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Dietary Supplementation With Orotate and Uracil Increases Adaptive Growth of Jejunal Mucosa After Massive Small Bowel Resection in Rats

Mary E. Evans, PhD^*,, Junqiang Tian, MD^*,, Li H. Gu, MD^*,, Dean P. Jones, PhD^*, and Thomas R. Ziegler, MD^*,

From the ^* Department of Medicine and the Center for Clinical and Molecular Nutrition, Emory University School of Medicine, Atlanta, Georgia

Correspondence: Thomas R. Ziegler, MD, Suite GG-23, General Clinical Research Center, Emory University Hospital, 1364 Clifton Rd, Atlanta, GA 30322. Electronic mail may be sent to tzieg01{at}emory.edu.

Background: Massive small-bowel resection (SBR) increases adaptive growth of residual intestine in animal models of short-bowel syndrome (SBS). Pyrimidine nucleotides are critical for DNA and RNA synthesis, but no previous study has evaluated whether supplementation of pyrimidines or their precursors in the diet enhances adaptive gut growth after SBR. This study determined growth responses in jejunal mucosa after 7 days of dietary supplementation with uracil, or its precursor, orotate, after massive SBR in rats. Methods: Sprague-Dawley rats (200 g) underwent 80% jejunoileal resection (RX) or ileal transection (TX; control). Rats were pair-fed a purified (AIN-93G) powdered diet supplemented with or without 1% (wt/wt) orotate or uracil until killing at 7 days postsurgery. Defined jejunal segments were obtained for analysis of mucosal villus height (VH), crypt depth (CD), total mucosal height, bromodeoxyuridine (BrdU) incorporation, an index of cell proliferation, and full-thickness DNA and protein content as measures of intestinal adaptive growth. Results: Jejunal VH increased significantly with SBR, as expected, and orotate further stimulated this response. Jejunal CD and total mucosal height increased significantly with both orotate and uracil supplementation compared with resected animals receiving standard diet. Orotate administration also increased jejunal DNA content compared with the increase observed with SBR alone. Finally, orotate, but not uracil, supplementation increased BrdU incorporation compared with resected rats fed standard or uracil-supplemented diet after SBR. Conclusions: Supplementation of oral diet with the pyrimidine precursor orotate and uracil stimulated adaptive jejunal growth after massive SBR in rats. Dietary orotate had more potent growth-stimulatory effects than uracil in this animal model. Dietary supplementation with orotate and uracil represents a novel nutrition approach to enhance small-bowel mucosal adaptive growth and absorptive capacity in SBS.

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