Effect of a polyphenol-rich dietary pattern on subjects aged ≥ 60 years with higher levels of inflammatory markers: insights into microbiome and metabolome

Abstract

Background: Aging may be associated with low-grade chronic inflammation (“inflammaging”) and gut microbiome alterations. Dietary polyphenols have been proposed as modulators of these processes. This study aimed to explore the effects of a polyphenol-rich diet (PR-diet) on inflammatory markers, gut microbiota, and metabolomic profiles in subjects aged ≥ 60 years stratified by baseline inflammation levels.

Methods: In this post-hoc analysis of the MaPLE (Microbiome mAnipulation through Polyphenols for managing Leakiness in the Elderly) randomized crossover trial, 50 subjects aged ≥ 60 years were categorized into two subgroups: high inflammation (cH) and low inflammation (cL). Participants received a PR-diet or a control diet for 8 weeks, with a washout period in between. Fecal, blood, and urine samples were analyzed using shallow shotgun metagenomics and untargeted metabolomics.

Results: The PR-diet was associated with a significant reduction in key inflammatory markers [e.g., interleukin-6 (IL-6), C-reactive protein] in the cH group. Distinct microbial shifts were observed, including an increase in Blautia and Dorea and a modest improvement in microbial diversity in cH subjects. Metabolomic analysis revealed group-specific changes, notably in polyphenol-derived metabolites.

Conclusion: These findings suggest that PR-diets may beneficially modulate inflammation and the gut microbial ecosystem in subjects aged ≥ 60 years with elevated baseline inflammation. Stratification by inflammatory status may improve the targeting and personalization of dietary interventions to support healthy aging.

Keywords

Microbiome / metabolomics / inflammaging / intestinal permeability / polyphenols / healthy aging

References

[1] Zheng D,Elinav E.Interaction between microbiota and immunity in health and disease.Cell Res2020;30:492-506 PMCID:PMC7264227

[2] Pisani A,Bang C.Dysbiosis in the gut microbiota in patients with inflammatory bowel disease during remission.Microbiol Spectr2022;10:e0061622 PMCID:PMC9241752

[3] Kriss M,Nusbacher NM,Lozupone CA.Low diversity gut microbiota dysbiosis: drivers, functional implications and recovery.Curr Opin Microbiol2018;44:34-40 PMCID:PMC6435260

[4] Franceschi C,Parini P,Santoro A.Inflammaging: a new immune-metabolic viewpoint for age-related diseases.Nat Rev Endocrinol2018;14:576-90

[5] Park HJ,Park SJ.Phenethyl isothiocyanate regulates inflammation through suppression of the TRIF-dependent signaling pathway of Toll-like receptors.Life Sci2013;92:793-8

[6] Kumazoe M,Horie F.Methylated (-)-epigallocatechin 3-O-gallate potentiates the effect of split vaccine accompanied with upregulation of Toll-like receptor 5.Sci Rep2021;11:23101 PMCID:PMC8630126

[7] Park SJ,Youn HS.Parthenolide inhibits TRIF-dependent signaling pathway of Toll-like receptors in RAW264.7 macrophages.Mol Cells2011;31:261-5 PMCID:PMC3932697

[8] Rath S,Pieper DH.Uncovering the trimethylamine-producing bacteria of the human gut microbiota.Microbiome2017;5:54 PMCID:PMC5433236

[9] Murros KE.Hydrogen sulfide produced by gut bacteria may induce Parkinson’s disease.Cells2022;11:978 PMCID:PMC8946538

[10] Saito Y,Nomoto K.Identification of phenol- and p-cresol-producing intestinal bacteria by using media supplemented with tyrosine and its metabolites.FEMS Microbiol Ecol2018;94 PMCID:PMC6424909

[11] Yao Y,Fei W,Zhao M.The role of short-chain fatty acids in immunity, inflammation and metabolism.Crit Rev Food Sci Nutr2022;62:1-12

[12] Li H,Li R.Synergic interactions between polyphenols and gut microbiota in mitigating inflammatory bowel diseases.Food Funct2020;11:4878-91

[13] Wang X,Zheng H.Dietary polyphenol, gut microbiota, and health benefits.Antioxidants2022;11:1212 PMCID:PMC9220293

[14] Li S,Zhang Y.Polyphenolic extracts of coffee cherry husks alleviated colitis-induced neural inflammation via NF-κB signaling regulation and gut microbiota modification.J Agric Food Chem2022;70:6467-77

[15] Fan R,Toney AM.Red raspberry polyphenols attenuate high-fat diet-driven activation of NLRP3 inflammasome and its paracrine suppression of adipogenesis via histone modifications.Mol Nutr Food Res2020;64:e1900995 PMCID:PMC9045478

[16] Han D,Lu D.Polyphenol-rich diet mediates interplay between macrophage-neutrophil and gut microbiota to alleviate intestinal inflammation.Cell Death Dis2023;14:656 PMCID:PMC10562418

[17] Guglielmetti S,Del Bo’ C.Effect of a polyphenol-rich dietary pattern on intestinal permeability and gut and blood microbiomics in older subjects: study protocol of the MaPLE randomised controlled trial.BMC Geriatr2020;20:77 PMCID:PMC7045478

[18] Marino M,Martini D.A (poly)phenol-rich diet reduces serum and faecal calprotectin in older adults with increased intestinal permeability: the MaPLE randomised controlled trial.BMC Geriatr2024;24:707 PMCID:PMC11344393

[19] Peron G,Meroño T.Crosstalk among intestinal barrier, gut microbiota and serum metabolome after a polyphenol-rich diet in older subjects with “leaky gut”: the MaPLE trial.Clin Nutr2021;40:5288-97

[20] Del Bo’ C,Cherubini A.A polyphenol-rich dietary pattern improves intestinal permeability, evaluated as serum zonulin levels, in older subjects: the MaPLE randomised controlled trial.Clin Nutr2021;40:3006-18

[21] Meroño T,Gargari G.The relevance of urolithins-based metabotyping for assessing the effects of a polyphenol-rich dietary intervention on intestinal permeability: a post-hoc analysis of the MaPLE trial.Food Res Int2022;159:111632

[22] Beghini F,Blanco-Míguez A.Integrating taxonomic, functional, and strain-level profiling of diverse microbial communities with bioBakery 3.Elife2021;10 PMCID:PMC8096432

[23] Hidalgo-Liberona N,Vegas E.Increased intestinal permeability in older subjects impacts the beneficial effects of dietary polyphenols by modulating their bioavailability.J Agric Food Chem2020;68:12476-84

[24] González-Domínguez R,Queipo-Ortuño MI.Characterization of the human exposome by a comprehensive and quantitative large-scale multianalyte metabolomics platform.Anal Chem2020;92:13767-75

[25] Johne B,Lyberg T.Functional and clinical aspects of the myelomonocyte protein calprotectin.Mol Pathol1997;50:113-23 PMCID:PMC379605

[26] Said EA,Al-Shizawi N.Defining IL-6 levels in healthy individuals: a meta-analysis.J Med Virol2021;93:3915-24

[27] Li G,Zhang X.Serum levels of tumor necrosis factor alpha in patients with IgA nephropathy are closely associated with disease severity.BMC Nephrol2018;19:326 PMCID:PMC6236996

[28] Bjarnason I.The use of fecal calprotectin in inflammatory bowel disease.Gastroenterol Hepatol2017;13:53-6 PMCID:PMC5390326

[29] Giosia P, Stamerra CA, Giorgini P, Jamialahamdi T, Butler AE, Sahebkar A. The role of nutrition in inflammaging.Ageing Res Rev2022;77:101596

[30] Fernando MR,Iannuzzi J,McKay DM.The pro-inflammatory cytokine, interleukin-6, enhances the polarization of alternatively activated macrophages.PLoS One2014;9:e94188 PMCID:PMC3988054

[31] Ferrucci L,Guralnik JM.Serum IL-6 level and the development of disability in older persons.J Am Geriatr Soc1999;47:639-46

[32] Rajab IM,Potempa LA.How C-reactive protein structural isoforms with distinctive bioactivities affect disease progression.Front Immunol2020;11:2126 PMCID:PMC7511658

[33] Man SF,Anthonisen NR,Tashkin DP.C-reactive protein and mortality in mild to moderate chronic obstructive pulmonary disease.Thorax2006;61:849-53 PMCID:PMC2104755

[34] Varadhan R,Matteini A.Simple biologically informed inflammatory index of two serum cytokines predicts 10 year all-cause mortality in older adults.J Gerontol A Biol Sci Med Sci2014;69:165-73 PMCID:PMC4038244

[35] Rheenen PF, Van de Vijver E, Fidler V. Faecal calprotectin for screening of patients with suspected inflammatory bowel disease: diagnostic meta-analysis.BMJ2010;341:c3369 PMCID:PMC2904879

[36] Kopi T, Shahrokh S, Mirzaei S, Asadzadeh Aghdaei H, Amini Kadijani A. The role of serum calprotectin as a novel biomarker in inflammatory bowel diseases: a review study.Gastroenterol Hepatol Bed Bench2019;12:183-9 PMCID:PMC6668766

[37] Biagi E,Rampelli S.Gut microbiota and extreme longevity.Curr Biol2016;26:1480-5

[38] Salazar N,Nogacka AM.Microbiome: effects of ageing and diet.Curr Issues Mol Biol2020;36:33-62

[39] Biagi E,Candela M.Through ageing, and beyond: gut microbiota and inflammatory status in seniors and centenarians.PLoS One2010;5:e10667 PMCID:PMC2871786

[40] Kong F,Zeng B,Li Y.Gut microbiota signatures of longevity.Curr Biol2016;26:R832-3

[41] Seishima J,Kitamura K.Gut-derived Enterococcus faecium from ulcerative colitis patients promotes colitis in a genetically susceptible mouse host.Genome Biol2019;20:252 PMCID:PMC6876129

[42] Fujiwara N,Enooku K.CPT2 downregulation adapts HCC to lipid-rich environment and promotes carcinogenesis via acylcarnitine accumulation in obesity.Gut2018;67:1493-504 PMCID:PMC6039238

[43] Ottosson F,Smith E.The gut microbiota-related metabolite phenylacetylglutamine associates with increased risk of incident coronary artery disease.J Hypertens2020;38:2427-34

[44] Mahdi J,Mahdi E.Pharmacological importance of simple phenolic compounds on inflammation, cell proliferation and apoptosis with a special reference to β-D-salicin and hydroxybenzoic acid.Eur J Inflamm2013;11:327-36

[45] Zhang B,Liu X.Distinctive anti-inflammatory effects of resveratrol, dihydroresveratrol, and 3-(4-hydroxyphenyl)-propionic acid on DSS-induced colitis in pseudo-germ-free mice.Food Chem2023;400:133904

[46] Günther I,Mack CI.The putative caloric restriction mimetic resveratrol has moderate impact on insulin sensitivity, body composition, and the metabolome in mice.Mol Nutr Food Res2020;64:e1901116

[47] Hollands WJ,Perez-Moral N,Savva GM.Monomeric flavanols are more efficient substrates for gut microbiota conversion to hydroxyphenyl-γ-valerolactone metabolites than oligomeric procyanidins: a randomized, placebo-controlled human intervention trial.Mol Nutr Food Res2020;64:e1901135 PMCID:PMC7378946

[48] Kumar A,Kumar M.Major phytochemicals: recent advances in health benefits and extraction method.Molecules2023;28:887 PMCID:PMC9862941

[49] Silva T de P,Toffolo MCF.The action of phytochemicals present in cocoa in the prevention of vascular dysfunction and atherosclerosis.J Clin Transl Res2022;8:509-51 PMCID:PMC9706317

[50] Vasconcelos PC,Di Stasi LC,Pellizzon CH.Epicatechin used in the treatment of intestinal inflammatory disease: an analysis by experimental models.Evid Based Complement Alternat Med2012;2012:508902 PMCID:PMC3546492

[51] Monacelli F,Giannotti C,Nencioni A.Vitamin C, aging and Alzheimer’s disease.Nutrients2017;9:670 PMCID:PMC5537785