Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan.
Center for Diagnostic and Therapeutic Endoscopy, Keio University School of Medicine, Tokyo, Japan.
Cell Mol Gastroenterol Hepatol. 2023;16(6):1011-1031. doi: 10.1016/j.jcmgh.2023.08.002. Epub 2023 Aug 9.
BACKGROUND & AIMS: D-amino acids, the chiral counterparts of protein L-amino acids, were primarily produced and utilized by microbes, including those in the human gut. However, little was known about how orally administered or microbe-derived D-amino acids affected the gut microbial community or gut disease progression.
The ratio of D- to L-amino acids was analyzed in feces and blood from patients with ulcerative colitis (UC) and healthy controls. Also, composition of microbe was analyzed from patients with UC. Mice were treated with D-amino acid in dextran sulfate sodium colitis model and liver cholangitis model.
The ratio of D- to L-amino acids was lower in the feces of patients with UC than that of healthy controls. Supplementation of D-amino acids ameliorated UC-related experimental colitis and liver cholangitis by inhibiting growth of Proteobacteria. Addition of D-alanine, a major building block for bacterial cell wall formation, to culture medium inhibited expression of the ftsZ gene required for cell fission in the Proteobacteria Escherichia coli and Klebsiella pneumoniae, thereby inhibiting growth. Overexpression of ftsZ restored growth of E. coli even when D-alanine was present. We found that D-alanine not only inhibited invasion of pathological K. pneumoniae into the host via pore formation in intestinal epithelial cells but also inhibited growth of E. coli and generation of antibiotic-resistant strains.
D-amino acids might have potential for use in novel therapeutic approaches targeting Proteobacteria-associated dysbiosis and antibiotic-resistant bacterial diseases by means of their effects on the intestinal microbiota community.
D-氨基酸是蛋白质 L-氨基酸的手性对应物，主要由微生物产生和利用，包括肠道内的微生物。然而，人们对于口服或微生物衍生的 D-氨基酸如何影响肠道微生物群落或肠道疾病的进展知之甚少。
分析溃疡性结肠炎（UC）患者和健康对照者粪便和血液中的 D-与 L-氨基酸的比值。还分析了 UC 患者的微生物组成。在葡聚糖硫酸钠结肠炎模型和肝内胆管炎模型中，用 D-氨基酸处理小鼠。
UC 患者粪便中的 D-与 L-氨基酸比值低于健康对照者。补充 D-氨基酸可通过抑制变形菌的生长来改善 UC 相关实验性结肠炎和肝内胆管炎。将 D-丙氨酸（细菌细胞壁形成的主要成分之一）添加到培养基中可抑制变形菌大肠杆菌和肺炎克雷伯菌细胞分裂所需的 ftsZ 基因的表达，从而抑制其生长。ftsZ 的过表达即使存在 D-丙氨酸也能恢复大肠杆菌的生长。我们发现，D-丙氨酸不仅通过在肠上皮细胞中形成孔抑制致病性肺炎克雷伯菌入侵宿主，还能抑制大肠杆菌的生长和产生抗生素耐药菌株。
D-氨基酸可能通过其对肠道微生物群落的影响，为针对与变形菌相关的肠道菌群失调和抗生素耐药细菌疾病的新型治疗方法提供潜力。
