David S Newburg1, Jae Sung Ko2, Serena Leone3, N Nanda Nanthakumar4. 1. Program in Glycobiology, Department of Biology, Boston College, Chestnut Hill, MA; newburgd@bc.edu nanda@vt.edu. 2. Department of Pediatrics, Seoul National University Children's Hospital, Jongno-gu, Seoul, Korea; and. 3. Program in Glycobiology, Department of Biology, Boston College, Chestnut Hill, MA; 4. Biomedical Sciences and Pathobiology, Virginia-Maryland Regional College of Veterinary Medicine, Virginia Polytechnic Institute and State University, Blacksburg, VA newburgd@bc.edu nanda@vt.edu.
Abstract
BACKGROUND: 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. OBJECTIVE: The objective was to test whether GOS can directly attenuate inflammation and to explore the components of immune signaling modulated by GOS. METHODS: 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. RESULTS: 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). CONCLUSION: 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.
BACKGROUND: 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. OBJECTIVE: The objective was to test whether GOS can directly attenuate inflammation and to explore the components of immune signaling modulated by GOS. METHODS: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. RESULTS: 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). CONCLUSION: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.
Authors: N Nanda Nanthakumar; Cheryl Young; Jae Sung Ko; Di Meng; Ji Chen; Timothy Buie; W Allan Walker Journal: Am J Physiol Gastrointest Liver Physiol Date: 2005-01 Impact factor: 4.052
Authors: I R Sanderson; R M Ezzell; M Kedinger; M Erlanger; Z X Xu; E Pringault; S Leon-Robine; D Louvard; W A Walker Journal: Proc Natl Acad Sci U S A Date: 1996-07-23 Impact factor: 11.205
Authors: Yoram Bouhnik; Laurent Raskine; Guy Simoneau; Eric Vicaut; Christel Neut; Bernard Flourié; Fred Brouns; Francis R Bornet Journal: Am J Clin Nutr Date: 2004-12 Impact factor: 7.045
Authors: Laura E J Searle; Angus Best; Alejandro Nunez; Francisco J Salguero; Linda Johnson; Ute Weyer; Alexandra H Dugdale; William A Cooley; Ben Carter; Gareth Jones; George Tzortzis; Martin J Woodward; Roberto M La Ragione Journal: J Med Microbiol Date: 2009-01 Impact factor: 2.472
Authors: Mike G Laukoetter; Porfirio Nava; Winston Y Lee; Eric A Severson; Christopher T Capaldo; Brian A Babbin; Ifor R Williams; Michael Koval; Eric Peatman; Jacquelyn A Campbell; Terence S Dermody; Asma Nusrat; Charles A Parkos Journal: J Exp Med Date: 2007-11-26 Impact factor: 14.307
Authors: J Y Soh; W C Chiang; C H Huang; C K Woo; I Ibrahim; K Heng; A Pramanick; B W Lee Journal: World Allergy Organ J Date: 2017-02-10 Impact factor: 4.084
Authors: Chunli Kong; Lianghui Cheng; Guido Krenning; Jolien Fledderus; Bart J de Haan; Marthe T C Walvoort; Paul de Vos Journal: J Nutr Date: 2020-08-01 Impact factor: 4.798