Indole-3-carbinol inhibits Citrobacter rodentium infection through multiple pathways including reduction of bacterial adhesion and enhancement of cytotoxic T cell activity

Authors: WU, YANBEI - Sichuan University; HE, QIANG - Sichuan University; YU, LIANGLI - University Of Maryland; Pham, Quynhchi; Cheung, Lumei; KIM, YOUNG - National Cancer Institute (NCI, NIH); Wang, Thomas - Tom; Smith, Allen

Submitted to: Nutrients
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 3/19/2020
Publication Date: 3/27/2020
Citation: Wu, Y., He, Q., Yu, L., Pham, Q., Cheung, L., Kim, Y.S., Wang, T.T., Smith, A.D. 2020. Indole-3-carbinol inhibits Citrobacter rodentium infection through multiple pathways including reduction of bacterial adhesion and enhancement of cytotoxic T cell activity. Nutrients. 12(4):917. https://doi.org/doi: 10.3390/nu12040917.
DOI: https://doi.org/10.3390/nu12040917

Interpretive Summary: This study focuses on understanding the role of diet-derived bioactive compounds on inflammation. Intestinal inflammation may result from dysregulated responses to commensal bacterial or in response to bacterial pathogens. Dietary modulation of intestinal inflammation may protect against the development of colon cancer. However, the precise diet-derived components, as well as the underlying mechanisms remain elusive. The present study utilized a Citrobacter rodentium (Cr) infection model to induce acute intestinal inflammation and examine the effects of a cruciferous vegetable-derived cancer-protective compound candidate, indole-3-carbinol (I3C), on the intestinal immune and inflammatory response, Cr growth and adhesion to colonic cells in vitro. C57BL/6J mice were infected with Cr on a diet with or without I3C. Compared to the infected mice fed a control diet, we found that the consumption of 1µmol I3C/g diet significantly reduced the peak fecal excretion of Cr, the Cr colonization of the colon and reduced colon crypt hyperplasia. Furthermore, expression of Cr-induced inflammatory markers such as IL-17A, IL-6, and IL1ß were attenuated in infected mice fed the I3C diet, compared to mice fed control diet. The expression of cytotoxic T cell markers CD8 and FasL mRNA were increased in I3C -fed infected mice. In-vitro, I3C inhibited Cr growth and adhesion to Caco-2 cells. I3C alleviates Cr-induced murine colitis through multiple mechanisms including the inhibition of Cr growth and adhesion to colonic cells in- vitro and enhancement of cytotoxic T cell activity. This study provides novel information on the relationship between the dietary compounds, immune system and the prevention of infection. The information will benefit basic and translational scientists who are studying the regulation and prevention of gut infection by diet.

Technical Abstract: Intestinal inflammation may result from dysregulated responses to commensal bacterial, or in response to bacterial pathogens. Dietary modulation of intestinal inflammation may protect against the development of colon cancer. However, the precise diet-derived components, as well as underlying mechanisms remain elusive. The present study utilized a Citrobacter rodentium (Cr) infection model to induce acute intestinal inflammation and examine the effects of a cruciferous vegetable-derived cancer protective compound candidate, indole-3-carbinol (I3C), on the intestinal immune and inflammatory response, Cr growth and adhesion to colonic cells in-vitro. Methods and results: C57BL/6J mice were infected with Cr on a diet with or without I3C. Compared to the infected mice fed a control diet, we found that the consumption of 1µmol I3C/g diet significantly reduced the peak fecal excretion of Cr, Cr colonization of the colon and reduced colon crypt hyperplasia. Furthermore, the expression of Cr-induced inflammatory markers such as IL-17A, IL-6, and IL1ß were attenuated in infected mice fed the I3C diet, compared to mice fed a control diet. The expression of cytotoxic T-cell markers CD8 and FasL mRNA were increased in the I3C-fed infected mice. In-vitro, I3C inhibited Cr growth and adhesion to Caco-2 cells. Conclusion: I3C alleviates Cr-induced murine colitis through multiple mechanisms including the inhibition of Cr growth and the adhesion to colonic cells in-vitro and the enhancement of cytotoxic T-cell activity.