Meeker Stacey M, Seamons Audrey, Treuting Piper M, Paik Jisun, Brabb Thea, Hsu Charlie C, Grady William M, Maggio-Price Lillian
Department of Comparative Medicine, University of Washington, Seattle, Washington; Ohio State University, Columbus, Ohio;, Email:
Department of Comparative Medicine, University of Washington, Seattle, Washington.
Comp Med. 2020 Apr 1;70(2):120-130. doi: 10.30802/AALAS-CM-19-000021. Epub 2020 Feb 3.
Both human epidemiologic data and animal studies suggest that low serum vitamin D increases the risk of inflammatory bowel disease (IBD) and consequently IBD-associated colorectal cancer. We tested the hypothesis that vitamin D deficiency increases the risk for colitis-associated colon cancer (CAC) by using an established CAC mouse model, 129-/J () mice, which have defective transforming growth factor β-signaling and develop colitis and CAC after the administration of dextran sodium sulfate (DSS). After determining a dietary regimen that induced chronic vitamin D deficiency in mice, we assessed the effects of vitamin D deficiency on CAC. Decreasing dietary vitamin D from 1 IU/g diet (control diet) to 0.2 IU /g diet did not decrease serum 25-hydroxyvitamin D (25(OH)D) levels in mice. A diet devoid of vitamin D (< 0.02 IU/g diet [no added vitamin D]; vitamin D-null) significantly decreased serum 25(OH)D levels in mice after 2 wk (null compared with control diet: 8.4 mg/mL compared with 12.2 ng/mL) and further decreased serum levels to below the detection limit after 9 wk but did not affect weight gain, serum calcium levels, bone histology, or bone mineral density. In light of these results, mice were fed a vitamin D-null diet and given DSS to induce colitis. Unexpectedly, DSS-treated mice fed a vitamin D-null diet had improved survival, decreased colon tumor incidence (8% compared with 36%), and reduced the incidence and severity of colonic dysplasia compared with mice fed the control diet. These effects correlated with increased epithelial cell proliferation and repair early in the disease, perhaps reducing the likelihood of developing chronic colitis and progression to cancer. Our results indicate that vitamin D deficiency is beneficial in some cases of CAC, possibly by promoting intestinal healing.
人类流行病学数据和动物研究均表明，血清维生素D水平低会增加炎症性肠病（IBD）的风险，进而增加IBD相关结直肠癌的风险。我们通过使用已建立的结肠炎相关结肠癌（CAC）小鼠模型129 - /J（）小鼠来验证维生素D缺乏会增加患CAC风险的假设，该小鼠的转化生长因子β信号传导存在缺陷，在给予葡聚糖硫酸钠（DSS）后会发生结肠炎和CAC。在确定了能诱导小鼠慢性维生素D缺乏的饮食方案后，我们评估了维生素D缺乏对CAC的影响。将饮食中的维生素D从1 IU/g饮食（对照饮食）降至0.2 IU/g饮食，并未降低小鼠血清25 - 羟基维生素D（25(OH)D）水平。缺乏维生素D的饮食（<0.02 IU/g饮食[未添加维生素D]；无维生素D饮食）在2周后显著降低了小鼠血清25(OH)D水平（无维生素D饮食与对照饮食相比：8.4 ng/mL与12.2 ng/mL），9周后血清水平进一步降至检测限以下，但不影响体重增加、血清钙水平、骨组织学或骨矿物质密度。鉴于这些结果，给小鼠喂食无维生素D饮食并给予DSS以诱导结肠炎。出乎意料的是，与喂食对照饮食的小鼠相比，喂食无维生素D饮食的DSS处理小鼠存活率提高，结肠肿瘤发病率降低（8%对比36%），结肠发育异常的发病率和严重程度降低。这些效应与疾病早期上皮细胞增殖和修复增加相关，可能降低了发生慢性结肠炎和进展为癌症的可能性。我们的结果表明，维生素D缺乏在某些CAC病例中是有益的，可能是通过促进肠道愈合实现的。
