Diet Modifies Colonic Microbiota and CD4⁺ T Cell Repertoire to Trigger Flares in a Novel Model of Colitis Induced by IL-23

Abstract

A wealth of experimental data points to immunological and environmental factors in the pathogenesis of inflammatory bowel disease (IBD). Here we study the role of IL-23, the microbiome, and the diet in the development of colitis. To promote IL-23 expression in vivo,we generated a mouse model in which IL-23 was conditionally expressed by CX 3 CR1 + myeloid cells, upon cyclic administration of tamoxifen in a specific diet (diet 2019). IL-23 expression induced an intestinal inflammatory disease that resembled ulcerative colitis in humans with cycles of acute disease and remission. The relapses were caused by the diet switch from the conventional diet used in our facility (diet 5053) to the diet 2019, and were not dependent on tamoxifen after the first cycle. The switch in the diet modified the microbiota, but did not alter the levels of IL-23. Colitis induction depended on the microbiota and required CD4 T lymphocytes. Colitis-inducing CD4 + T cells were found in the mesenteric lymph node and large intestine during remission and were able to trigger disease when transferred to lymphopenic mice, but only upon diet modification. The CD4 TCR repertoire in the diseased recipient Rag -/-mice had reduced diversity associated with the expansion of dominant T cell clones. These findings reveal a critical role for IL-23 in generation of a CD4 + T cell population in mice that is sensitive to a modification of intestinal bacterial flora subsequent to a dietary manipulation. Dietary changes occurring in the context of altered IL-23 expression may contribute to the onset and progression of IBD.

Food colorants metabolized by commensal bacteria promote colitis in mice with dysregulated expression of interleukin-23

“…In our previous study, we found that overexpression of IL-23 by myeloid cells does not appear to be sufficient for induction of colitis in adult mice (Chen et al, 2018). The mice we developed conditionally express IL-23 in CX3CR1-positive myeloid cells (R23FR mice).…”

“…The mice we developed conditionally express IL-23 in CX3CR1-positive myeloid cells (R23FR mice). R23FR mice were generated by crossing Rosa26-lox-STOP-lox-IL23 mice with CX3CR1 CreER mice (FR mice) (Chen et al, 2018). Upon tamoxifen (TAM) treatment, R23FR mice express IL-23 in CX3CR1-positive cells but do not develop colitis when fed the standard diet used in our facility (Labdiet 5053).…”

Interleukin 22 mediates interleukin 23-induced pathology in newborn mice by disrupting the function of pancreatic and intestinal cells

“…To further study the biology of IL-23 in neonates we engineered mice in which expression of IL-23 was targeted constitutively to CX3CR1 + cells, which are the cells that predominantly express IL-23 in the intestine. This was accomplished by intercrossing mice containing a IL-23 cassette preceded by a floxed STOP signal in the ROSA 26 locus (R23 mice) (Chen et al, 2018), with mice containing a cre recombinase gene inserted into the CX3CR1 locus (CX3CR1-cre mice) (Yona et al, 2013). We refer to these animals as CXR23 mice (Fig.…”

“…Mice. R23 mice were described in (Chen et al, 2018). R23 mice were backcrossed into the C57BL/6 background for 11 generations.…”

“…All statistical analyses were performed with GraphPad Prism 5 software. (Chen et al, 2018)) were crossed to CX3CR1-cre mice (described in (Yona et al, 2013)) to generate CXR23 mice. (B) Relative expression of p19 and p40 mRNA in the intestine of WT and CXR23 mice at postnatal day 1 (P1) (n = 10 mice/group).…”