Genotype-dependency of butyrate efficacy in children with congenital chloride diarrhea
Genotype-dependency of butyrate efficacy in children with congenital chloride diarrhea
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DOI：
10.1186/1750-1172-8-194
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发表时间：
2013-12-19
影响因子：
3.7
通讯作者：
Castaldo, Giuseppe
中科院分区：
文献类型：
--
作者：
Canani, Roberto Berni;Terrin, Gianluca;Castaldo, Giuseppe
背景资料：先天性氯化物腹泻（CLD）是一种常染色体隐性遗传疾病，其特征是终生严重腹泻并伴有肠道氯吸收不良。它是由于溶质载体家族26成员3（SLC 26 A3）基因突变导致的腺瘤交换蛋白（AAP）活性降低所致。目前可用的治疗无法限制CLD中腹泻的严重程度。口服丁酸盐的治疗效果已报告的结果：我们调查了口服丁酸盐（100 mg/kg/天）在7个CLD儿童与不同的SLC 26 A3基因型的效果。鼻上皮细胞，以评估丁酸盐的两个主要的Cl-转运蛋白的表达的影响：β-氨基丁酸和假定的阴离子转运蛋白-1（PAT-1）。结果：观察到一个变量丁酸盐的临床反应，粪便模式和粪便离子损失。在错义突变和缺失突变受试者中观察到最佳缓解。对丁酸盐的可变反应也观察到SLC 26 A3（PAT 1）和SLC 26 A6（PAT 1）基因表达在鼻上皮细胞CLD patients.Conclusions：我们证明了基因型依赖性丁酸盐治疗CLD的疗效。丁酸盐的作用部分与上皮细胞的两个主要顶端膜Cl-交换器（SLC 26阴离子家族的成员）的表达的不同调制有关。
Background: Congenital chloride diarrhea (CLD) is an autosomal recessive disorder characterized by life-long, severe diarrhea with intestinal Cl-malabsorption. It results from a reduced activity of the down regulated in adenoma exchanger (DRA), due to mutations in the solute carrier family 26, member 3 (SLC26A3) gene. Currently available therapies are not able to limit the severity of diarrhea in CLD. Conflicting results have been reported on the therapeutic efficacy of oral butyrate.Methods: We investigated the effect of oral butyrate (100 mg/kg/day) in seven CLD children with different SLC26A3 genotypes. Nasal epithelial cells were obtained to assess the effect of butyrate on the expression of the two main Cl-transporters: DRA and putative anion transporter-1 (PAT-1).Results: A variable clinical response to butyrate was observed regarding the stool pattern and fecal ion loss. The best response was observed in subjects with missense and deletion mutations. Variable response to butyrate was also observed on SLC26A3 (DRA) and SLC26A6 (PAT1) gene expression in nasal epithelial cells of CLD patients.Conclusions: We demonstrate a genotype-dependency for butyrate therapeutic efficacy in CLD. The effect of butyrate is related in part on a different modulation of the expression of the two main apical membrane Cl-exchangers of epithelial cells, members of the SLC26 anion family.