Nutrition Research and Practice

The Korean Nutrition Society (한국영양학회)
권호 표지
DOI QR코드

DOI QR Code

Probiotic supplementation has sex-dependent effects on immune responses in association with the gut microbiota in community-dwelling older adults: a randomized, double-blind, placebo-controlled, multicenter trial

  • Chong-Su Kim (Department of Food and Nutrition, College of Natural Information Sciences, Dongduk Women's University) ;
  • Min Ho Jung (Department of Biomedical Sciences, Seoul National University College of Medicine) ;
  • Eun Young Choi (Department of Biomedical Sciences, Seoul National University College of Medicine) ;
  • Dong-Mi Shin (Department of Food and Nutrition, College of Human Ecology, Seoul National University)
  • Received : 2022.10.26
  • Accepted : 2023.05.19
  • Published : 2023.10.01
Download PDF
⟨ Previous Next ⟩

Abstract

BACKGROUND/OBJECTIVES: Probiotics have been suggested as potent modulators of age-related disorders in immunological functions, yet little is known about sex-dependent effects of probiotic supplements. Therefore, we aimed to investigate sex-dependent effects of probiotics on profiles of the gut microbiota and peripheral immune cells in healthy older adults. SUBJECTS/METHODS: In a randomized, double-blind, placebo-controlled, multicenter trial, healthy elderly individuals ≥ 65 yrs old were administered probiotic capsules (or placebo) for 12 wk. Gut microbiota was analyzed using 16S rRNA gene sequencing and bioinformatic analyses. Peripheral immune cells were profiled using flow cytometry for lymphocytes (natural killer, B, CD4+ T, and CD8+ T cells), dendritic cells, monocytes, and their subpopulations. RESULTS: Compared with placebo, phylum Firmicutes was significantly reduced in the probiotic group in women, but not in men. At the genus level, sex-specific responses included reductions in the relative abundances of pro-inflammatory gut microbes, including Catabacter and unclassified_Coriobacteriales, and Burkholderia and unclassified Enterobacteriaceae, in men and women, respectively. Peripheral immune cell profiling analysis revealed that in men, probiotics significantly reduced the proportions of dendritic cells and CD14+ CD16- monocytes; however, these effects were not observed in women. In contrast, the proportion of total CD4+ T cells was significantly reduced in women in the probiotic group. Additionally, serum lipopolysaccharide-binding protein levels showed a decreasing tendency that were positively associated with changes in gut bacteria, including Catabacter (ρ = 0.678, P < 0.05) and Burkholderia (ρ = 0.673, P < 0.05) in men and women, respectively. CONCLUSIONS: These results suggest that probiotic supplementation may reduce the incidence of inflammation-related diseases by regulating the profiles of the gut microbiota and peripheral immune cells in healthy elders in a sex-specific manner.

Keywords

Acknowledgement

This research was supported by the Technology Innovation Program (No. 20014744) funded by the Ministry of Trade, Industry & Energy (MOTIE, Republic of Korea).

References

  1. Nikolich-Zugich J. The twilight of immunity: emerging concepts in aging of the immune system. Nat Immunol 2018;19:10-9. https://doi.org/10.1038/s41590-017-0006-x
  2. Franceschi C, Garagnani P, Parini P, Giuliani C, Santoro A. Inflammaging: a new immune-metabolic viewpoint for age-related diseases. Nat Rev Endocrinol 2018;14:576-90. https://doi.org/10.1038/s41574-018-0059-4
  3. Deleidi M, Jaggle M, Rubino G. Immune aging, dysmetabolism, and inflammation in neurological diseases. Front Neurosci 2015;9:172.
  4. Marchesi JR, Adams DH, Fava F, Hermes GD, Hirschfield GM, Hold G, Quraishi MN, Kinross J, Smidt H, Tuohy KM, et al. The gut microbiota and host health: a new clinical frontier. Gut 2016;65:330-9. https://doi.org/10.1136/gutjnl-2015-309990
  5. Rooks MG, Garrett WS. Gut microbiota, metabolites and host immunity. Nat Rev Immunol 2016;16:341-52. https://doi.org/10.1038/nri.2016.42
  6. Sharma R, Padwad Y. Probiotic bacteria as modulators of cellular senescence: emerging concepts and opportunities. Gut Microbes 2020;11:335-49. https://doi.org/10.1080/19490976.2019.1697148
  7. Vaiserman AM, Koliada AK, Marotta F. Gut microbiota: a player in aging and a target for anti-aging intervention. Ageing Res Rev 2017;35:36-45. https://doi.org/10.1016/j.arr.2017.01.001
  8. Gill HS, Rutherfurd KJ, Cross ML, Gopal PK. Enhancement of immunity in the elderly by dietary supplementation with the probiotic Bifidobacterium lactis HN019. Am J Clin Nutr 2001;74:833-9. https://doi.org/10.1093/ajcn/74.6.833
  9. Gill HS, Rutherfurd KJ, Cross ML. Dietary probiotic supplementation enhances natural killer cell activity in the elderly: an investigation of age-related immunological changes. J Clin Immunol 2001;21:264-71. https://doi.org/10.1023/A:1010979225018
  10. Leblanc V, Hudon AM, Royer MM, Corneau L, Dodin S, Begin C, Lemieux S. Differences between men and women in dietary intakes and metabolic profile in response to a 12-week nutritional intervention promoting the Mediterranean diet. J Nutr Sci 2015;4:e13.
  11. Bedard A, Riverin M, Dodin S, Corneau L, Lemieux S. Sex differences in the impact of the Mediterranean diet on cardiovascular risk profile. Br J Nutr 2012;108:1428-34. https://doi.org/10.1017/S0007114511006969
  12. Yaqoob P. Ageing alters the impact of nutrition on immune function. Proc Nutr Soc 2017;76:347-51. https://doi.org/10.1017/S0029665116000781
  13. Kim CS, Cha L, Sim M, Jung S, Chun WY, Baik HW, Shin DM. Probiotic supplementation improves cognitive function and mood with changes in gut microbiota in community-dwelling older adults: a randomized, double-blind, placebo-controlled, multicenter trial. J Gerontol A Biol Sci Med Sci 2021;76:32-40. https://doi.org/10.1093/gerona/glaa090
  14. Caporaso JG, Kuczynski J, Stombaugh J, Bittinger K, Bushman FD, Costello EK, Fierer N, Pena AG, Goodrich JK, Gordon JI, et al. QIIME allows analysis of high-throughput community sequencing data. Nat Methods 2010;7:335-6. https://doi.org/10.1038/nmeth.f.303
  15. Maijo M, Clements SJ, Ivory K, Nicoletti C, Carding SR. Nutrition, diet and immunosenescence. Mech Ageing Dev 2014;136-137:116-28. https://doi.org/10.1016/j.mad.2013.12.003
  16. Pae M, Meydani SN, Wu D. The role of nutrition in enhancing immunity in aging. Aging Dis 2012;3:91-129.
  17. Fortes C, Forastiere F, Agabiti N, Fano V, Pacifici R, Virgili F, Piras G, Guidi L, Bartoloni C, Tricerri A, et al. The effect of zinc and vitamin A supplementation on immune response in an older population. J Am Geriatr Soc 1998;46:19-26. https://doi.org/10.1111/j.1532-5415.1998.tb01008.x
  18. Arunachalam K, Gill HS, Chandra RK. Enhancement of natural immune function by dietary consumption of Bifidobacterium lactis (HN019). Eur J Clin Nutr 2000;54:263-7. https://doi.org/10.1038/sj.ejcn.1600938
  19. Dong H, Rowland I, Thomas LV, Yaqoob P. Immunomodulatory effects of a probiotic drink containing Lactobacillus casei Shirota in healthy older volunteers. Eur J Nutr 2013;52:1853-63. https://doi.org/10.1007/s00394-012-0487-1
  20. Cancro MP, Hao Y, Scholz JL, Riley RL, Frasca D, Dunn-Walters DK, Blomberg BB. B cells and aging: molecules and mechanisms. Trends Immunol 2009;30:313-8. https://doi.org/10.1016/j.it.2009.04.005
  21. Panda A, Arjona A, Sapey E, Bai F, Fikrig E, Montgomery RR, Lord JM, Shaw AC. Human innate immunosenescence: causes and consequences for immunity in old age. Trends Immunol 2009;30:325-33. https://doi.org/10.1016/j.it.2009.05.004
  22. Franceschi C, Garagnani P, Vitale G, Capri M, Salvioli S. Inflammaging and 'Garb-aging'. Trends Endocrinol Metab 2017;28:199-212. https://doi.org/10.1016/j.tem.2016.09.005
  23. Aziz M, Holodick NE, Rothstein TL, Wang P. The role of B-1 cells in inflammation. Immunol Res 2015;63:153-66. https://doi.org/10.1007/s12026-015-8708-3
  24. Pence BD. Fanning the flames of inflammaging: impact of monocyte metabolic reprogramming. Immunometabolism 2020;2:e200025. 
  25. Hearps AC, Martin GE, Angelovich TA, Cheng WJ, Maisa A, Landay AL, Jaworowski A, Crowe SM. Aging is associated with chronic innate immune activation and dysregulation of monocyte phenotype and function. Aging Cell 2012;11:867-75. https://doi.org/10.1111/j.1474-9726.2012.00851.x
  26. Brestoff JR, Artis D. Commensal bacteria at the interface of host metabolism and the immune system. Nat Immunol 2013;14:676-84.
  27. Schroeder BO, Birchenough GM, Stahlman M, Arike L, Johansson ME, Hansson GC, Backhed F. Bifidobacteria or fiber protects against diet-induced microbiota-mediated colonic mucus deterioration. Cell Host Microbe 2018;23:27-40.e7. https://doi.org/10.1016/j.chom.2017.11.004
  28. Bergmann KR, Liu SX, Tian R, Kushnir A, Turner JR, Li HL, Chou PM, Weber CR, De Plaen IG. Bifidobacteria stabilize claudins at tight junctions and prevent intestinal barrier dysfunction in mouse necrotizing enterocolitis. Am J Pathol 2013;182:1595-606. https://doi.org/10.1016/j.ajpath.2013.01.013
  29. Quince C, Ijaz UZ, Loman N, Eren AM, Saulnier D, Russell J, Haig SJ, Calus ST, Quick J, Barclay A, et al. Extensive modulation of the fecal metagenome in children with Crohn's disease during exclusive enteral nutrition. Am J Gastroenterol 2015;110:1718-29. https://doi.org/10.1038/ajg.2015.357
  30. Sampson T. The impact of indigenous microbes on Parkinson's disease. Neurobiol Dis 2020;135:104426.
  31. Zakostelska Z, Malkova J, Klimesova K, Rossmann P, Hornova M, Novosadova I, Stehlikova Z, Kostovcik M, Hudcovic T, Stepankova R, et al. Intestinal microbiota promotes psoriasis-like skin inflammation by enhancing Th17 response. PLoS One 2016;11:e0159539.
  32. Linton PJ, Dorshkind K. Age-related changes in lymphocyte development and function. Nat Immunol 2004;5:133-9. https://doi.org/10.1038/ni1033
  33. Goronzy JJ, Weyand CM. Immune aging and autoimmunity. Cell Mol Life Sci 2012;69:1615-23. https://doi.org/10.1007/s00018-012-0970-0
  34. Weksler ME, Hutteroth TH. Impaired lymphocyte function in aged humans. J Clin Invest 1974;53:99-104. https://doi.org/10.1172/JCI107565
  35. Mittelbrunn M, Kroemer G. Hallmarks of T cell aging. Nat Immunol 2021;22:687-98. https://doi.org/10.1038/s41590-021-00927-z
  36. Vaiserman A, Romanenko M, Piven L, Moseiko V, Lushchak O, Kryzhanovska N, Guryanov V, Koliada A. Differences in the gut Firmicutes to Bacteroidetes ratio across age groups in healthy Ukrainian population. BMC Microbiol 2020;20:221.
  37. Magrone T, Jirillo E. The interaction between gut microbiota and age-related changes in immune function and inflammation. Immun Ageing 2013;10:31.
  38. Fink J, Steer JH, Joyce DA, McWilliam AS, Stewart GA. Pro-inflammatory effects of Burkholderia cepacia on cystic fibrosis respiratory epithelium. FEMS Immunol Med Microbiol 2003;38:273-82. https://doi.org/10.1016/S0928-8244(03)00169-X
  39. Shrivastava SR, Shrivastava PS, Ramasamy J. World health organization releases global priority list of antibiotic-resistant bacteria to guide research, discovery, and development of new antibiotics. J Med Soc 2018;32:76.
  40. Hegazy AN, West NR, Stubbington MJ, Wendt E, Suijker KI, Datsi A, This S, Danne C, Campion S, Duncan SH, et al. Circulating and tissue-resident CD4+ T cells with reactivity to intestinal microbiota are abundant in healthy individuals and function is altered during inflammation. Gastroenterology 2017;153:1320-1337.e16. https://doi.org/10.1053/j.gastro.2017.07.047
  41. Cassotta A, Goldstein JD, Durini G, Jarrossay D, Baggi Menozzi F, Venditti M, Russo A, Falcone M, Lanzavecchia A, Gagliardi MC, et al. Broadly reactive human CD4+  T cells against Enterobacteriaceae are found in the naive repertoire and are clonally expanded in the memory repertoire. Eur J Immunol 2021;51:648-61. https://doi.org/10.1002/eji.202048630
  42. Djuric Z. Obesity-associated cancer risk: the role of intestinal microbiota in the etiology of the host proinflammatory state. Transl Res 2017;179:155-67.  https://doi.org/10.1016/j.trsl.2016.07.017
  43. Kavanagh K, Hsu FC, Davis AT, Kritchevsky SB, Rejeski WJ, Kim S. Biomarkers of leaky gut are related to inflammation and reduced physical function in older adults with cardiometabolic disease and mobility limitations. Geroscience 2019;41:923-33. https://doi.org/10.1007/s11357-019-00112-z
  44. Roberts LM, Buford TW. Lipopolysaccharide binding protein is associated with CVD risk in older adults. Aging Clin Exp Res 2021;33:1651-8. https://doi.org/10.1007/s40520-020-01684-z
  45. Stehle JR Jr, Leng X, Kitzman DW, Nicklas BJ, Kritchevsky SB, High KP. Lipopolysaccharide-binding protein, a surrogate marker of microbial translocation, is associated with physical function in healthy older adults. J Gerontol A Biol Sci Med Sci 2012;67:1212-8. https://doi.org/10.1093/gerona/gls178
  46. Everard A, Lazarevic V, Gaia N, Johansson M, Stahlman M, Backhed F, Delzenne NM, Schrenzel J, Francois P, Cani PD. Microbiome of prebiotic-treated mice reveals novel targets involved in host response during obesity. ISME J 2014;8:2116-30. https://doi.org/10.1038/ismej.2014.45
  47. Gonzalez-Sarrias A, Nunez-Sanchez MA, Avila-Galvez MA, Monedero-Saiz T, Rodriguez-Gil FJ, Martinez-Diaz F, Selma MV, Espin JC. Consumption of pomegranate decreases plasma lipopolysaccharide-binding protein levels, a marker of metabolic endotoxemia, in patients with newly diagnosed colorectal cancer: a randomized controlled clinical trial. Food Funct 2018;9:2617-22. https://doi.org/10.1039/C8FO00264A
  48. Pei R, DiMarco DM, Putt KK, Martin DA, Gu Q, Chitchumroonchokchai C, White HM, Scarlett CO, Bruno RS, Bolling BW. Low-fat yogurt consumption reduces biomarkers of chronic inflammation and inhibits markers of endotoxin exposure in healthy premenopausal women: a randomised controlled trial. Br J Nutr 2017;118:1043-51. https://doi.org/10.1017/S0007114517003038
  49. Wiersinga WJ, de Vos AF, de Beer R, Wieland CW, Roelofs JJ, Woods DE, van der Poll T. Inflammation patterns induced by different Burkholderia species in mice. Cell Microbiol 2008;10:81-7.
  50. Bolnick DI, Snowberg LK, Hirsch PE, Lauber CL, Org E, Parks B, Lusis AJ, Knight R, Caporaso JG, Svanback R. Individual diet has sex-dependent effects on vertebrate gut microbiota. Nat Commun 2014;5:4500.
  51. David LA, Maurice CF, Carmody RN, Gootenberg DB, Button JE, Wolfe BE, Ling AV, Devlin AS, Varma Y, Fischbach MA, et al. Diet rapidly and reproducibly alters the human gut microbiome. Nature 2014;505:559-63.
  52. 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;339:1084-8. https://doi.org/10.1126/science.1233521
  53. Moore RJ, Stanley D. Experimental design considerations in microbiota/inflammation studies. Clin Transl Immunology 2016;5:e92.
  54. Xyda SE, Vuckovic I, Petterson XM, Dasari S, Lalia AZ, Parvizi M, Macura SI, Lanza IR. Distinct influence of omega-3 fatty acids on the plasma metabolome of healthy older adults. J Gerontol A Biol Sci Med Sci 2020;75:875-84. https://doi.org/10.1093/gerona/glz141
  55. Nagpal R, Neth BJ, Wang S, Craft S, Yadav H. Modified Mediterranean-ketogenic diet modulates gut microbiome and short-chain fatty acids in association with Alzheimer's disease markers in subjects with mild cognitive impairment. EBioMedicine 2019;47:529-42.  https://doi.org/10.1016/j.ebiom.2019.08.032