Vitamin A is an essential dietary nutrient, available to humans in 2 forms: preformed vitamin A (retinol and retinyl ester) and plantbased provitamin A carotenoids. Most of the body’s vitamin A is stored in the liver as hepatic retinyl esters. Vitamin A blood levels are homeostatically regulated to maintain a narrow range. Preformed and provitamin A must be metabolized intracellularly by gut mucosal cells to retinal and retinoic acid, the active forms that support biological functions. Lounder et al review vitamin A’s known immunological roles in the health of the intestinal mucosa; simply put, most of the existing literature supports its anti-inflammatory role in limiting chemical and infectious gut injuries (albeit some contradictory mouse data exist). Therefore, to understand their GVHD observation, Lounder et al explored associations between higher and lower vitamin A levels and measurements of retinol-binding protein 4, intestinal fatty acid–binding protein, interleukin-22 (IL-22), CCR9, and effector memory T cells (see figure). In the last few decades, our understanding of GVHD pathophysiology has expanded much beyond conditioning-mediated disruption of the intestinal mucosa and the classic interaction of donor T cells with hematopoietic antigen-presenting cells. We better appreciate how perturbation of the fecal microbiota integrates with the cellular immune system to promote inflammatory disease and diarrhea. A nonexhaustive list of important players in this regard includes: intestinal stem cells and their closely aligned Paneth cells, the protective intestinal mucous layer, intestinal fatty acids like butyrate, bacterial composition of the feces and its regulation by defensins. 2, 3 Antibiotic therapy and diet can further disrupt the fecal microbiota and in turn affect mucosal integrity. It is worth viewing the intriguing results of Lounder et al through the lens of this broader understanding of GVHD pathophysiology and with a shift in focus to GVHD interventions that move beyond traditional systemic immunosuppressive therapies.

Recognizing the critical integration of fecal microbiota and gut immunology, our gastroenterology colleagues have also explored associations with intestinal disease. One study found that among children diagnosed with “persistent diarrhea”(. 14 days) but not with inflammatory bowel disease (IBD) per se, diversity of the gut microbiota and its key bacterial phylotypes differed significantly between groups with normal or deficient vitamin A levels. 4 They have also studied alternatives to systemic immunosuppressive therapy in IBD. A detailed and well-designed meta-analysis of therapy in pediatric Crohn disease examined 5 randomized clinical trials and 2 further nonrandomized trials. 5 The authors concluded