Parabacteroides distasonis attenuates toll‐like receptor 4 signaling and Akt activation and blocks colon tumor formation in high‐fat diet‐fed azoxymethane‐treated mice

Abstract

Gut dysbiosis may play an etiological role in colorectal tumorigenesis. We previously observed that the abundance of Parabacteroides distasonis (Pd) in stool was inversely associated with intestinal tumor burden and IL-1β concentrations in mice. Here, we assessed the anti-inflammatory capacity of Pd membrane fraction (PdMb) in colon cancer cell lines. In addition, we tested whether Pd could suppress colon tumorigenesis in mice. Six-week old male A/J mice were fed a low-fat diet (LF), high-fat diet (HF), or HF+ whole freeze-dried Pd (HF+Pd, 0.04% w/w) for 24 weeks. After 1 week on diet, mice received 4 weekly injections of azoxymethane (AOM). PdMb robustly suppressed the production of pro-inflammatory cytokines and lowered the abundance of MyD88 and pAkt (ser473) induced by E. coli lipopolysaccharide in colon cancer cell lines. Moreover, PdMb induced apoptosis in colon cancer cell lines and blocked TLR4 activation in a reporter line. Colon tumors were observed in 0% of LF (0 of 19), 25% of HF (5 of 20) and 0% of HF+Pd mice (0 of 20) (P = 0.005). The latter group also displayed a lower abundance of MyD88 and pAkt (ser473) in colonic mucosa than HF mice. Taken together, these data suggest that Pd has anti-inflammatory and anti-cancer properties that are likely mediated by the suppression of TLR4 and Akt signaling, as well as promotion of apoptosis. Further work is needed to confirm these findings in additional models and fully elaborate the mechanism of action. This article is protected by copyright. All rights reserved.

Parabacteroides distasonis Alleviates Obesity and Metabolic Dysfunctions via Production of Succinate and Secondary Bile Acids

“…Amuc_1100*, a thermostable outer-membrane protein of A. muciniphila, reportedly possesses beneficial effects on reducing fat mass and improving metabolic syndrome in dietinduced obese mice (Plovier et al, 2017). A previous study also showed that the membranous fraction of P. distasonis prevented DSS-induced increases in proinflammatory cytokines and blocked colon tumor formation in HFD-fed azoxymethanetreated mice (Koh et al, 2018;Kverka et al, 2011). In this study, ob/ob mice treated with KPD did not show improvements in most parameters measured, indicating that cellular components make few contributions to the metabolic benefits of P. distasonis.…”

Moderate alteration to gut microbiota brought by colorectal adenoma resection

“…Oral supplement of this bacterium can effectively alleviate acute and chronic intestinal inflammation . More importantly, Parabacteroides not only hydrolyzes carbohydrates prior to proteins to produce butyrate but also defends against pathogenic invasion via bacteriocin . Hence, Parabacteroides play an anti‐inflammatory and anticancer role in the intestinal barrier.…”

“…18 More importantly, Parabacteroides not only hydrolyzes carbohydrates prior to proteins to produce butyrate 19,20 but also defends against pathogenic invasion via bacteriocin. 21 Hence, Parabacteroides play an anti-inflammatory and anticancer role in the intestinal barrier. The growth trend of these bacteria after adenoma resection indicates the ameliorating role of adenoma resection for the colorectal microenvironment.…”

Gut Microbiota Imbalance is Related to Sporadic Colorectal Neoplasms. A Pilot Study

“…In their report, the Authors attributed to Pa.d. anti-inflammatory and anti-cancer properties that are likely mediated by the suppression of TLR4 and Akt signaling, as well as promotion of apoptosis [27].…”