Journal
GUT MICROBES
Volume 13, Issue 1, Pages -Publisher
TAYLOR & FRANCIS INC
DOI: 10.1080/19490976.2021.1987780
Keywords
Microbiome; colorectal cancer; Th17 cells; interleukin 17; gnotobiotics; Fusobacterium nucleatum; altered Schaedler's flora
Categories
Funding
- Cancer Research UK [C10674/A27140]
- Damon Runyon Cancer Research Foundation [DRG-2205-14]
- G. Harold and Leila Y. Mathers Foundation [GHLYMF]
- National Cancer Institute [R01CA154426, T32CA207021]
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Fusobacterium nucleatum influences intestinal immunity by shaping Th17 responses in an FFAR2-dependent manner. Further studies are necessary to clarify the precise role of FFAR2.
The colorectal cancer (CRC)-associated microbiota creates a pro-tumorigenic intestinal milieu and shapes immune responses within the tumor microenvironment. However, how oncomicrobes - like Fusobacterium nucleatum, found in the oral cavity and associated with CRC tissues- affect these distinct aspects of tumorigenesis is difficult to parse. Herein, we found that neonatal inoculation of Apc(Min/+) mice with F. nucleatum strain Fn7-1 circumvents technical barriers preventing its intestinal colonization, drives colonic Il17a expression prior to tumor formation, and potentiates intestinal tumorigenesis. Using gnotobiotic mice colonized with a minimal complexity microbiota (the altered Schaedler's flora), we observed that intestinal Fn7-1 colonization increases colonic Th17 cell frequency and their IL-17A and IL-17F expression, along with a concurrent increase in colonic lamina propria Il23p19 expression. As Fn7-1 stably colonizes the intestinal tract in our models, we posited that microbial metabolites, specifically short-chain fatty acids (SCFA) that F. nucleatum abundantly produces in culture and, as we demonstrate, in the intestinal tract, might mediate part of its immunomodulatory effects in vivo. Supporting this hypothesis, we found that Fn7-1 did not alter ROR gamma t(+) CD4(+)T cell frequency in the absence of the SCFA receptor FFAR2. Taken together, our work suggests that F. nucleatum influences intestinal immunity by shaping Th17 responses in an FFAR2-dependent manner, although further studies are necessary to clarify the precise and multifaceted roles of FFAR2. The potential to increase intestinal Th17 responses is shared by another oncomicrobe, enterotoxigenic Bacteroides fragilis, highlighting a conserved pathway that could potentially be targeted to slow oncomicrobe-mediated CRC.
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