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

• Published in: Carcinogenesis (New York) Vol. 41; no. 7; pp. 909 - 917
• Main Authors: Koh, Gar Yee, Kane, Anne V, Wu, Xian, Crott, Jimmy W
• Format: Journal Article
• Language: English
• Published: UK Oxford University Press 14.07.2020
• Subjects: Animals; Azoxymethane - pharmacology; Bacteroidetes - genetics; Bacteroidetes - metabolism; Carcinogenesis - genetics; Colon - pathology; Colonic Neoplasms - genetics; Colonic Neoplasms - metabolism; Colonic Neoplasms - microbiology; Colonic Neoplasms - pathology; Humans; Inflammation - genetics; Inflammation - microbiology; Inflammation - pathology; Interleukin-4 - genetics; Intestinal Mucosa - metabolism; Intestinal Mucosa - microbiology; Mice; Obesity - metabolism; Obesity - microbiology; Obesity - pathology; Signal Transduction - genetics; Toll-Like Receptor 4 - genetics; Transforming Growth Factor beta - genetics
• ISSN: 0143-3334; 1460-2180
• DOI: 10.1093/carcin/bgaa018

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: (i) chow diet (CTR); (ii) chow with 0.04% wt/wt freeze-dried Pd (Pd-Early) or (iii) 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 6 weekly injections of the colon carcinogen azoxymethane (AOM; 10 mg/kg I.P.) starting after 1 week on diet. Colon tumors were observed in 77, 55 and 40% in CTR, Pd-Early and Pd-Late mice, respectively (X2 = 0.047). Colonic expression of toll-like receptor 4, IL-4 and TNF-α was 40% (P < 0.01), 58% (P = 0.05) and 55% (P < 0.001) lower, respectively, in Pd-Early compared with CTR mice. Pd-Late mice displayed a 217% (P = 0.05) and 185% (P < 0.001) increase in colonic IL-10 and TGF-β expression, respectively, compared with 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 Zonula occludens-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.