Newburg David S, Ko Jae Sung, Leone Serena, Nanthakumar N Nanda
Program in Glycobiology, Department of Biology, Boston College, Chestnut Hill, MA;
Department of Pediatrics, Seoul National University Children's Hospital, Jongno-gu, Seoul, Korea; and.
J Nutr. 2016 Feb;146(2):358-67. doi: 10.3945/jn.115.220749. Epub 2015 Dec 23.
The immature intestinal mucosa responds excessively to inflammatory insult, but human milk protects infants from intestinal inflammation. The ability of galactosyllactoses [galactosyloligosaccharides (GOS)], newly found in human milk oligosaccharides (HMOS), to suppress inflammation was not known.
The objective was to test whether GOS can directly attenuate inflammation and to explore the components of immune signaling modulated by GOS.
Galactosyllactose composition was measured in sequential human milk samples from days 1 through 21 of lactation and in random colostrum samples from 38 mothers. Immature [human normal fetal intestinal epithelial cell (H4)] and mature [human metastatic colonic epithelial cell (T84) and human normal colon mucosal epithelial cell (NCM-460)] enterocyte cell lines were treated with the pro-inflammatory molecules tumor necrosis factor-α (TNF-α) or interleukin-1β (IL-1β) or infected with Salmonella or Listeria. The inflammatory response was measured as induction of IL-8, monocyte chemoattractant protein 1 (MCP-1), or macrophage inflammatory protein-3α (MIP-3α) protein by ELISA and mRNA by quantitative reverse transcriptase-polymerase chain reaction. The ability of HMOS or synthetic GOS to attenuate this inflammation was tested in vitro and in immature human intestinal tissue ex vivo.
The 3 galactosyllactoses (3'-GL, 4-GL, and 6'-GL) expressed in colostrum rapidly declined over early lactation (P < 0.05). In H4 cells, HMOS attenuated TNF-α- and IL-1β-induced expression of IL-8, MIP-3α, and MCP-1 to 48-51% and pathogen-induced IL-8 and MCP-1 to 26-30% of positive controls (P < 0.001). GOS reduced TNF-α- and IL-1β-induced inflammatory responses to 25-26% and pathogen-induced IL-8 and MCP-1 to 36-39% of positive controls (P < 0.001). GOS and HMOS mitigated nuclear translocation of nuclear transcription factor κB (NF-κB) p65. HMOS quenched the inflammatory response to Salmonella infection by immature human intestinal tissue ex vivo to 26% and by GOS to 50% of infected controls (P < 0.01).
Galactosyllactose attenuated NF-κB inflammatory signaling in human intestinal epithelial cells and in human immature intestine. Thus, galactosyllactoses are strong physiologic anti-inflammatory agents in human colostrum and early milk, contributing to innate immune modulation. The potential clinical utility of galactosyllactose warrants investigation.
未成熟的肠黏膜对炎症刺激反应过度，但母乳可保护婴儿免受肠道炎症侵害。人乳寡糖（HMOS）中新发现的半乳糖乳糖[低聚半乳糖（GOS）]抑制炎症的能力尚不清楚。
测试GOS是否能直接减轻炎症，并探索受GOS调节的免疫信号传导成分。
在哺乳期第1天至第21天的连续母乳样本以及38位母亲的随机初乳样本中测量半乳糖乳糖成分。用促炎分子肿瘤坏死因子-α（TNF-α）或白细胞介素-1β（IL-1β）处理未成熟[人正常胎儿肠上皮细胞（H4）]和成熟[人转移性结肠上皮细胞（T84）和人正常结肠黏膜上皮细胞（NCM-460）]肠上皮细胞系，或用沙门氏菌或李斯特菌感染。通过酶联免疫吸附测定法（ELISA）测量炎症反应，即诱导白细胞介素-8（IL-8）、单核细胞趋化蛋白1（MCP-1）或巨噬细胞炎性蛋白-3α（MIP-3α）蛋白，并通过定量逆转录聚合酶链反应测量mRNA。在体外和未成熟的人肠道组织中测试HMOS或合成GOS减轻这种炎症的能力。
初乳中表达的3种半乳糖乳糖（3'-GL、4-GL和6'-GL）在哺乳早期迅速下降（P<0.05）。在H4细胞中，HMOS将TNF-α和IL-1β诱导的IL-8、MIP-3α和MCP-1表达降低至阳性对照的48%-51%，将病原体诱导的IL-8和MCP-1降低至阳性对照的26%-30%（P<0.001）。GOS将TNF-α和IL-1β诱导的炎症反应降低至阳性对照的25%-26%，将病原体诱导的IL-8和MCP-1降低至阳性对照的36%-39%（P<0.001）。GOS和HMOS减轻了核转录因子κB（NF-κB）p65的核转位。HMOS将未成熟人肠道组织对沙门氏菌感染的炎症反应在体外降低至感染对照的26%，GOS降低至50%（P<0.01）。
半乳糖乳糖减弱了人肠上皮细胞和人未成熟肠道中的NF-κB炎症信号传导。因此，半乳糖乳糖是人类初乳和早期乳汁中强大的生理性抗炎剂，有助于先天免疫调节。半乳糖乳糖的潜在临床应用价值值得研究。
