Sex differences in gut fermentation and immune parameters in rats fed an oligofructose-supplemented diet

Biology of Sex Differences

Julia M. Green-Johnson¹  Stephen P.J. Brooks²  Martin Kalmokoff³  Justin McCarville¹  Padmaja Shastri¹ 

[1]Applied Bioscience Graduate Program and Faculty of Science, University of Ontario Institute of Technology, 2000 Simcoe Street North, Oshawa L1H 7K4, Ontario, Canada

[2]Bureau of Nutritional Sciences, Health Canada, Ottawa K1A 0K9, Ontario, Canada

[3]Atlantic Food and Horticulture Research Center, Agriculture and Agri-Food Canada, Kentville B4N 1J5, Nova Scotia, Canada

关键词: Butyrate;    Liver;    IgA;    Microbiota;    Oligofructose;    Sex;   

Others  :  1224031
DOI  :  10.1186/s13293-015-0031-0

 received in 2015-05-07, accepted in 2015-07-10,  发布年份 2015

【 摘 要 】

Background

Mechanistic data to support health claims is often generated using rodent models, and the influence of prebiotic supplementation has largely been evaluated using male rodents. Given that sex-based differences in immune parameters are well recognized and recent evidence suggests differences in microbiota composition between sexes, validation of the effectiveness of prebiotics merits assessment in both males and females. Here, we have compared the effect of oligofructose (OF) supplementation on the fecal bacterial community, short chain fatty acid profiles, and gut mucosal and systemic immune parameters in male and female rats.

Methods

Male and female rats were fed rodent chow or chow supplemented with OF (5 % w/w). Fecal community change was examined by analyzing 16S rRNA gene content. To compare effects of OF between sexes at the gut microbial and mucosal immune level, fecal short chain fatty acid and tissue cytokine profiles were measured. Serum lipopolysaccharide levels were also evaluated by the limulus amebocyte lysate assay as an indirect means of determining gut permeability between sexes.

Results

In the fecal community of females, OF supplementation altered community structure by increasing abundance in the Phylum Bacteroidetes. In male rats, no changes in fecal community structure were observed, although fecal butyrate levels significantly increased. Liver Immunoglobulin A (IgA) levels were higher in males relative to females fed OF, and serum LPS concentrations were higher in males independent of diet. Females had higher basal levels of the regulatory cytokine interleukin-10 (IL-10) in the colon and liver, while males had higher basal levels of the pro-inflammatory cytokines IL-6 and cytokine-induced neutrophil chemoattractant-1 (CINC-1) in the cecum and liver.

Conclusions

We have shown that male and female rat gut communities metabolize an OF-supplemented diet differently. Sex-specific responses in both the fecal community and systemic immune parameters suggest that this difference may result from an increase in the availability of gut peptidyl-nitrogen in the males. These findings demonstrate the importance of performing sex-comparative studies when investigating potential health effects of prebiotics using rodent models.

【 授权许可】

   
2015 Shastri et al.

【 图 表 】

Fig. 1.

Fig. 2.

Fig. 3.

Fig. 4.

【 参考文献 】

• [1]Pineiro M, Asp NG, Reid G, Macfarlane S, Morelli L, Brunser O, Tuohy K. FAO Technical meeting on prebiotics. J Clin Gastroenterol. 2008; 42 Suppl 3 Pt 2:S156-159.
• [2]Brooks SPJ, Kalmokoff ML. Prebiotics and probiotics: Some thoughts on demonstration of efficacy within the regulatory sphere. J AOAC Internat. 2012; 95(1):2-4.
• [3]Sankaran-Walters S, Macal M, Grishina I, Nagy L, Goulart L, Coolidge K, Li J, Fenton A, Williams T, Miller MK, Flamm J, Prindiville T, George M, Dandekar S. Sex differences matter in the gut: effect on mucosal immune activation and inflammation. Biol Sex Differ. 2013; 4(1):10. BioMed Central Full Text
• [4]Steegenga WT, Mischke M, Lute C, Boekschoten MV, Pruis MG, Lendvai A, Verkade HJ, Boekhorst J, Timmerman HM, Plösch T, Müller M. Sexually dimorphic characteristics of the small intestine and colon of prepubescent C57BL/6 mice. Biol Sex Differ. 2014; 5:11. BioMed Central Full Text
• [5]Markle JG, Frank DN, Mortin-Toth S, Robertson CE, Feazel LM, Rolle-Kampczyk U, von Bergen M, McCoy KD, Macpherson AJ, Danska JS. Sex differences in the gut microbiome drive hormone-dependent regulation of autoimmunity. Science. 2013; 339(6123):1084-8.
• [6]Bernbom N, Norrung B, Saadbye P, Lolbak L, Vogensen FK, Licht TR. Comparison of methods and animal models commonly used for investigation of caecal microbiota: effect of time, host and sex. J Microbiol Methods. 2006; 66(1):87-95.
• [7]Li M, Wang B, Zhang M, Rantalainen M, Wang S, Zhou H, Zhang Y, Shen J, Pang X, Zhang M, Wei H, Chen Y, Lu H, Zuo J, Su M, Qiu Y, Jia W, Xiao C, Smith LM, Yang S, Holmes E, Tang H, Zhao G, Nicholson JK, Li L, Zhao L. Symbiotic gut microbes modulate human metabolic phenotypes. Proc Natl Acad Sci. 2008; 105(6):2117-22.
• [8]McOrist AL, Miller RB, Bird AR, Keogh JB, Noakes M, Topping DL, Conlon MA. Fecal butyrate levels vary widely among individuals but are usually increased by a diet high in resistant starch. J Nutr. 2011; 141(5):883-889.
• [9]Bolnick DI, Snowberg LK, Hirsch PE, Lauber CL, Org E, Parks B, Lusis AJ, Knight R, Caporaso JG, Svanbäck R. Individual diet has sex-dependent effects on vertebrate gut microbiota. Nat Commun. 2014; 5:4500.
• [10]Hendry GAF. Evolutionary origins and natural functions of fructans – a climatological, biogeographic and mechanistic appraisal. New Phytol. 1993; 123(1):3-14.
• [11]Coussement PAA. Inulin and oligofructose: safe intakes and legal status. J Nutr. 1999; 129(7 Suppl):1412S-1417S.
• [12]Singh RS, Singh RP. Fructooligosaccharides from inulin as prebiotics. Food Technol Biotechnol. 2010; 48:435-450.
• [13]Bornet FR, Brouns F, Tashiro Y, Duvillier V. Nutritional aspects of short-chain fructooligosaccharides: natural occurrence, chemistry, physiology and health implications. Dig Liver Dis. 2002; 34 Suppl 2:S111-120.
• [14]Looijer-van Langen MA, Dieleman LA. Prebiotics in chronic intestinal inflammation. Inflamm Bowel Dis. 2009; 15(3):454-462.
• [15]MacFarlane S, MacFarlane GT, Cummings JH. Prebiotics in the gastrointestinal tract. Aliment Pharmacol Ther. 2006; 24(5):701-714.
• [16]Howard MD, Gordon DT, Garleb KA, Kerley MS. Dietary fructooligosaccharide, xylooligosaccharide and gum Arabic have variable effects on caecal and colonic microbiota and epithelial cell proliferation in mice and rats. J Nutr. 1995; 125(10):2604-2609.
• [17]Sghir A, Chow JM, Mackie RI. Continuous culture selection of bifidobacteria and lactobacilli from human faecal samples using fructooligosaccharide as selective substrate. J Appl Microbiol. 1998; 85(4):769-777.
• [18]Le Blay GM, Michel CD, Blottière HM, Cherbut CJ. Raw potato starch and short-chain fructo-oligosaccharides affect the composition and metabolic activity of rat intestinal microbiota differently depending on the caecocolonic segment involved. J Appl Microbiol. 2003; 94(2):312-320.
• [19]Hartemink R, Van Laere KMJ, Rombouts FM. Growth of enterobacteria on fructo-oligosaccharides. J Appl Microbiol. 1997; 83(3):367-374.
• [20]Apajalahti JH, Kettunen H, Kettunen A, Holben WE, Nurminen PH, Rautonen N, Mutanen M. Culture-independent microbial community analysis reveals that inulin in the diet primarily affects previously unknown bacteria in the mouse cecum. Appl Environ Microbiol. 2002; 68(10):4986-4995.
• [21]Gourgue-Jeannot C, Kalmokoff ML, Kheradpir E, Kwan J, Lampi BJ, McAllister M, Brooks SP. Dietary fructooligosaccharides alter the cultivable faecal population of rats but do not stimulate the growth of intestinal bifidobacteria. Can J Microbiol. 2006; 52(10):924-933.
• [22]Campbell JM, Fahey GC, Wolf BW. Selected indigestible oligosaccharides affect large bowel mass, caecal and fecal short-chain fatty acids, pH and microflora in rats. J Nutr. 1997; 127(1):130-136.
• [23]Le Blay G, Michel C, Blottière HM, Cherbut C. Prolonged intake of fructo-oligosaccharides induces a short-term elevation of lactic acid-producing bacteria and a persistent increase in caecal butyrate in rats. J Nutr. 1999; 129(12):2231-2235.
• [24]Perrin P, Pierre F, Patry Y, Champ M, Berreur M, Pradal G, Bornet F, Meflah K, Menanteau J. Only fibres promoting a stable butyrate producing colonic ecosystem decrease the rate of aberrant crypt foci in rats. Gut. 2001; 48(1):53-61.
• [25]Tsukahara T, Iwasaki Y, Nakayama K, Ushida K. Stimulation of butyrate production in the large intestine of weaning piglets by dietary fructooligosaccharides and its influence on the histological variables of the large intestinal mucosa. J Nutr Sci Vitaminology. 2003; 49(6):414-421.
• [26]MacFarlane GT, MacFarlane S. Bacteria, colonic fermentation, and gastrointestinal health. J AOAC Internat. 2012; 95(1):50-60.
• [27]Ten Bruggencate SJ, Bovee-Oudenhoven IM, Lettink-Wissink ML, van der Meer R. Dietary fructo-oligosaccharides dose-dependently increase translocation of Salmonella in rats. J Nutr. 2003; 133(7):2313-2318.
• [28]Ten Bruggencate SJ, Bovee-Oudenhoven IM, Lettink-Wissink ML, Katan MB, van Der Meer R. Dietary fructo-oligosaccharides and inulin decrease resistance of rats to Salmonella: protective role of calcium. Gut. 2004; 53(4):530-5.
• [29]Ten Bruggencate SJ, Bovee-Oudenhoven MJ, Lettink-Wissink ML, van der Meer R. Dietary fructooligosaccharides increase intestinal permeability in rats. J Nutr. 2005; 135(4):837-842.
• [30]Fontaine N, Meslin JC, Lory S, Andrieux C. Intestinal mucin distribution in the germ-free rat and in the heteroxenic rat harbouring a human bacterial flora: effect of inulin in the diet. Br J Nutr. 1996; 75(6):881-892.
• [31]Ten Bruggencate SJ, Bovee-Oudenhoven IM, Lettink-Wissink ML, Katan MB, van der Meer R. Dietary fructooligosaccharides affect intestinal barrier function in healthy men. J Nutr. 2006; 136(1):70-74.
• [32]Scholtens PA, Alles MS, Willemsen LE, van den Braak C. Dietary fructooligosaccharides in healthy adults do not negatively affect faecal cytotoxicity: a randomised, double-blind, placebo-controlled crossover trial. Br J Nutr. 2007; 95(6):1143-1149.
• [33]Argenzio RA, Meuten DJ. Short-chain fatty acids induce reversible injury of porcine colon. Dig Dis Sci. 1991; 36(10):1459-68.
• [34]Manhart N, Spittler A, Bergmeister H, Mittlböck M, Roth E. Influence of fructooligosaccharides on Peyer’s patch lymphocyte numbers in healthy and endotoxemic mice. Nutrition. 2003; 19(7–8):657-660.
• [35]Ryz NR, Meddings JB, Taylor CG. Long-chain inulin increases dendritic cells in the Peyer’s patches and increases ex vivo cytokine secretion in the spleen and mesenteric lymph nodes of growing female rats, independent of zinc status. Br J Nutr. 2009; 101(11):1653-63.
• [36]Hosono A, Ozawa A, Kato R, Ohnishi Y, Nakanishi Y, Kimura T, Nakamura R. Dietary fructooligosaccharides induce immunoregulation of intestinal IgA secretion by murine Peyer’s patch cells. Biosci Biotechnol Biochem. 2003; 67(4):758-764.
• [37]Nakamura Y, Nosaka S, Suzuki M, Nagafuchi S. Dietary fructooligosaccharides up-regulate immunoglobulin A response and polymeric immunoglobulin receptor expression in intestines of infant mice. Clin Exp Immunol. 2004; 137(1):52-58.
• [38]Watzl B, Girrbach S, Roller M. Inulin, oligofructose and immunomodulation. Br J Nutr. 2005; 93 Suppl 1:S49-S55.
• [39]Brandtzaeg P. Homeostatic impact of indigenous microbiota and secretory immunity. Benef Microbes. 2010; 1(3):211-227.
• [40]Vinolo MA, Rodrigues HG, Hatanaka E, Hebeda CB, Farsky SH, Curi R. Short-chain fatty acids stimulate the migration of neutrophils to inflammatory sites. Clin Sci (Lond). 2009; 117(9):331-8.
• [41]Capitán-Cañadas F, Ortega-González M, Guadix E, Zarzuelo A, Suárez MD, de Medina FS, Martínez-Augustin O. Prebiotic oligosaccharides directly modulate proinflammatory cytokine production in monocytes via activation of TLR4. Mol Nutr Food Res. 2013; 57(5):1-13.
• [42]Vogt L, Ramasamy U, Meyer D, Pullens G, Venema K, Faas MM, Henk A, Schols HA, de Vos P. Immune modulation by different types of β2 → 1-fructans is Toll-like receptor dependent. PLoS ONE. 2013; 8(7): Article ID e68367
• [43]Hansen CH, Frøkiær H, Christensen AG, Bergström A, Licht TR, Hansen AK, Metzdorff SB. Dietary xylooligosaccharide downregulates IFN-γ and the low-grade inflammatory cytokine IL-1β systemically in mice. J Nutr. 2013; 143(4):533-40.
• [44]Buddington KK, Donahoo JB, Buddington RK. Dietary oligofructose and inulin protect mice from enteric and systemic pathogens and tumor inducers. J Nutr. 2002; 132(3):472-7.
• [45]Racanelli V, Rehermann B. The liver as an immunological organ. Hepatology. 2006; 43(2 Suppl 1):S54-62.
• [46]Crispe IN. The liver as a lymphoid organ. Annu Rev Immunol. 2009; 27:147-163.
• [47]Yang X, Schadt EE, Wang S, Wang H, Arnold AP, Ingram-Drake L, Drake TA, Lusis AJ. Tissue-specific expression and regulation of sexually dimorphic genes in mice. Genome Res. 2006; 16(8):995-1004.
• [48]Ahluwalia A, Clodfelter KH, Waxman DJ. Sexual dimorphism of rat liver gene expression: regulatory role of growth hormone revealed by deoxyribonucleic acid microarray analysis. Mol Endocrinol. 2004; 18(3):747-60.
• [49]Weaver GA, Tangel CT, Krause JA, Parfitt MM, Jenkins PL, Rader JM, Lewis BA, Miller TL, Wolin MJ. Acarbose enhances human colonic butyrate production. J Nutr. 1997; 127(5):717-23.
• [50]Kalmokoff M, Zwicker B, O'Hara M, Matias F, Green J, Shastri P, Green-Johnson J, Brooks SP. Temporal change in the gut community of rats fed high amylose cornstarch is driven by endogenous urea rather than strictly on carbohydrate availability. J Appl Microbiol. 2013; 114(5):1516-1528.
• [51]Abnous K, Brooks SP, Kwan J, Matias F, Green-Johnson J, Selinger LB, Thomas M, Kalmokoff M. Diets enriched in oat bran or wheat bran temporally and differentially alter the composition of the fecal community of rats. J Nutr. 2009; 139(11):2024-31.
• [52]Quast C, Pruesse E, Yilmaz P, Gerken J, Schweer T, Yarza P, Peplies J, Glöckner FO. The SILVA ribosomal RNA gene database project: improved data processing and web-based tools. Nucleic Acids Res. 2013; 41D(Database Issue):D590-D596.
• [53]Schloss PD, Westcott SL, Ryabin T, Hall JR, Hartmann M, Hollister EB, Lesniewski RA, Oakley BB, Parks DH, Robinson CJ, Sahl JW, Stres B, Thallinger GG, Van Horn DJ, Weber CF. Introducing Mothur: open-source, platform-independent, community-supported software for describing and comparing microbial communities. Appl Environ Microbiol. 2009; 75(23):7537-41.
• [54]Gouy M, Guindon S, Gascuel O. SeaView version 4: a multiplatform graphical user interface for sequence alignment and phylogenetic tree building. Mol Biol Evol. 2010; 27(2):221-224.
• [55]Cole JR, Wang Q, Cardenas E, Fish J, Chai B, Farris RJ, Kulam-Syed-Mohideen AS, McGarrell DM, Marsh T, Garrity GM, Tiedje JM. The ribosomal database project: improved alignments and new tools for rRNA analysis. Nucleic Acids Res. 2009; 37(Database Issue):D141-5.
• [56]Rinttilä T, Kassinen A, Malinen E, Krogius L, Palva A. Development of an extensive set of 16S rDNA‐targeted primers for quantification of pathogenic and indigenous bacteria in faecal samples by real‐time PCR. J Appl Microbiol. 2004; 97(6):1166-1177.
• [57]Castillo M, Martín-Orúe SM, Manzanilla EG, Badiola I, Martín M, Gasa J. Quantification of total bacteria, enterobacteria and lactobacilli populations in pig digesta by real-time PCR. Vet Microbiol. 2006; 114(1):165-170.
• [58]Hoentjen F, Welling GW, Harmsen HJ, Zhang X, Snart J, Tannock GW, Lien K, Churchill TA, Lupicki M, Dieleman LA. Reduction of colitis by prebiotics in HLA-B27 transgenic rats is associated with microflora changes and immunomodulation. Inflamm Bowel Dis. 2005; 11(11):977-85.
• [59]Talke H, Schubert GE. Enzymatic urea determination in the blood and serum in the Warburg optical test. Klin Wochenschr. 1965; 43:174-5.
• [60]Shingadia D, O'Gorman M, Rowley AH, Shulman ST. Surface and cytoplasmic immunoglobulin expression in circulating B-lymphocytes in acute Kawasaki disease. Pediatr Res. 2001; 50(4):538-43.
• [61]Onodera S, Suzuki K, Matsuno T, Kaneda K, Takagi M, Nishihira J. Macrophage migration inhibitory factor induces phagocytosis of foreign particles by macrophages in autocrine and paracrine fashion. Immunol. 1997; 92(1):131-137.
• [62]Yu Y, Breitbart M, McNairnie P, Rohwer F. FastGroupII: A web-based bioinformatics platform for analyses of large 16S rDNA libraries. BMC Bioinformatics. 2006; 7:57. BioMed Central Full Text
• [63]Onishi H. A knowledge-based variable selection method for Box-Cox transformation. J Jpn Stat Soc. 2002; 32(1):15-42.
• [64]Kalmokoff M, Franklin J, Petronella N, Green J, Brooks SPJ. Phylum level change in the cecal and fecal gut communities of rats fed diets containing different fermentable substrates supports a role for nitrogen as a factor contributing to community structure. Nutrients. 2015; 7(5):3279-3299.
• [65]Fushuku S, Fukuda K. Sex difference in the composition of fecal flora in laboratory mice, as detected by denaturing gradient gel electrophoresis (DGGE). Exp Anim. 2008; 57(5):489-493.
• [66]Wen Z, Morrison M. The NAD(P)H-dependent glutamate dehydrogenase activities of Prevotella ruminicola B(1)4 can be attributed to one enzyme (GdhA), and gdhA expression is regulated in response to the nitrogen source available for growth. Appl Environ Microbiol. 1996; 62(10):3826-3833.
• [67]Fuller MF, Reeds PJ. Nitrogen cycling in the gut. Ann Rev Nutr. 1998; 18:385-411.
• [68]Chacko A, Cummings JH. Nitrogen losses from the human small bowel: obligatory losses and the effect of physical form of food. Gut. 1988; 29(6):809-815.
• [69]Cummings JH, Macfarlane GT. The control and consequences of bacterial fermentation in the human colon. J Appl Microbiol. 1991; 70(6):443-459.
• [70]Christensen EG, Licht TR, Leser TD, Bahl MI. Dietary xylo-oligosaccharide stimulates intestinal bifidobacteria and lactobacilli but has limited effect on intestinal integrity in rats. BMC. 2014; 7(1):660.
• [71]Inglis GD, Thomas MC, Thomas DK, Kalmokoff ML, Brooks SP, Selinger LB. Molecular methods to measure intestinal bacteria: a review. J AOAC Int. 2012; 95(1):5-23.
• [72]Homma H, Hoy E, Xu DZ, Lu Q, Feinman R, Deitch EA. The female intestine is more resistant than the male intestine to gut injury and inflammation when subjected to conditions associated with shock states. Am J Physiol Gastrointest Liver Physiol. 2005; 288(3):G466-G472.
• [73]Rakoff-Nahoum S, Paglino J, Eslami-Varzaneh F, Edberg S, Medzhitov R. Recognition of commensal microflora by toll-like receptors is required for intestinal homeostasis. Cell. 2004; 118(2):229-241.
• [74]Reed KL, Fruin AB, Gower AC, Gonzales KD, Stucchi AF, Andry CD, O'Brien M, Becker JM. NF-kappaB activation precedes increases in mRNA encoding neurokinin-1 receptor, proinflammatory cytokines, and adhesion molecules in dextran sulfate sodium-induced colitis in rats. Dig Dis Sci. 2005; 50(12):2366-2378.
• [75]Woof JM, Kerr MA. The function of immunoglobulin A in immunity. J Pathol. 2006; 208(2):270-282.
• [76]Brenchley JM, Douek DC. Microbial translocation across the GI tract. Annu Rev Immunol. 2012; 30:149-173.
• [77]Tappenden KA, Thomson AB, Wild GA, McBurney MI. Short chain fatty acid-supplemented total parenteral nutrition enhances functional adaptation to intestinal resection in rats. Gastroenterology. 1997; 112(3):792-802.
• [78]Mariadason JM, Corner GA, Augenlicht LH. Genetic reprogramming in pathways of colonic cell maturation induced by short chain fatty acids: comparison with trichostatin A, sulindac and curcumin and implications for chemoprevention of colon cancer. Cancer Res. 2000; 60(16):4561-72.
• [79]Malloy KJ, Powrie F. Intestinal homeostasis and its breakdown in inflammatory bowel disease. Nature. 2011; 474(7351):298-306.
• [80]Romagnani S. Th1/Th2 cells. Inflamm Bowel Dis. 1999; 5(4):285-94.
• [81]Bulek K, Swaidani S, Aronica M, Li X. Epithelium: the interplay between innate and Th2 immunity. Immunol Cell Biol. 2010; 88(3):257-68.
• [82]Mantovani A, Sozzani S, Locati M, Allavena P, Sica A. Macrophage polarization: tumor-associated macrophages as a paradigm for polarized M2 mononuclear phagocytes. Trends Immunol. 2002; 23(11):549-555.
• [83]Hardy H, Harris J, Lyon E, Beal J, Foey AD. Probiotics, prebiotics and immunomodulation of gut mucosal defences: homeostasis and immunopathology. Nutrients. 2013; 5(6):1869-1912.