Division of Gastroenterology, Department of Internal Medicine, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chu-o-ku, Kobe, Hyogo, 650-0017, Japan.
Division of Metabolomics Research, Department of Internal Related, Kobe University Graduate School of Medicine, Kobe, Hyogo, 650-0017, Japan.
Dig Dis Sci. 2018 Apr;63(4):881-889. doi: 10.1007/s10620-017-4905-3. Epub 2018 Jan 11.
Proton pump inhibitors (PPIs) are among the most frequently prescribed medications. Side effects including an increased risk of intestinal infections have been reported. It is assumed that PPIs can increase susceptibility to enteropathogens; however, the underlying mechanisms are unknown. Here in this study, we explored whether Lansoprazole (Laz), one of the PPIs, increases the susceptibility to enteropathogens, and further investigated the mechanism of it.
Mice were administered Laz intraperitoneally once daily and orally infected with Citrobacter rodentium (C. rodentium). The establishment of intestinal infection was assessed by histology and inflammatory cytokine expression levels measured by quantitative PCR. To test whether Laz changes the intestinal environment to influence the susceptibility, intestinal pH, microbiota, metabolites and immune cell distributions were evaluated via pH measurement, 16S rRNA gene sequencing, metabolome, and flow cytometry analyses after Laz administration.
Colitis was induced with less C. rodentium in Laz-treated mice as compared with the controls. We found that increased numbers of C. rodentium could reach the cecum following Laz administration. Laz increased pH in the stomach but not in the intestines. It induced dysbiosis and changed the metabolite content of the small intestine. However, these changes did not lead to alterations of immune cell distribution.
Laz raised susceptibility to C. rodentium as increased numbers of the pathogen reach the site of infection. Our results suggest that it was due to increased stomach pH which allowed more peroral enteropathogens to pass the stomach, but not because of changes of intestinal environment.
质子泵抑制剂（PPIs）是最常被开的药物之一。已报道其存在包括增加肠道感染风险在内的副作用。据推测，PPIs 会增加对肠道病原体的易感性；然而，其潜在机制尚不清楚。在本研究中，我们探讨了质子泵抑制剂中的兰索拉唑（Laz）是否会增加对肠道病原体的易感性，并进一步研究了其机制。
通过腹腔内每天一次给予小鼠 Laz，并经口感染柠檬酸杆菌（C. rodentium）。通过组织学评估和定量 PCR 测量炎症细胞因子表达水平来评估肠道感染的建立。为了测试 Laz 是否通过改变肠道环境来影响易感性，在 Laz 给药后通过 pH 值测量、16S rRNA 基因测序、代谢组学和流式细胞术分析评估肠道 pH 值、微生物群、代谢物和免疫细胞分布。
与对照组相比，Laz 处理的小鼠中结肠炎的诱导需要更少的 C. rodentium。我们发现 Laz 给药后更多数量的 C. rodentium 可以到达盲肠。Laz 增加了胃中的 pH 值，但没有增加肠道中的 pH 值。它引起了肠道菌群失调并改变了小肠的代谢物含量。然而，这些变化并没有导致免疫细胞分布的改变。
Laz 提高了对 C. rodentium 的易感性，因为更多的病原体到达感染部位。我们的结果表明，这是由于胃 pH 值升高，允许更多的经口肠道病原体通过胃，但不是由于肠道环境的改变。
