El-Zaatari Mohamad, Chang Yu-Ming, Zhang Min, Franz Matthew, Shreiner Andrew, McDermott Andrew J, van der Sluijs Koenraad F, Lutter René, Grasberger Helmut, Kamada Nobuhiko, Young Vincent B, Huffnagle Gary B, Kao John Y
Department of Internal Medicine-Gastroenterology, University of Michigan, Ann Arbor, MI 48109;
Department of Microbiology and Immunology, University of Michigan, Ann Arbor, MI 48109;
J Immunol. 2014 Jul 15;193(2):807-16. doi: 10.4049/jimmunol.1302913. Epub 2014 Jun 16.
The interplay between Clostridium difficile and the host's metabolome is believed to influence the severity of infection. However, the mechanism for this phenomenon remains unclear. In this study, we model one of these metabolic pathways by focusing on tryptophan metabolism in the host. We found that inhibition of tryptophan catabolism in IDO1-knockout mice led to increased mucosal destruction, cecal hemorrhage, and increased production of IFN-γ in response to C. difficile infection, but no significant change in mucosal effector or regulatory T cell numbers or IL-10 mRNA expression. The increased immunopathology in infected IDO1-knockout mice was associated with a lower C. difficile burden and an increased percentage of IFN-γ-expressing neutrophils. We further demonstrated the ability of kynurenine to induce apoptosis in bone marrow-derived neutrophils, whereas the presence of tryptophan reversed this effect, providing a possible mechanism for the increased neutrophil accumulation in IDO1(-/-) mice. We conclude that C. difficile induces tryptophan catabolism in cecal lamina propria cells, which restricts C. difficile-associated immunopathology and the accumulation of IFN-γ-expressing neutrophils. This might represent a self-regulatory mechanism for neutrophils, via the IFN-γ-IDO1 pathway, to restrict their own accumulation during infection. These findings have important clinical implications because IDO inhibitors are used to treat cancer in clinical trials (in patients particularly susceptible to getting C. difficile infection), and treatment with IDO1 inhibitors may exacerbate the severity of C. difficile colitis.
艰难梭菌与宿主代谢组之间的相互作用被认为会影响感染的严重程度。然而，这一现象的机制仍不清楚。在本研究中，我们通过关注宿主中的色氨酸代谢来模拟其中一条代谢途径。我们发现，在IDO1基因敲除小鼠中抑制色氨酸分解代谢会导致黏膜破坏增加、盲肠出血以及对艰难梭菌感染产生的IFN-γ产量增加，但黏膜效应或调节性T细胞数量以及IL-10 mRNA表达没有显著变化。感染的IDO1基因敲除小鼠中免疫病理学的增加与较低的艰难梭菌负荷以及表达IFN-γ的中性粒细胞百分比增加有关。我们进一步证明了犬尿氨酸诱导骨髓来源中性粒细胞凋亡的能力，而色氨酸的存在则逆转了这种效应，这为IDO1基因敲除小鼠中中性粒细胞积累增加提供了一种可能的机制。我们得出结论，艰难梭菌诱导盲肠固有层细胞中的色氨酸分解代谢，这限制了与艰难梭菌相关的免疫病理学以及表达IFN-γ的中性粒细胞的积累。这可能代表了中性粒细胞通过IFN-γ-IDO1途径在感染期间限制自身积累的一种自我调节机制。这些发现具有重要的临床意义，因为IDO抑制剂在临床试验中用于治疗癌症（在特别容易感染艰难梭菌的患者中），而用IDO1抑制剂治疗可能会加重艰难梭菌结肠炎的严重程度。
