Abstract
Objectives
Gut dysbiosis or imbalance of the gut microbial community promotes inflammation and contributes to pathogenesis of several conditions such as aging, obesity, and colorectal cancer (CRC). Previously, we demonstrated that feeding Parabacteroides distasonis (Pd) to mice suppressed obesity-driven colorectal tumorigenesis. Here, we investigated if Pd could suppress the development and progression of colon tumors in mice independent of obesity.
Methods
Six-week old male A/J mice (n = 23/group) were randomly assigned to one of the 3 diet regimens: 1) standard chow diet for 24 weeks (CTR), 2) chow supplemented with 0.04% w/w freeze-dried Pd for 24 weeks (Pd-Early), or 3) chow diet for 19 weeks followed by chow diet supplemented with 0.04% w/w freeze-dried Pd for a further 5 weeks (Pd-Late). All mice were given 6 weekly injections of the colon carcinogen azoxymethane (AOM; 10 mg/kg I.P.) starting after 1 week on diet and were euthanized after 24 weeks on diet.
Results
Histologically confirmed neoplastic colonic polyps were observed in 77%, 55%, and 40% in CTR, Pd-Early, and Pd-Late mice, respectively (X2 = 0.047). The expression of IL-4 and TNFα was 58% (P = 0.05) and 55% (P < 0.001) lower, respectively, in Pd-Early compared to CTR mice. Interestingly, Pd-Late mice displayed a 217% (P = 0.05) and 185% (P < 0.001) increase in IL-10 and TGF-β expression, respectively, compared to CTR mice. Both Pd-Early and Pd-Late mice demonstrated an increased expression of tight junction proteins, ZO-1 (P < 0.001) and occludin (P < 0.001), by 2–3 fold, compared to controls.
Conclusions
Our results support a protective role for Pd in colonic tumorigenesis and maintenance of intestinal epithelial barrier in AOM-treated mice. Moreover, our data suggest a differential regulation of immune responses by Pd when administered at different stages of tumorigenesis. Future investigation is warranted to delineate the effect of Pd on the immune system and how this may affect tumorigenesis and tumor progression.
Funding Sources
This study is supported by 2017 HNRCA Pilot Grant and the USDA CRIS fund.