Department of Physiology and Biophysics, University of California, Irvine, California, United States.
Veterans Affairs Medical Center, Long Beach, California, United States.
Am J Physiol Gastrointest Liver Physiol. 2024 Jul 1;327(1):G36-G46. doi: 10.1152/ajpgi.00065.2024. Epub 2024 May 7.
Humans and mammals obtain vitamin B1 from dietary and gut microbiota sources. A considerable amount of the microbiota-generated vitamin exists in the form of thiamine pyrophosphate (TPP), and colonocytes are capable of absorbing TPP via a specific carrier-mediated process that involves the colonic TPP transporter (cTPPT encoded by ). Little is known about the relative contribution of the SLC44A4 transporter toward total colonic carrier-mediated TPP uptake and its role in colon physiology. To address these issues, we generated an knockout (KO) mouse model (by Cre-Lox recombination) and found a near-complete inhibition in colonic carrier-mediated [H]TPP uptake in the KO compared with wild-type (WT) littermates. We also observed a significant reduction in KO mice's body weight and a shortening of their colon compared with WT. Using RNAseq and Ingenuity pathway analysis (IPA) approaches, we found that knocking out the colonic led to changes in the level of expression of many genes, including upregulation in those associated with intestinal inflammation and colitis. Finally, we found that the KO mice were more susceptible to the effect of the colitogenic dextran sodium sulfate (DSS) compared with WT animals, a finding that lends support to the recent prediction by multiple genome-wide association studies (GWAS) that is a possible colitis susceptibility gene. In summary, the results of these investigations show that Slc44a4 is the predominant or only transporter involved in the colonic uptake of TPP, that the transporter is important for colon physiology, and that its deletion increases susceptibility to inflammation. This study shows that Slc44a4 is the predominant or only transport system involved in the uptake of the gut microbiota-generated thiamine pyrophosphate (TPP) in the colon and that its deletion affects colon physiology and increases its susceptibility to inflammation.
人类和哺乳动物从饮食和肠道微生物群来源获得维生素 B1。相当数量的微生物群生成的维生素以硫胺素焦磷酸（TPP）的形式存在，而结肠细胞能够通过涉及结肠 TPP 转运体（由 编码的 ）的特定载体介导的过程吸收 TPP。关于 SLC44A4 转运体对总结肠载体介导的 TPP 摄取的相对贡献及其在结肠生理学中的作用知之甚少。为了解决这些问题，我们生成了一个 敲除（KO）小鼠模型（通过 Cre-Lox 重组），并发现与野生型（WT）同窝仔相比， KO 中结肠载体介导的 [H]TPP 摄取几乎完全受到抑制。我们还观察到 KO 小鼠的体重显著减轻，结肠缩短。使用 RNAseq 和 Ingenuity 途径分析（IPA）方法，我们发现敲除结肠 导致许多基因表达水平的变化，包括与肠道炎症和结肠炎相关的基因上调。最后，我们发现与 WT 动物相比， KO 小鼠对致结肠炎的葡聚糖硫酸钠（DSS）的作用更敏感，这一发现支持了多个全基因组关联研究（GWAS）的最新预测，即 是一个可能的结肠炎易感性基因。总之，这些研究的结果表明 Slc44a4 是参与 TPP 结肠摄取的主要或唯一转运体，该转运体对结肠生理学很重要，其缺失会增加炎症易感性。本研究表明，Slc44a4 是参与肠道微生物群生成的硫胺素焦磷酸（TPP）在结肠摄取的主要或唯一转运系统，其缺失会影响结肠生理学并增加其炎症易感性。
