Microbiome-associated human genetic variants impact phenome-wide disease risk

Markowitz, Robert H George; LaBella, Abigail L.; Shi, Mingjian; Rokas, Antonis; Capra, John A.; Ferguson, Jane F.; Mosley, Jonathan D.; Bordenstein, Seth R.

doi:10.1073/pnas.2200551119

Cited by 13 publications

(9 citation statements)

References 133 publications

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“…137 Several microbe-associated single-nucleotide polymorphisms also associate with disease phenotypes, suggesting that one mechanism linking human genetic variation with disease may be through modulation of commensal microbes. [138][139][140][141] Suggested associations include Ruminococcus flavefaciens and hypertension, Clostridium and platelet count, 142 and Lachnospiraceae and several autoimmune diseases 138 ; however, these associations require more validation and remain to be proven experimentally. While human genetic variation may contribute to interindividuality in gut microbiota, this may be relatively minor compared with other determinants of microbial composition.…”

Section: Genetic Determinants Of Microbiome Compositionmentioning

confidence: 99%

Gut Microbiota and Microbial Metabolism in Early Risk of Cardiometabolic Disease

Gabriel

Ferguson

2023

Circulation Research

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Cardiometabolic disease comprises cardiovascular and metabolic dysfunction and underlies the leading causes of morbidity and mortality, both within the United States and worldwide. Commensal microbiota are implicated in the development of cardiometabolic disease. Evidence suggests that the microbiome is relatively variable during infancy and early childhood, becoming more fixed in later childhood and adulthood. Effects of microbiota, both during early development, and in later life, may induce changes in host metabolism that modulate risk mechanisms and predispose toward the development of cardiometabolic disease. In this review, we summarize the factors that influence gut microbiome composition and function during early life and explore how changes in microbiota and microbial metabolism influence host metabolism and cardiometabolic risk throughout life. We highlight limitations in current methodology and approaches and outline state-of-the-art advances, which are improving research and building toward refined diagnosis and treatment options in microbiome-targeted therapies.

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Section: Genetic Determinants Of Microbiome Compositionmentioning

confidence: 99%

Gut Microbiota and Microbial Metabolism in Early Risk of Cardiometabolic Disease

Gabriel

Ferguson

2023

Circulation Research

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“…A cutting-edge work by Markowitz et al showed the triangular association between human genome variations, gut microbiome composition and health and disease predisposition [ 59 ]. The authors screened nearly a thousand gut microbiome-associated genetic variants (MAVs) and their impact on phenotypes reported in electronic health records from tens of thousands of human individuals (mainly European).…”

Section: Gut Metagenome In Health and Diseasementioning

confidence: 99%

“…In the investigation by Markowitz et al, 925 MAVs were detected and 908 had annotation according to wide genomic population-based database matching [ 59 ]. Interestingly, only 4 of 908 MAVs were protein coding (namely two synonymous and two non-synonymous variants).…”

Section: Gut Metagenome In Health and Diseasementioning

confidence: 99%

Human Genes Involved in the Interaction between Host and Gut Microbiome: Regulation and Pathogenic Mechanisms

Boccuto

Tack

Ianiro

et al. 2023

Genes

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Introduction: The umbrella term “human gut microbiota” describes the complex ecosystem harboring our gut. It includes bacteria, viruses, protozoa, archaea, fungi, and yeasts. This taxonomic classification does not describe its functions, which encompass nutrients digestion and absorption, immune system regulation, and host metabolism. “Gut microbiome” indicates instead the genome belonging to these “microbes” actively involved in these functions. However, the interaction between the host genome and the microbial ones determines the fine functioning of our organism. Methods: We reviewed the data available in the scientific literature on the definition of gut microbiota, gut microbiome, and the data on human genes involved in the interaction with the latter. We consulted the main medical databases using the following keywords, acronyms, and their associations: gut microbiota, gut microbiome, human genes, immune function, and metabolism. Results: Candidate human genes encoding enzymes, inflammatory cytokines, and proteins show similarity with those included in the gut microbiome. These findings have become available through newer artificial intelligence (AI) algorithms allowing big data analysis. From an evolutionary point of view, these pieces of evidence explain the strict and sophisticated interaction at the basis of human metabolism and immunity regulation in humans. They unravel more and more physiopathologic pathways included in human health and disease. Discussion: Several lines of evidence also obtained through big data analysis support the bi-directional role of gut microbiome and human genome in host metabolism and immune system regulation.

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“…On the other hand, the role of host genetics in determining gut microbiome composition has been discussed (Hall et al, 2017;Rothschild et al, 2018). Recently, some microbiome-associated human genetic variants that could correlate with the relative abundance of microorganisms at the strain level were described (Markowitz et al, 2022). Interestingly, a functional FUT2 gene encodes alpha1,2fucosyltransferase II that is responsible for the fucosylation of mucosal surfaces of the gut.…”

Section: Introductionmentioning

confidence: 99%

Influence of perinatal and childhood exposure to tobacco and mercury in children’s gut microbiota

Pérez-Castro,

D’Auria,

Llambrich

et al. 2024

Front. Microbiol.

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BackgroundEarly life determinants of the development of gut microbiome composition in infants have been widely investigated; however, if early life pollutant exposures, such as tobacco or mercury, have a persistent influence on the gut microbial community, its stabilization at later childhood remains largely unknown.ObjectiveIn this exposome-wide study, we aimed at identifying the contribution of exposure to tobacco and mercury from the prenatal period to childhood, to individual differences in the fecal microbiome composition of 7-year-old children, considering co-exposure to a width of established lifestyle and clinical determinants.MethodsGut microbiome was studied by 16S rRNA amplicon sequencing in 151 children at the genus level. Exposure to tobacco was quantified during pregnancy through questionnaire (active tobacco consumption, second-hand smoking -SHS) and biomonitoring (urinary cotinine) at 4 years (urinary cotinine, SHS) and 7 years (SHS). Exposure to mercury was quantified during pregnancy (cord blood) and at 4 years (hair). Forty nine other potential environmental determinants (12 at pregnancy/birth/infancy, 15 at 4 years and 22 at 7 years, such as diet, demographics, quality of living/social environment, and clinical records) were registered. We used multiple models to determine microbiome associations with pollutants including multi-determinant multivariate analysis of variance and linear correlations (wUnifrac, Bray-Curtis and Aitchison ß-diversity distances), single-pollutant permutational multivariate analysis of variance adjusting for co-variates (Aitchison), and multivariable association model with single taxa (MaAsLin2; genus). Sensitivity analysis was performed including genetic data in a subset of 107 children.ResultsActive smoking in pregnancy was systematically associated with microbiome composition and ß-diversity (R2 2–4%, p < 0.05, Aitchison), independently of other co-determinants. However, in the adjusted single pollutant models (PERMANOVA), we did not find any significant association. An increased relative abundance of Dorea and decreased relative abundance of Akkermansia were associated with smoking during pregnancy (q < 0.05).DiscussionOur findings suggest a long-term sustainable effect of prenatal tobacco exposure on the children’s gut microbiota. This effect was not found for mercury exposure or tobacco exposure during childhood. Assessing the role of these exposures on the children’s microbiota, considering multiple environmental factors, should be further investigated.

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Microbiome-associated human genetic variants impact phenome-wide disease risk

Cited by 13 publications

References 133 publications

Gut Microbiota and Microbial Metabolism in Early Risk of Cardiometabolic Disease

Gut Microbiota and Microbial Metabolism in Early Risk of Cardiometabolic Disease

Human Genes Involved in the Interaction between Host and Gut Microbiome: Regulation and Pathogenic Mechanisms

Influence of perinatal and childhood exposure to tobacco and mercury in children’s gut microbiota

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