Non-digestible oligosaccharides directly regulate host kinome to modulate host inflammatory responses without alterations in the gut microbiota
Tóm tắt
Prebiotics are non-digestible food ingredients that enhance the growth of certain microbes within the gut microbiota. Prebiotic consumption generates immune-modulatory effects that are traditionally thought to reflect microbial interactions within the gut. However, recent evidence suggests they may also impart direct microbe-independent effects on the host, though the mechanisms of which are currently unclear. Kinome arrays were used to profile the host intestinal signaling responses to prebiotic exposures in the absence of microbes. Identified pathways were functionally validated in Caco-2Bbe1 intestinal cell line and in vivo model of murine endotoxemia. We found that prebiotics directly regulate host mucosal signaling to alter response to bacterial infection. Intestinal epithelial cells (IECs) exposed to prebiotics are hyporesponsive to pathogen-induced mitogen-activated protein kinase (MAPK) and nuclear factor kappa B (NF-κB) activations, and have a kinome profile distinct from non-treated cells pertaining to multiple innate immune signaling pathways. Consistent with this finding, mice orally gavaged with prebiotics showed dampened inflammatory response to lipopolysaccharide (LPS) without alterations in the gut microbiota. These findings provide molecular mechanisms of direct host-prebiotic interactions to support prebiotics as potent modulators of host inflammation.
Tài liệu tham khảo
Bindels LB, Delzenne NM, Cani PD, Walter J. Towards a more comprehensive concept for prebiotics. Nat Rev Gastroenterol Hepatol. 2015;12:303–10.
Vogt L, Meyer D, Pullens G, Faas M, Smelt M, Venema K, et al. Immunological properties of inulin-type fructans. Crit Rev Food Sci Nutr. 2015;55:414–36.
Jain N, Walker WA. Diet and host–microbial crosstalk in postnatal intestinal immune homeostasis. Nat Rev Gastroenterol Hepatol. 2014;12:14–25.
Eiwegger T, Stahl B, Schmitt J, Boehm G, Gerstmayr M, Pichler J, et al. Human milk-derived oligosaccharides and plant-derived oligosaccharides stimulate cytokine production of cord blood T-cells in vitro. Pediatr Res. 2004;56:536–40.
Capitán-Cañadas F, Ortega-González M, Guadix E, Zarzuelo A, Suárez MD, de Medina FS, et al. Prebiotic oligosaccharides directly modulate proinflammatory cytokine production in monocytes via activation of TLR4. Mol Nutr Food Res. 2014;58:1098–110.
Lehmann S, Hiller J, van Bergenhenegouwen J, Knippels LMJ, Garssen J, Traidl-Hoffmann C. In vitro evidence for immune-modulatory properties of non-digestible oligosaccharides: direct effect on human monocyte derived dendritic cells. PLoS One. 2015;10:e0132304.
Vogt L, Ramasamy U, Meyer D, Pullens G, Venema K, Faas MM, et al. Immune modulation by different types of β2→1-Fructans is toll-like receptor dependent. PLoS One. 2013;8:e68367.
Bindels LB, Segura Munoz RR, Gomes-Neto JC, Mutemberezi V, Martínez I, Salazar N, et al. Resistant starch can improve insulin sensitivity independently of the gut microbiota. Microbiome. 2017;5(1):12.
Fransen F, Sahasrabudhe NM, Elderman M, Bosveld M, El Aidy S, Hugenholtz F, et al. β2→1-fructans modulate the immune system in vivo in a microbiota-dependent and -independent fashion. Front Immunol. 2017;8:154.
Wu RY, Abdullah M, Määttänen P, AVC P, Scruten E, Johnson-Henry KC, et al. Protein kinase C δ signaling is required for dietary prebiotic-induced strengthening of intestinal epithelial barrier function. Sci Rep. 2017;7:40820.
Johnson SA, Hunter T. Kinomics: methods for deciphering the kinome. Nat Methods. 2005;2:17–25.
Trost B, Kindrachuk J, Määttänen P, Napper S, Kusalik A. PIIKA 2: an expanded, web-based platform for analysis of kinome microarray data. PLoS One. 2013;8:e80837.
Good M, Sodhi CP, Egan CE, Afrazi A, Jia H, Yamaguchi Y, et al. Breast milk protects against the development of necrotizing enterocolitis through inhibition of toll-like receptor 4 in the intestinal epithelium via activation of the epidermal growth factor receptor. Mucosal Immunol. 2015;8:1166–79.
Berin MC, Darfeuille-Michaud A, Egan LJ, Miyamoto Y, Kagnoff MF. Role of EHEC O157:H7 virulence factors in the activation of intestinal epithelial cell NF-kappaB and MAP kinase pathways and the upregulated expression of interleukin 8. Cell Microbiol. 2002;4:635–48.
Huang DW, Sherman BT, Lempicki RA. Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources. Nat Protoc. 2008;4:44–57.
Barton GM, Kagan JC. A cell biological view of toll-like receptor function: regulation through compartmentalization. Nat Rev Immunol. 2009;9:535–42.
Mostafavi S, Ray D, Warde-Farley D, Grouios C, Morris Q. GeneMANIA: a real-time multiple association network integration algorithm for predicting gene function. Genome Biol. 2008;9(Suppl 1):S4.
Jacobs MD, Harrison SC. Structure of an IkappaBalpha/NF-kappaB complex. Cell. 1998;95:749–58.
Kaminska B. MAPK signalling pathways as molecular targets for anti-inflammatory therapy-from molecular mechanisms to therapeutic benefits. Biochim Biophys Acta. 2005;1754:253–62.
Langille MGI, Zaneveld J, Caporaso JG, McDonald D, Knights D, Reyes JA, et al. Predictive functional profiling of microbial communities using 16S rRNA marker gene sequences. Nat Biotechnol. 2013;31:814–21.
Cani PD, Possemiers S, Van de Wiele T, Guiot Y, Everard A, Rottier O, et al. Changes in gut microbiota control inflammation in obese mice through a mechanism involving GLP-2-driven improvement of gut permeability. Gut. 2009;58:1091–103.
Johnson-Henry KC, Pinnell LJ, Waskow AM, Irrazabal T, Martin A, Hausner M, et al. Short-chain fructo-oligosaccharide and inulin modulate inflammatory responses and microbial communities in caco2-bbe cells and in a mouse model of intestinal injury. J Nutr. 2014;144:1725–33.
Woting A, Pfeiffer N, Hanske L, Loh G, Klaus S, Blaut M. Alleviation of high fat diet-induced obesity by oligofructose in gnotobiotic mice is independent of presence of Bifidobacterium longum. Mol Nutr Food Res. 2015;59:2267–78.
Breton J, Plé C, Guerin-Deremaux L, Pot B, Lefranc-Millot C, Wils D, et al. Intrinsic immunomodulatory effects of low-digestible carbohydrates selectively extend their anti-inflammatory prebiotic potentials. Biomed Res Int. 2015;2015:162398.
Vogt LM, Meyer D, Pullens G, Faas MM, Venema K, Ramasamy U, et al. Toll-like receptor 2 activation by β2→1-fructans protects barrier function of t84 human intestinal epithelial cells in a chain length-dependent manner. J Nutr. 2014;144:1002–8.
Cario E, Gerken G, Podolsky DK. Toll-like receptor 2 enhances ZO-1-associated intestinal epithelial barrier integrity via protein kinase C. Gastroenterology. 2004;127:224–38.
Turer EE, Tavares RM, Mortier E, Hitotsumatsu O, Advincula R, Lee B, et al. Homeostatic MyD88-dependent signals cause lethal inflamMation in the absence of A20. J Exp Med. 2008;205:451–64.
Leaphart CL, Cavallo J, Gribar SC, Cetin S, Li J, Branca MF, et al. A critical role for TLR4 in the pathogenesis of necrotizing enterocolitis by modulating intestinal injury and repair. J Immunol Baltim Md 1950. 2007;179:4808–20.
Autran CA, Schoterman MHC, Jantscher-Krenn E, Kamerling JP, Bode L. Sialylated galacto-oligosaccharides and 2′-fucosyllactose reduce necrotising enterocolitis in neonatal rats. Br J Nutr. 2016;116:294–9.
Jantscher-Krenn E, Zherebtsov M, Nissan C, Goth K, Guner YS, Naidu N, et al. The human milk oligosaccharide disialyllacto-N-tetraose prevents necrotising enterocolitis in neonatal rats. Gut. 2012;61:1417–25.
He Y, Liu S, Kling DE, Leone S, Lawlor NT, Huang Y, et al. The human milk oligosaccharide 2′-fucosyllactose modulates CD14 expression in human enterocytes, thereby attenuating LPS-induced inflammation. Gut. 2016;65(1):33–46.
Armanian A-M, Sadeghnia A, Hoseinzadeh M, Mirlohi M, Feizi A, Salehimehr N, et al. The effect of neutral oligosaccharides on reducing the incidence of necrotizing enterocolitis in preterm infants: a randomized clinical trial. Int J Prev Med. 2014;5:1387–95.
Dilli D, Aydin B, Fettah ND, Özyazıcı E, Beken S, Zenciroğlu A, et al. The propre-save study: effects of probiotics and prebiotics alone or combined on necrotizing enterocolitis in very low birth weight infants. J Pediatr. 2015;166:545–51. e1
Janssens S, Beyaert R. Functional diversity and regulation of different interleukin-1 receptor-associated kinase (IRAK) family members. Mol Cell. 2003;11:293–302.
Chassin C, Kocur M, Pott J, Duerr CU, Gütle D, Lotz M, et al. miR-146a mediates protective innate immune tolerance in the neonate intestine. Cell Host Microbe. 2010;8:358–68.
Lotz M, Gütle D, Walther S, Ménard S, Bogdan C, Hornef MW. Postnatal acquisition of endotoxin tolerance in intestinal epithelial cells. J Exp Med. 2006;203:973–84.
Otte J-M, Cario E, Podolsky DK. Mechanisms of cross hyporesponsiveness to toll-like receptor bacterial ligands in intestinal epithelial cells. Gastroenterology. 2004;126:1054–70.
Parikh K, Zhou L, Somasundaram R, Fuhler GM, Deuring JJ, Blokzijl T, et al. Suppression of p21Rac signaling and increased innate immunity mediate remission in Crohn’s disease. Sci Transl Med. 2014;6:233ra53.
Branger J, van den Blink B, Weijer S, Madwed J, Bos CL, Gupta A, et al. Anti-inflammatory effects of a p38 mitogen-activated protein kinase inhibitor during human endotoxemia. J Immunol. 2002;168:4070–7.
Li Y, Liu H, Xu Q-S, Du Y-G, Xu J. Chitosan oligosaccharides block LPS-induced O-GlcNAcylation of NF-κB and endothelial inflammatory response. Carbohydr Polym. 2014;99:568–78.
Shen-Tu G, Kim H, Liu M, Johnson-Henry KC, Sherman PM. Protein kinase c mediates enterohemorrhagic escherichia coli o157:h7-induced attaching and effacing lesions. Infect Immun. 2014;82:1648–56.
Maattanen P, Trost B, Scruten E, Potter A, Kusalik A, Griebel P, et al. Divergent immune responses to mycobacterium avium subsp. paratuberculosis infection correlate with kinome responses at the site of intestinal infection. Infect Immun. 2013;81:2861–72.
Falcinelli S, Gowen BB, Trost B, Napper S, Kusalik A, Johnson RF, et al. Characterization of the host response to pichinde virus infection in the syrian golden hamster by species-specific kinome analysis. Mol Cell Proteomics. 2015;14:646–57.
Robertson AJ, Trost B, Scruten E, Robertson T, Mostajeran M, Connor W, et al. Identification of developmentally-specific kinotypes and mechanisms of Varroa mite resistance through whole-organism, kinome analysis of honeybee. Front Genet. 2014;5:139.
Reich M, Liefeld T, Gould J, Lerner J, Tamayo P, Mesirov JP. GenePattern 2.0. Nat Genet. 2006;38:500–1.
Cline MS, Smoot M, Cerami E, Kuchinsky A, Landys N, Workman C, et al. Integration of biological networks and gene expression data using Cytoscape. Nat Protoc. 2007;2:2366–82.
Whelan FJ, Verschoor CP, Stearns JC, Rossi L, Luinstra K, Loeb M, et al. The loss of topography in the microbial communities of the upper respiratory tract in the elderly. Ann Am Thorac Soc. 2014;11:513–21.
Tatusov RL, Koonin EV, Lipman DJ. A genomic perspective on protein families. Science. 1997;278:631–7.
Parks DH, Tyson GW, Hugenholtz P, Beiko RG. STAMP: statistical analysis of taxonomic and functional profiles. Bioinforma Oxf Engl. 2014;30:3123–4.
Whelan FJ, Surette MG. A comprehensive evaluation of the sl1p pipeline for 16S rRNA gene sequencing analysis. Microbiome. 2017;5(1):100.