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Transcription factor ISX mediates the cross talk between diet and immunity

Significance The intestine is the major entrance site for nutrients, electrolytes, and water while constituting an effective barrier against toxins, antigens, and enteric flora. Hence, the intestinal mucosa harbors one of the largest populations of lymphocytes in the body. Nutrients such as vitamin A have been recognized to influence gut homing and differentiation of these cells. We identified the ISX protein as a critical molecular mediator of this cross talk between diet and immunity. This transcription factor regulates vitamin A production from dietary precursor molecules. Loss of this control in mice disrupts vitamin A homeostasis and impairs immunity. Reported genetic polymorphisms in the Isx gene have been associated with inflammatory disorders in humans, indicating that our findings in mice have clinical implications. The intestinal epithelium is a major site for the conversion of dietary β-carotene to retinaldehyde by the enzyme BCO1. The majority of retinaldehyde is further metabolized to retinol (vitamin A), esterified and packaged into triacylglycerol-rich chylomicrons for bodily distribution. Some serve on-site for the synthesis of retinoic acid, a hormone-like compound, which exerts pleiotropic and dominant effects on gastrointestinal immunity. We report here that the intestine-specific homeobox protein ISX is critical to control the metabolic flow of β-carotene through this important branching point of vitamin A metabolism. This transcription factor represses Bco1 gene expression in response to retinoic acid signaling. In ISX-deficient mice, uncontrolled Bco1 gene expression led to increased retinoid production in the intestine. Systemically, this production resulted in highly elevated hepatic retinoid stores. In the intestine, it increased the expression of retinoic acid-inducible target genes such as Aldh1a2, Dhrs3, and Ccr9. The β-carotene–inducible disruption of retinoid homeostasis affected gut-homing and differentiation of lymphocytes and displayed morphologically in large lymphoid follicles along the intestine. Furthermore, it was associated with an infiltration of the pancreas by gut-derived lymphocytes that manifested as a pancreatic insulitis with β-islet cell destruction and systemic glucose intolerance. Thus, our study identifies an important molecular interlink between diet and immunity and indicates that vitamin A homeostasis must be tightly controlled by ISX to maintain immunity and tolerance at the intestinal barrier.