Dietary Indole-3-Carbinol Activates AhR in the Gut, Alters Th17-Microbe Interactions, and Exacerbates Insulitis in NOD Mice.

Heather M Kahalehili,Jamie M Pennington,Natalia Shulzhenko,Allison K Ehrlich,Nancy I Kerkvliet,Nolan K Newman,Siva K Kolluri,Andrey Morgun

doi:10.3389/fimmu.2020.606441

Heather M Kahalehili, Jamie M Pennington + Show 6 more

Open Access

https://doi.org/10.3389/fimmu.2020.606441

Copy DOI

Abstract

The diet represents one environmental risk factor controlling the progression of type 1 diabetes (T1D) in genetically susceptible individuals. Consequently, understanding which specific nutritional components promote or prevent the development of disease could be used to make dietary recommendations in prediabetic individuals. In the current study, we hypothesized that the immunoregulatory phytochemcial, indole-3-carbinol (I3C) which is found in cruciferous vegetables, will regulate the progression of T1D in nonobese diabetic (NOD) mice. During digestion, I3C is metabolized into ligands for the aryl hydrocarbon receptor (AhR), a transcription factor that when systemically activated prevents T1D. In NOD mice, an I3C-supplemented diet led to strong AhR activation in the small intestine but minimal systemic AhR activity. In the absence of this systemic response, the dietary intervention led to exacerbated insulitis. Consistent with the compartmentalization of AhR activation, dietary I3C did not alter T helper cell differentiation in the spleen or pancreatic draining lymph nodes. Instead, dietary I3C increased the percentage of CD4+RORγt+Foxp3- (Th17 cells) in the lamina propria, intraepithelial layer, and Peyer’s patches of the small intestine. The immune modulation in the gut was accompanied by alterations to the intestinal microbiome, with changes in bacterial communities observed within one week of I3C supplementation. A transkingdom network was generated to predict host-microbe interactions that were influenced by dietary I3C. Within the phylum Firmicutes, several genera (Intestinimonas, Ruminiclostridium 9, and unclassified Lachnospiraceae) were negatively regulated by I3C. Using AhR knockout mice, we validated that Intestinimonas is negatively regulated by AhR. I3C-mediated microbial dysbiosis was linked to increases in CD25high Th17 cells. Collectively, these data demonstrate that site of AhR activation and subsequent interactions with the host microbiome are important considerations in developing AhR-targeted interventions for T1D.

Highlights

Type 1 diabetes (T1D) is characterized by uncontrolled hyperglycemia resulting from autoimmune-mediated destruction of insulin-producing beta cells
Understanding how immune modulation is impacted by different aryl hydrocarbon receptor (AhR) ligands, their routes of administration, and their biodistribution is important for determining if AhR ligands may act as an environmental risk factor for type 1 diabetes (T1D) development, and/or how AhR can be exploited as a target for T1D treatment
In the current study we found that gut-localized AhR activation by I3C increased Th17 cells and exacerbated T1D in nonobese diabetic (NOD) mice, in contrast to our previous findings that systemic AhR activation by Cl-BBQ and TCDD reduced Th17 cells and prevented the development of T1D [10, 44]

Summary

Introduction

Type 1 diabetes (T1D) is characterized by uncontrolled hyperglycemia resulting from autoimmune-mediated destruction of insulin-producing beta cells. While a diet rich in AhR ligands would be predicted to mimic the studies showing the therapeutic benefit of high affinity ligands in preventing the progression of T1D, it is possible that consumption of a diet low in AhR ligands could contribute to T1D progression. This concern arises based on our recent studies demonstrating that a low level of AhR activation can lead to the differentiation of Th17 cells instead of Tregs [15], which could promote, rather than prevent T1D progression [16,17,18,19]

Methods

Results

Conclusion