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

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.

Parabacteroides distasonis: intriguing aerotolerant gut anaerobe with emerging antimicrobial resistance and pathogenic and probiotic roles in human health

“…Studies by other researchers have suggested that P. distasonis has anti-inflammatory and antitumor properties mediated by the reduction of signaling via TLR4, MYD88, and Akt and the stimulation of apoptosis. 86 These results are in agreement with observations of reduced microbiome levels of P. distasonis in mouse models of colorectal cancer. 44 In a study by Koh et al 86 that was previously noted for revealing P. distasonis effect on the expression of tight junction proteins, the same mice were later treated with the carcinogen azoxymethane (AOM).…”

“…Multiple researchers have identified that levels of P. distasonis in stool are inversely correlated to the presence of intestinal tumors. 101 Koh et al 86 determined that P. distasonis membrane fractions were responsible for suppressing the production of proinflammatory cytokines in a colon cancer cell line. Studies by other researchers have suggested that P. distasonis has anti-inflammatory and antitumor properties mediated by the reduction of signaling via TLR4, MYD88, and Akt and the stimulation of apoptosis.…”

“…In mice fed a diet containing P. distasonis after switching from a chow diet, the IL-10 and TGF-β expression were 217% (p = .05) and 185% (p < .001) higher compared to mice fed a chow diet without P. distasonis. 86 Furthermore, Gu et al 101 found that the abundance of P. distasonis, in addition to that of Bacteroides vulgatus, decreased in response to CEACAM proteins disrupting TGF-β signaling. This alteration in the intestinal microbiome in turn promoted colorectal carcinogenesis, thus providing further evidence of P. distasonis potential role in preventing colorectal carcinogenesis.…”

Colon Carcinogenesis: The Interplay Between Diet and Gut Microbiota

“…When fed to BALB/C mice, P. distasonis could reduce the severity of intestinal inflammation of acute and chronic colitis (Kverka et al, 2011). Likewise, Koh et al (2020) has reported the beneficial role of P. distasonis in attenuating colonic tumorigenesis and maintaining intestinal epithelial barrier in azoxymethane (AOM)-treated mice (Koh et al, 2020).…”

Probiotic bacteria and bile acid profile are modulated by prebiotic diet and associate with facilitated diurnal clock/sleep realignment after chronic disruption of rhythms

“…Findings from prior research show that Parabacteroides distasonis, Ruminiclostridium 5, and Clostridium leptum are associated with positive health states, whereas reduced levels are associated with negative health states. Oral administration of Parabacteroides distasonis, for example, suppresses colon tumorigenesis and sustains epithelial barrier function in a mouse model (Koh et al 2019). In addition, recovery from sleep fragmentation (Maki et al 2020) is associated with increased relative abundance of Ruminiclostridium 5.…”