Indole-3-carbinol prevents colitis and associated microbial dysbiosis in an IL-22–dependent manner

Busbee, Philip Brandon; Menzel, Lorenzo P.; Alrafas, Haider Rasheed; Dopkins, Nicholas; Becker, William; Miranda, Kathryn; Tang, Chaunbing; Chatterjee, Saurabh; Singh, Udai P.; Nagarkatti, Mitzi; Nagarkatti, Prakash

doi:10.1172/jci.insight.127551

Cited by 95 publications

(101 citation statements)

References 93 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Production of IL-1β and IL-17A and the AhR receptor pathway have been reported to modulate the production of IL-22 [ 40 , 41 , 42 ]. Additionally, I3C may stimulate IL-22 production via the gut microbiota [ 43 ]. Given the systemic inhibitory effects of I3C consumption on IL-1β, IL-17A and its known action as an AhR agonist, it is likely that I3C is acting through AhR to maintain IL-22 expression and while repressing expression of pro-inflammatory cytokines.…”

Section: Discussionmentioning

confidence: 99%

Dietary Indole-3-Carbinol Alleviated Spleen Enlargement, Enhanced IgG Response in C3H/HeN Mice Infected with Citrobacter rodentium

Wang

et al. 2020

Nutrients

View full text Add to dashboard Cite

Enteropathogenic and enterohemorrhagic Escherichia coli are important enteric pathogens that induce hemorrhagic colitis or even fatal hemolytic uremic syndrome. Emerging evidence shows that some bio-actives derived from fruits and vegetables may serve as alternatives to antibiotics for overcoming multidrug resistant E. coli infections. In this study, the Citrobacter rodentium (Cr) infection model was utilized to mimic E. coli-induced acute intestinal inflammation, and the effects of a cruciferous vegetable-derived cancer protective compound, indole-3-carbinol (I3C), on the immune responses of Cr-susceptible C3H/HeN mice were investigated. Dietary I3C significantly inhibited the loss of body weight and the increase in spleen size in Cr infected mice. In addition, I3C treatment reduced the inflammatory response to Cr infection by maintaining anti-inflammatory cytokine IL-22 mRNA levels while reducing expression of other pro-inflammatory cytokines including IL17A, IL6, IL1β, TNF-α, and IFN-γ. Moreover, the serum cytokine levels of IL17, TNF-α, IL12p70, and G-CSF also were down-regulated by I3C in Cr-infected mice. Additionally, dietary I3C specifically enhanced the Cr-specific IgG response to Cr infection. In general, dietary I3C reduced the Cr-induced pro-inflammatory response in susceptible C3H/HeN mice and alleviated the physiological changes and tissue damage induced by Cr infection but not Cr colonization.

show abstract

Section: Discussionmentioning

confidence: 99%

Dietary Indole-3-Carbinol Alleviated Spleen Enlargement, Enhanced IgG Response in C3H/HeN Mice Infected with Citrobacter rodentium

Wang

et al. 2020

Nutrients

View full text Add to dashboard Cite

show abstract

“…While the precise mechanisms that lead to such contrasting effects of AhR ligands on Treg/Th17 differentiation remain unclear, this may depend on the dose and duration of AhR activation [ 70 ], affinity of the ligand, and epigenetic alterations such as induction of miRNA that trigger pro- or anti-inflammatory activities [ 37 , 48 , 71 ], and the nature of microbiota [ 72 ]. In addition, because of the plasticity of T cells, and reciprocal regulation of Tregs vs. Th17 cells, it is possible that AhR activation may lead to the differentiation of either of these subsets based on the nature of antigenic stimulation, and cytokines that are found in the microenvironment.…”

Section: Ahr Ligands and How They Impact The Differentiation Of Trmentioning

confidence: 99%

“…I3C may also act through the regulation of gut microbiota, as shown in a recent study in which AhR activation by I3C led to increased production of butyrate and attenuation of colitis. Thus, when mice with colitis were given butyrate, there was a decrease in colonic inflammation resulting from the suppression of Th17 and the induction of Tregs [ 72 ]. Additionally, IL-22 was increased following treatment with I3C but not with butyrate, and neutralization of IL-22 blocked the beneficial effects of I3C against colitis [ 72 ].…”

Section: Epigenetic Regulation Of T Cell Differentiation and Inflamentioning

confidence: 99%

“…Thus, when mice with colitis were given butyrate, there was a decrease in colonic inflammation resulting from the suppression of Th17 and the induction of Tregs [ 72 ]. Additionally, IL-22 was increased following treatment with I3C but not with butyrate, and neutralization of IL-22 blocked the beneficial effects of I3C against colitis [ 72 ]. This study suggested that I3C activation of AhR attenuates colitis primarily through the induction of IL-22, which leads to dysbiosis that promotes the production of anti-inflammatory butyrate [ 72 ].…”

Section: Epigenetic Regulation Of T Cell Differentiation and Inflamentioning

confidence: 99%

See 1 more Smart Citation

From Suppressor T Cells to Regulatory T Cells: How the Journey that Began with the Discovery of the Toxic Effects of TCDD Led to Better Understanding of the Role of AhR in Immunoregulation

Singh

Nagarkatti

2020

IJMS

Self Cite

View full text Add to dashboard Cite

Aryl hydrocarbon receptor (AhR) was identified in the early 1970s as a receptor for the ubiquitous environmental contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD, dioxin), which is a member of halogenated aromatic hydrocarbons (HAHs). TCDD was found to be highly toxic to the immune system, causing thymic involution and suppression of a variety of T and B cell responses. The fact that environmental chemicals cause immunosuppression led to the emergence of a new field, immunotoxicology. While studies carried out in early 1980s demonstrated that TCDD induces suppressor T cells that attenuate the immune response to antigens, further studies on these cells were abandoned due to a lack of specific markers to identify such cells. Thus, it was not until 2001 when FoxP3 was identified as a master regulator of Regulatory T cells (Tregs) that the effect of AhR activation on immunoregulation was rekindled. The more recent research on AhR has led to the emergence of AhR as not only an environmental sensor but also as a key regulator of immune response, especially the differentiation of Tregs vs. Th17 cells, by a variety of endogenous, microbial, dietary, and environmental ligands. This review not only discusses how the role of AhR emerged from it being an environmental sensor to become a key immunoregulator, but also confers the identification of new AhR ligands, which are providing novel insights into the mechanisms of Treg vs. Th17 differentiation. Lastly, we discuss how AhR ligands can trigger epigenetic pathways, which may provide new opportunities to regulate inflammation and treat autoimmune diseases.

show abstract

“…The AHR pathway mediates crosstalk between particular metabolites in the environment and immune cells, which is important for gut barrier protection and mucosal immunity. I3C can prevent TNBS-induced colitis in mice primarily through inducing IL-22 production by ILC3s (137). Furthermore, fecal microbiota transplantation (FMT) and indigo naturalis (IN), a traditional herbal medicine used for UC, can attenuate DSS-induced colitis in mice by up-regulating the expression or activity of AHR (138,139).…”

Section: Therapeutic Potential Of Ilc3s In Ibdmentioning

confidence: 99%

Metabolic Regulation of Group 3 Innate Lymphoid Cells and Their Role in Inflammatory Bowel Disease

2020

View full text Add to dashboard Cite

Inflammatory bowel disease (IBD) is characterized by chronic and relapsing inflammatory disorder of the intestine. IBD is associated with complex pathogenesis, and considerable data suggest that innate lymphoid cells contribute to the development and progression of the condition. Group 3 innate lymphoid cells (ILC3s) not only play a protective role in maintaining intestinal homeostasis and gut barrier function, but also a pathogenic role in intestinal inflammation. ILC3s can sense environmental and host-derived signals and combine these cues to modulate cell expansion, migration and function, and transmit information to the broader immune system. Herein, we review current knowledge of how ILC3s can be regulated by dietary nutrients, microbiota and their metabolites, as well as other metabolites. In addition, we describe the phenotypic and functional alterations of ILC3s in IBD and discuss the therapeutic potential of ILC3s in the treatment of IBD.

show abstract

Indole-3-carbinol prevents colitis and associated microbial dysbiosis in an IL-22–dependent manner

Cited by 95 publications

References 93 publications

Dietary Indole-3-Carbinol Alleviated Spleen Enlargement, Enhanced IgG Response in C3H/HeN Mice Infected with Citrobacter rodentium

Dietary Indole-3-Carbinol Alleviated Spleen Enlargement, Enhanced IgG Response in C3H/HeN Mice Infected with Citrobacter rodentium

From Suppressor T Cells to Regulatory T Cells: How the Journey that Began with the Discovery of the Toxic Effects of TCDD Led to Better Understanding of the Role of AhR in Immunoregulation

Metabolic Regulation of Group 3 Innate Lymphoid Cells and Their Role in Inflammatory Bowel Disease

Contact Info

Product

Resources

About