There is limited work on the association between the gut microbiome and Alzheimer's disease and related dementia (AD/ADRD) in Latinos.
Objective
We examined, within the Hispanic Community Health Study/Study of Latinos (HCHS/SOL) cohort, the association between gut microbiome and cognitive function.
Methods
We analyzed the fecal metagenomes of 2471 HCHS/SOL participants to identify microbial taxonomic and functional features associated with global cognitive function. Omnibus (PERMANOVA) and feature-wise analyses (MaAsLin2) were conducted to identify microbiome-cognition associations, and specific microbial species and pathways (Kyoto Encyclopedia of Genes and Genomes (KEGG modules) associated with cognition.
Results
Eubacterium species (E. siraeum and E. eligens), and C phoceensis, among other species were associated with better cognition. Several KEGG modules, most strongly Ornithine, Serine biosynthesis and Urea Cycle, were associated with worse cognition.
Conclusions
In a large Hispanic/Latino cohort, we identified several microbial taxa and KEGG pathways associated with cognition.
RoundJLMazmanianSK. The gut microbiota shapes intestinal immune responses during health and disease. Nat Rev Immunol2009; 9: 313–323.
2.
HooperLVMidtvedtTGordonJI. How host-microbial interactions shape the nutrient environment of the mammalian intestine. Ann Rev Nutr2002; 22: 283–307.
3.
SansonettiPJMedzhitovR. Learning tolerance while fighting ignorance. Cell2009; 138: 416–420.
4.
BackhedFDingHWangT, et al.The gut microbiota as an environmental factor that regulates fat storage. Proc Natl Acad Sci U S A2004; 101: 15718–15723.
5.
BercikPCollinsSMVerduEF. Microbes and the gut-brain axis. Neurogastroenterol Motil2012; 24: 405–413.
6.
WiertsemaSPvan BergenhenegouwenJGarssenJ, et al.The interplay between the gut microbiome and the immune system in the context of infectious diseases throughout life and the role of nutrition in optimizing treatment strategies. Nutrients2021; 13: 886.
7.
VighiGMarcucciFSensiL, et al.Allergy and the gastrointestinal system. Clin Exp Immunol2008; 153: 3–6.
8.
GhaisasSMaherJKanthasamyA. Gut microbiome in health and disease: linking the microbiome-gut-brain axis and environmental factors in the pathogenesis of systemic and neurodegenerative diseases. Pharmacol Ther2016; 158: 52–62.
9.
TremlettHBauerKCAppel-CresswellS, et al.The gut microbiome in human neurological disease: a review. Ann Neurol2017; 81: 369–382.
10.
MacphersonAJHarrisNL. Interactions between commensal intestinal bacteria and the immune system. Nat Rev Immunol2004; 4: 478–485.
11.
GonzalezHMTarrafWGouskovaN, et al.Neurocognitive function among middle-aged and older Hispanic/Latinos: results from the Hispanic Community Health Study/Study of Latinos. Arch Clin Neuropsychol2015; 30: 68–77.
12.
TangMXSternYMarderK, et al.The APOE-epsilon4 allele and the risk of Alzheimer disease among African Americans, whites, and Hispanics. JAMA1998; 279: 751–755.
13.
MehtaKMYeoGW. Systematic review of dementia prevalence and incidence in United States race/ethnic populations. Alzheimers Dement2017; 13: 72–83.
14.
VegaIECabreraLYWygantCM, et al.Alzheimer's disease in the Latino community: intersection of genetics and social determinants of health. J Alzheimers Dis2017; 58: 979–992.
15.
DominguezKPenman-AguilarAChangMH, et al.Vital signs: leading causes of death, prevalence of diseases and risk factors, and use of health services among Hispanics in the United States - 2009-2013. MMWR Morb Mortal Wkly Rep2015; 64: 469–478.
16.
ColbySLOrtmanJM. Population Estimates and Projections. Current Population Reports. Washington, DC: US Census Bureau, 2015.
17.
ChinALNegashSHamiltonR. Diversity and disparity in dementia: the impact of ethnoracial differences in Alzheimer disease. Alzheimer Dis Assoc Disord2011; 25: 187–195.
18.
LuoHYuGWuB. Self-reported cognitive impairment across racial/ethnic groups in the United States, national health interview survey, 1997-2015. Prev Chronic Dis2018; 15: E06.
19.
FitzpatrickALRappSRLuchsingerJ, et al.Sociodemographic correlates of cognition in the Multi-Ethnic Study of Atherosclerosis (MESA). Am J Geriatr Psychiatry2015; 23: 684–697.
20.
GonzalezHMTarrafWGouskovaN, et al.Life's simple 7's cardiovascular health metrics are associated with Hispanic/Latino neurocognitive function: HCHS/SOL results. J Alzheimers Dis2016; 53: 955–965.
21.
AlmahmoudMFGonzalezHMSwettK, et al.Association of cardiac structure and function with neurocognition in Hispanics/Latinos: the echocardiographic study of Latinos. Mayo Clin Proc Innov Qual Outcomes2018; 2: 165–175.
22.
TarrafWRodríguezCJDaviglusML, et al.Blood pressure and Hispanic/Latino cognitive function: Hispanic community health study/study of Latinos results. J Alzheimers Dis2017; 59: 31–42.
23.
LamarMWuDDurazo-ArvizuRA, et al.Cognitive associates of current and more intensive control of hypertension: findings from the Hispanic community health study/study of Latinos. Am J Hypertens2017; 30: 624–631.
24.
LamarMDurazo-ArvizuRASachdevaS, et al.Cardiovascular disease risk factor burden and cognition: implications of ethnic diversity within the Hispanic community health study/study of Latinos. PLoS One2019; 14: e0215378.
25.
MuñozEGalloLCHuaS, et al.Stress is associated with neurocognitive function in Hispanic/Latino adults: results from HCHS/SOL socio-cultural ancillary study. J Gerontol B Psychol Sci Soc Sci2021; 76: e122–e128.
26.
GonzálezHMTarrafWGonzálezKA, et al.Diabetes, cognitive decline, and mild cognitive impairment among diverse Hispanics/Latinos: study of Latinos-investigation of neurocognitive aging results (HCHS/SOL). Diabetes Care2020; 43: 1111–1117.
27.
GonzálezHMTarrafWVásquezP, et al.Metabolic syndrome and neurocognition among diverse middle-aged and older Hispanics/Latinos: HCHS/SOL results. Diabetes Care2018; 41: 1501–1509.
28.
KaplanRCWangZUsykM, et al.Gut microbiome composition in the Hispanic community health study/study of Latinos is shaped by geographic relocation, environmental factors, and obesity. Genome Biol2019; 20: 219.
29.
VerdiSJacksonMABeaumontM, et al.An investigation into physical frailty as a link between the gut microbiome and cognitive health. Front Aging Neurosci2018; 10: 398.
30.
CattaneoACattaneNGalluzziS, et al.Association of brain amyloidosis with pro-inflammatory gut bacterial taxa and peripheral inflammation markers in cognitively impaired elderly. Neurobiol Aging2017; 49: 60–68.
31.
ShengCYangKHeB, et al.Combination of gut microbiota and plasma amyloid-β as a potential index for identifying preclinical Alzheimer's disease: a cross-sectional analysis from the SILCODE study. Alzheimers Res Ther2022; 14: 35.
32.
ShengCLinLLinH, et al.Altered gut microbiota in adults with subjective cognitive decline: the SILCODE study. J Alzheimers Dis2021; 82: 513–526.
33.
HestonMBHanslikKLZarbockKR, et al.Gut inflammation associated with age and Alzheimer's disease pathology: a human cohort study. Sci Rep2023; 13: 18924.
34.
MiriSYeoJAbubakerS, et al.Neuromicrobiology, an emerging neurometabolic facet of the gut microbiome?Front Microbiol2023; 14: 1098412.
ManderinoLCarrollIAzcarate-PerilMA, et al.Preliminary evidence for an association between the composition of the gut microbiome and cognitive function in neurologically healthy older adults. J Int Neuropsychol Soc2017; 23: 700–705.
44.
VogtNMKerbyRLDill-McFarlandKA, et al.Gut microbiome alterations in Alzheimer's disease. Sci Rep2017; 7: 13537.
45.
LiangXFuYCaoWT, et al.Gut microbiome, cognitive function and brain structure: a multi-omics integration analysis. Transl Neurodegener2022; 11: 49.
46.
ZhangLWangYXiayuX, et al.Altered gut microbiota in a mouse model of Alzheimer's disease. J Alzheimers Dis2017; 60: 1241–1257.
47.
HarachTMarungruangNDuthilleulN, et al.Reduction of Abeta amyloid pathology in APPPS1 transgenic mice in the absence of gut microbiota. Sci Rep2017; 7: 41802.
48.
GrabruckerSMarizzoniMSilajdžićE, et al.Microbiota from Alzheimer's patients induce deficits in cognition and hippocampal neurogenesis. Brain2023; 146: 4916–4934.
49.
LingZZhuMYanX, et al.Structural and functional dysbiosis of fecal microbiota in Chinese patients with Alzheimer's disease. Front Cell Dev Biol2020; 8: 634069.
50.
HaranJPBhattaraiSKFoleySE, et al.Alzheimer's disease microbiome is associated with dysregulation of the anti-inflammatory P-glycoprotein pathway. mBio2019; 10: e00632–19.
51.
SawinEADe WolfeTJAktasB, et al.Glycomacropeptide is a prebiotic that reduces Desulfovibrio bacteria, increases cecal short-chain fatty acids, and is anti-inflammatory in mice. Am J Physiol Gastrointest Liver Physiol2015; 309: G590–G601.
52.
LavangeLMKalsbeekWDSorliePD, et al.Sample design and cohort selection in the Hispanic community health study/study of Latinos. Ann Epidemiol2010; 20: 642–649.
53.
SorliePDAviles-SantaLMWassertheil-SmollerS, et al.Design and implementation of the Hispanic community health study/study of Latinos. Ann Epidemiol2010; 20: 629–641.
54.
GonzálezHMTarrafWFornageM, et al.A research framework for cognitive aging and Alzheimer's disease among diverse US Latinos: design and implementation of the Hispanic community health study/study of Latinos-investigation of neurocognitive aging (SOL-INCA). Alzheimers Dement2019; 15: 1624–1632.
55.
GonzálezHMMungasDReedBR, et al.A new verbal learning and memory test for English- and Spanish-speaking older people. J Int Neuropsychol Soc2001; 7: 544–555.
56.
LezakMDHowiesonDBLoringDW, et al.Neuropsychological assessment. New York: Oxford University Press, 2004.
MarotzCAmirAHumphreyG, et al.DNA Extraction for streamlined metagenomics of diverse environmental samples. Biotechniques2017; 62: 290–293.
61.
GlennTCNilsenRAKieranTJ, et al.Adapterama I: universal stubs and primers for 384 unique dual-indexed or 147,456 combinatorially-indexed Illumina libraries (iTru & iNext). PeerJ2019; 7: e7755.
62.
CostelloMFlehartyMAbreuJ, et al.Characterization and remediation of sample index swaps by non-redundant dual indexing on massively parallel sequencing platforms. BMC Genomics2018; 19: 332.
63.
O'LearyNAWrightMWBristerJR, et al.Reference sequence (RefSeq) database at NCBI: current status, taxonomic expansion, and functional annotation. Nucleic Acids Res2016; 44: D733–D745.
64.
LangmeadBSalzbergSL. Fast gapped-read alignment with Bowtie 2. Nat Methods2012; 9: 357–359.
65.
McMurdiePJHolmesS. phyloseq: an R package for reproducible interactive analysis and graphics of microbiome census data. PLoS One2013; 8: e61217.
66.
Oksanen JBFKindtRLegendreP, et al.Multivariate analysis of ecological communities in R: vegan tutorial. R package version 1.7. 2013.
67.
KanehisaMSatoYKawashimaM, et al.KEGG As a reference resource for gene and protein annotation. Nucleic Acids Res2016; 44: D457–D462.
68.
HillmannBAl-GhalithGAShields-CutlerRR, et al.SHOGUN: a modular, accurate and scalable framework for microbiome quantification. Bioinformatics2020; 36: 4088–4090.
69.
PernicovaIKorbonitsM. Metformin–mode of action and clinical implications for diabetes and cancer. Nat Rev Endocrinol2014; 10: 143–156.
70.
American Diabetes Association. Diagnosis and classification of diabetes mellitus. Diabetes Care2013; 36: S67–S74.
71.
ZhernakovaAKurilshikovABonderMJ, et al.Population-based metagenomics analysis reveals markers for gut microbiome composition and diversity. Science2016; 352: 565–569.
72.
PetersBAYiSSBeasleyJM, et al.US Nativity and dietary acculturation impact the gut microbiome in a diverse US population. ISME J2020; 14: 1639–1650.
73.
VangayPJohnsonAJWardTL, et al.US Immigration westernizes the human gut microbiome. Cell2018; 175: 962–972.e910.
74.
Siega-RizAMSotres-AlvarezDAyalaGX, et al.Food-group and nutrient-density intakes by Hispanic and Latino backgrounds in the Hispanic community health study/study of Latinos. Am J Clin Nutr2014; 99: 1487–1498.
75.
ForslundKHildebrandFNielsenT, et al.Disentangling type 2 diabetes and metformin treatment signatures in the human gut microbiota. Nature2015; 528: 262–266.
76.
MallickHRahnavardAMcIverLJ, et al.Miltivariable association discovery in population-scale meta-omics studies. PLoS Comput Biol2021; 17: e1009442.
77.
KandulaNRDiez-RouxAVChanC, et al.Association of acculturation levels and prevalence of diabetes in the multi-ethnic study of atherosclerosis (MESA). Diabetes Care2008; 31: 1621–1628.
78.
MallickHRahnavardAMcIverLJ, et al.Multivariable association discovery in population-sclae meta-omics studies. PLoS Comput Biol2020; 17: e1009442.
79.
ParkerBJWearschPAVelooACM, et al.The genus alistipes: gut bacteria with emerging implications to inflammation, cancer, and mental health. Front Immunol2020; 11: 906.
80.
HeSGranot-HershkovitzEZhangY, et al.Blood metabolites predicting mild cognitive impairment in the study of Latinos-investigation of neurocognitive aging (HCHS/SOL). Alzheimers Dement (Amst)2022; 14: e12259.
81.
MerinoEJensenRAYanofskyC. Evolution of bacterial trp operons and their regulation. Curr Opin Microbiol2008; 11: 78–86.
82.
SergerELuengo-GutierrezLChadwickJS, et al.The gut metabolite indole-3 propionate promotes nerve regeneration and repair. Nature2022; 607: 585–592.
83.
ZhouYChenYHeH, et al.The role of the indoles in microbiota-gut-brain axis and potential therapeutic targets: a focus on human neurological and neuropsychiatric diseases. Neuropharmacology2023; 239: 109690.
84.
OtaruNYeKMujezinovicD, et al.GABA Production by human intestinal bacteroides spp.: prevalence, regulation, and role in acid stress tolerance. Front Microbiol2021; 12: 656895.
85.
SajiNMurotaniKHisadaT, et al.The relationship between the gut microbiome and mild cognitive impairment in patients without dementia: a cross-sectional study conducted in Japan. Sci Rep2019; 9: 19227.
86.
SajiNNiidaSMurotaniK, et al.Analysis of the relationship between the gut microbiome and dementia: a cross-sectional study conducted in Japan. Sci Rep2019; 9: 1008.
87.
LarsenNVogensenFKvan den BergFW, et al.Gut microbiota in human adults with type 2 diabetes differs from non-diabetic adults. PLoS One2010; 5: e9085.
88.
KimEJKimJSParkSE, et al.Association between mild cognitive impairment and gut microbiota in elderly Korean patients. J Microbiol Biotechnol2023; 33: 1376–1383.
89.
KaiyrlykyzyAKozhakhmetovSBabenkoD, et al.Study of gut microbiota alterations in Alzheimer's dementia patients from Kazakhstan. Sci Rep2022; 12: 15115.
90.
LiZLiangHHuY, et al.Gut bacterial profiles in Parkinson's disease: a systematic review. CNS Neurosci Ther2023; 29: 140–157.
91.
WangZXiaoGYaoY, et al.The role of bifidobacteria in gut barrier function after thermal injury in rats. J Trauma2006; 61: 650–657.
92.
AhoVTEPereiraPABVoutilainenS, et al.Gut microbiota in Parkinson's disease: temporal stability and relations to disease progression. EBioMedicine2019; 44: 691–707.
93.
BolliriCFontanaACeredaE, et al.Gut microbiota in monozygotic twins discordant for Parkinson's disease. Ann Neurol2022; 92: 631–636.
94.
WallenZDDemirkanATwaG, et al.Metagenomics of Parkinson's disease implicates the gut microbiome in multiple disease mechanisms. Nat Commun2022; 13: 6958.
95.
LinAZhengWHeY, et al.Gut microbiota in patients with Parkinson's disease in southern China. Parkinsonism Relat Disord2018; 53: 82–88.
96.
LiYLiRXDuYT, et al.[Features of gut microbiota in patients with idiopathic Parkinson's disease]. Zhonghua Yi Xue Za Zhi2020; 100: 1017–1022.
97.
UngerMMSpiegelJDillmannKU, et al.Short chain fatty acids and gut microbiota differ between patients with Parkinson's disease and age-matched controls. Parkinsonism Relat Disord2016; 32: 66–72.
98.
BarichellaMSevergniniMCiliaR, et al.Unraveling gut microbiota in Parkinson's disease and atypical parkinsonism. Mov Disord2019; 34: 396–405.
99.
Hill-BurnsEMDebeliusJWMortonJT, et al.Parkinson's disease and Parkinson's disease medications have distinct signatures of the gut microbiome. Mov Disord2017; 32: 739–749.
100.
PetrovVASaltykovaIVZhukovaIA, et al.Analysis of gut microbiota in patients with Parkinson's disease. Bull Exp Biol Med2017; 162: 734–737.
101.
PalaciosNWilkinsonJBjornevikK, et al.Metagenomics of the gut microbiome in Parkinson's disease: prodromal changes. Ann Neurol2023; 94: 486–501.
102.
PalmasVPisanuSMadauV, et al.Gut microbiota markers and dietary habits associated with extreme longevity in healthy sardinian centenarians. Nutrients2022; 14: 2436.
103.
BarrettERossRPO'ToolePW, et al.γ-Aminobutyric acid production by culturable bacteria from the human intestine. J Appl Microbiol2012; 113: 411–417.
104.
La ReauAJSuenG. The Ruminococci: key symbionts of the gut ecosystem. J Microbiol2018; 56: 199–208.
105.
OlsonCAVuongHEYanoJM, et al.The gut microbiota mediates the anti-seizure effects of the ketogenic diet. Cell2018; 173: 1728–1741.e1713.
106.
BravoJAForsythePChewMV, et al.Ingestion of Lactobacillus strain regulates emotional behavior and central GABA receptor expression in a mouse via the vagus nerve. Proc Natl Acad Sci U S A2011; 108: 16050–16055.
107.
Calvo-Flores GuzmánBVinnakotaCGovindpaniK, et al.The GABAergic system as a therapeutic target for Alzheimer's disease. J Neurochem2018; 146: 649–669.
108.
GovindpaniKCalvo-Flores GuzmánBVinnakotaC, et al.Towards a better understanding of GABAergic remodeling in Alzheimer's disease. Int J Mol Sci2017; 18: 1813.
109.
LiuPFleeteMSJingY, et al.Altered arginine metabolism in Alzheimer's disease brains. Neurobiol Aging2014; 35: 1992–2003.
110.
LiuPJingYZhangH. Age-related changes in arginine and its metabolites in memory-associated brain structures. Neuroscience2009; 164: 611–628.
111.
PaleyEL. Diet-related metabolic perturbations of gut microbial shikimate pathway-tryptamine-tRNA aminoacylation-protein synthesis in human health and disease. Int J Tryptophan Res2019; 12: 1178646919834550.
112.
PaleyELMerkulova-RainonTFaynboymA, et al.Geographical distribution and diversity of gut microbial NADH: ubiquinone oxidoreductase sequence associated with Alzheimer's disease. J Alzheimers Dis2018; 61: 1531–1540.
113.
PaleyELPerryG. Towards an integrative understanding of tRNA aminoacylation-diet-host-gut microbiome interactions in neurodegeneration. Nutrients2018; 10: 410.
114.
FaithJJGurugeJLCharbonneauM, et al.The long-term stability of the human gut microbiota. Science2013; 341: 1237439.
115.
FranzosaEAHuangKMeadowJF, et al.Identifying personal microbiomes using metagenomic codes. Proc Natl Acad Sci U S A2015; 112: E2930–E2938.
116.
MehtaRSAbu-AliGSDrewDA, et al.Stability of the human faecal microbiome in a cohort of adult men. Nat Microbiol2018; 3: 347–355.
Supplementary Material
Please find the following supplemental material available below.
For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.
For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.
