Downregulation of Th17 Cells in the Small Intestine by Disruption of Gut Flora in the Absence of Retinoic Acid

Abstract

Retinoic acid (RA), a well-known vitamin A metabolite, mediates inhibition of the IL-6-driven induction of proinflammatory Th17 cells and promotes anti-inflammatory regulatory T cell generation in the presence of TGF-β, which is mainly regulated by dendritic cells. To directly address the role of RA in Th17/regulatory T cell generation in vivo, we generated vitamin A-deficient (VAD) mice by continuous feeding of a VAD diet beginning in gestation. We found that a VAD diet resulted in significant inhibition of Th17 cell differentiation in the small intestine lamina propria by as early as age 5 wk. Furthermore, this diet resulted in low mRNA expression levels of IL-17, IFN regulatory factor 4, IL-21, IL-22, and IL-23 without alteration of other genes, such as RORγt, TGF-β, IL-6, IL-25, and IL-27 in the small intestine ileum. In vitro results of enhanced Th17 induction by VAD dendritic cells did not mirror in vivo results, suggesting the existence of other regulation factors. Interestingly, the VAD diet elicited high levels of mucin MUC2 by goblet cell hyperplasia and subsequently reduced gut microbiome, including segmented filamentous bacteria. Much like wild-type mice, the VAD diet-fed MyD88−/−TRIF−/− mice had significantly fewer IL-17–secreting CD4+ T cells than the control diet-fed MyD88−/−TRIF−/− mice. The results strongly suggest that RA deficiency altered gut microbiome, which in turn inhibited Th17 differentiation in the small intestine lamina propria.

IFN-γ Secreted by CD103+ Dendritic Cells Leads to IgG Generation in the Mesenteric Lymph Node in the Absence of Vitamin A

“…One recent study reported that segmented filamentous bacteria in the small intestine are sufficient to induce the appearance of CD4 + T cells that produce IL-17 and IL-22 in the SI-LP (35). In this regard, our study revealed that a VAD diet altered the quantity and composition of gut microbiota including segmented filamentous bacteria, resulting in downregulation of Th17 cells in the SI-LP (25). We also found morphological and functional alterations in the intestinal epithelial cells (IEC) of mice fed a VAD diet (25).…”

“…In this regard, our study revealed that a VAD diet altered the quantity and composition of gut microbiota including segmented filamentous bacteria, resulting in downregulation of Th17 cells in the SI-LP (25). We also found morphological and functional alterations in the intestinal epithelial cells (IEC) of mice fed a VAD diet (25). How do altered gut microbiota and IEC function in the absence of vitamin A to accelerate secretory IgG production?…”

“…In our previous study, VAD mice maintained predominant numbers of IFN-g-secreting T cells in the SI-LP (25). Of note, APCs isolated from VAD mice stimulated greater IFN-g secretion than APCs from control diet-fed mice; however, IFN-g secretion was altered when RA was added (33).…”

“…We and others have previously shown that VAD mice have an abnormal intestinal epithelial barrier that causes alteration of populations and quantities of commensal intestinal bacteria (24,25). To investigate the role of gut microbiota in IgG generation in VAD mice, we fed antibiotics to VAD mice daily from 3 wk after birth to age 10 wk.…”

Vitamins: Preparing for the Next 100 Years

“…The ability of the gut microbiota to produce folate and cobalamin could affect host DNA methylation patterns, but little is yet known about how these relationships between the host, host diet, and microbial community evolve and shape physiological phenotypes. However, it is interesting to note that vitamin A has the potential to modulate immune responses through direct interactions with immune cells as well as indirectly by modulating the composition of the microbiota (Cha et al 2010). Research is needed to identify new host and microbial biomarkers and mediators of vitamin status to better establish the nutritional and health value of various foods.…”