven colorectal tumorigenesis in mice. Here, we investigated if Pd could suppress the development of colon tumors in mice independent of obesity. Six-week old male A/J mice were assigned to receive: 1) chow diet (CTR); 2) chow with 0.04% w/w freeze-dried Pd (Pd-Early); or 3) chow diet before switching to 0.04% Pd diet (Pd-Late). Mice remained on diet for 25 weeks with the switch for Pd-Late mice occurring after 19 weeks. All mice received six weekly injections of the colon carcinogen azoxymethane (AOM; 10 mg/kg I.P.) starting after one week on diet. Colon tumors were observed in 77%, 55%, and 40% in CTR, Pd-Early, and Pd-Late mice, respectively (X^2 = 0.047). Colonic expression of TLR4, IL-4, and TNFalpha was 40% (P<0.01) 58% (P=0.05) and 55% (P<0.001) lower, respectively, in Pd-Early compared to CTR mice. Pd-Late mice displayed a 217% (P=0.05) and 185% (P<0.001) increase in colonic IL-10 and TGFbeta expression, respectively, compared to CTR mice and similar increases in protein abundances were detected (47-145% P<0.05). Pd-Early and Pd-Late mice both demonstrated increased colonic expression of the tight junction proteins ZO-1 (P< 0.001) and occludin (P< 0.001) at the transcript (2-3 fold; P<0.01) and protein level (30-50%; P<0.05) relative to CTR. Our results support a protective role for Pd in colonic tumorigenesis and maintenance of intestinal epithelial barrier in AOM-treated mice.