A Fecal Metabolite Signature of Impaired Fasting Glucose: results from two independent population-based cohorts

Ana Nogal; Francesca Tettamanzi; Qiuling Dong; Panayiotis Louca; Alessia Visconti; Colette Christiansen; Taylor Breuninger; Jakob Linseisen; Harald Grallert; Nina Wawro; Francesco Asnicar; Kari Wong; Andrei-Florin Baleanu; Gregory A Michelotti; Nicola Segata; Mario Falchi; Annette Peters; Paul W Franks; Vincenzo Bagnardi; Tim D Spector; Jordana T Bell; Christian Gieger; Ana M Valdes; Cristina Menni

doi:10.2337/db23-0170

A Fecal Metabolite Signature of Impaired Fasting Glucose: results from two independent population-based cohorts

Ana Nogal
, Francesca Tettamanzi
, Qiuling Dong
, Panayiotis Louca
, Alessia Visconti
, Colette Christiansen
, Taylor Breuninger
, Jakob Linseisen
, Harald Grallert
, Nina Wawro
, Francesco Asnicar
, Kari Wong
, Andrei-Florin Baleanu
, Gregory A Michelotti
, Nicola Segata
, Mario Falchi
, Annette Peters
, Paul W Franks
, Vincenzo Bagnardi
, Tim D Spector

Jordana T Bell, Christian Gieger, Ana M Valdes, Cristina Menni

Twin Research & Genetic Epidemiology

King's College Hospital
Institute of Epidemiology I and Institute of Medical Informatics, Biometry and Epidemiology, Chair of Epidemiology and , Klinikum Grosshadern, 81377 Munich, Germany and.
Department of Twin Research
School of Mathematics and Statistics, Guangdong University of Finance and Economics
Faculty of Health and Social Care, The Open University
Epidemiology, Medical Faculty, University of Augsburg, Augsburg, Germany.
University of Trento
Metabolon Inc
Department of Oncology, Lund University, Lund, Sweden12Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.
7 University of Milan-Bicocca, Italy.
Department of Anesthesia, Nottingham University Hospitals NHS Trust, Nottingham, United Kingdom; Anesthesia and Critical Care Section, Division of Clinical Neuroscience, University of Nottingham, Nottingham, United Kingdom

Research output: Contribution to journal › Article › peer-review

11 Citations (Scopus)

Abstract

Prediabetes is a metabolic condition associated with gut mi-crobiome composition, although mechanisms remain elu-sive. We searched for fecal metabolites, a readout of gut microbiome function, associated with impaired fasting glucose (IFG) in 142 individuals with IFG and 1,105 healthy individuals from the UK Adult Twin Registry (TwinsUK). We used the Cooperative Health Research in the Region of Augsburg (KORA) cohort (318 IFG individuals, 689 healthy individuals) to replicate our findings. We linearly combined eight IFG-positively associated metabolites (1-methylxantine, nicoti-nate, glucuronate, uridine, cholesterol, serine, caffeine, and protoporphyrin IX) into an IFG-metabolite score, which was significantly associated with higher odds ratios (ORs) for IFG (TwinsUK: OR 3.9 [95% CI 3.02–5.02], P < 0.0001, KORA: OR 1.3 [95% CI 1.16–1.52], P < 0.0001) and incident type 2 diabetes (T2D; TwinsUK: hazard ratio 4 [95% CI 1.97–8], P = 0.0002). Although these are host-produced me-tabolites, we found that the gut microbiome is strongly associated with their fecal levels (area under the curve >70%). Abundances of Faecalibacillus intestinalis, Dorea formicigenerans, Ruminococcus torques, and Dorea sp. AF24-7LB were positively associated with IFG, and such associations were partially mediated by 1-methylxanthine and nicotinate (variance accounted for mean 14.4% [SD 5.1], P < 0.05). Our results suggest that the gut microbiome is linked to prediabetes not only via the production of microbial metabolites but also by affecting intestinal absorption/excretion of host-produced metabolites and xenobiotics, which are correlated with the risk of IFG. Fecal metabolites enable modeling of another mechanism of gut microbiome effect on prediabetes and T2D onset.

Original language	English
Pages (from-to)	1870-1880
Number of pages	11
Journal	Diabetes
Volume	72
Issue number	12
Early online date	12 Sept 2023
DOIs	https://doi.org/10.2337/db23-0170
Publication status	Published - Dec 2023

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SDG 3 Good Health and Well-being

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10.2337/db23-0170

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Nogal, A., Tettamanzi, F., Dong, Q., Louca, P., Visconti, A., Christiansen, C., Breuninger, T., Linseisen, J., Grallert, H., Wawro, N., Asnicar, F., Wong, K., Baleanu, A.-F., Michelotti, G. A., Segata, N., Falchi, M., Peters, A., Franks, P. W., Bagnardi, V., ... Menni, C. (2023). A Fecal Metabolite Signature of Impaired Fasting Glucose: results from two independent population-based cohorts. Diabetes, 72(12), 1870-1880. https://doi.org/10.2337/db23-0170

@article{5c872f6f169a4823a6b70c1e2799a7f6,

title = "A Fecal Metabolite Signature of Impaired Fasting Glucose: results from two independent population-based cohorts",

abstract = "Prediabetes is a metabolic condition associated with gut mi-crobiome composition, although mechanisms remain elu-sive. We searched for fecal metabolites, a readout of gut microbiome function, associated with impaired fasting glucose (IFG) in 142 individuals with IFG and 1,105 healthy individuals from the UK Adult Twin Registry (TwinsUK). We used the Cooperative Health Research in the Region of Augsburg (KORA) cohort (318 IFG individuals, 689 healthy individuals) to replicate our findings. We linearly combined eight IFG-positively associated metabolites (1-methylxantine, nicoti-nate, glucuronate, uridine, cholesterol, serine, caffeine, and protoporphyrin IX) into an IFG-metabolite score, which was significantly associated with higher odds ratios (ORs) for IFG (TwinsUK: OR 3.9 [95\% CI 3.02–5.02], P < 0.0001, KORA: OR 1.3 [95\% CI 1.16–1.52], P < 0.0001) and incident type 2 diabetes (T2D; TwinsUK: hazard ratio 4 [95\% CI 1.97–8], P = 0.0002). Although these are host-produced me-tabolites, we found that the gut microbiome is strongly associated with their fecal levels (area under the curve >70\%). Abundances of Faecalibacillus intestinalis, Dorea formicigenerans, Ruminococcus torques, and Dorea sp. AF24-7LB were positively associated with IFG, and such associations were partially mediated by 1-methylxanthine and nicotinate (variance accounted for mean 14.4\% [SD 5.1], P < 0.05). Our results suggest that the gut microbiome is linked to prediabetes not only via the production of microbial metabolites but also by affecting intestinal absorption/excretion of host-produced metabolites and xenobiotics, which are correlated with the risk of IFG. Fecal metabolites enable modeling of another mechanism of gut microbiome effect on prediabetes and T2D onset.",

author = "Ana Nogal and Francesca Tettamanzi and Qiuling Dong and Panayiotis Louca and Alessia Visconti and Colette Christiansen and Taylor Breuninger and Jakob Linseisen and Harald Grallert and Nina Wawro and Francesco Asnicar and Kari Wong and Andrei-Florin Baleanu and Michelotti, \{Gregory A\} and Nicola Segata and Mario Falchi and Annette Peters and Franks, \{Paul W\} and Vincenzo Bagnardi and Spector, \{Tim D\} and Bell, \{Jordana T\} and Christian Gieger and Valdes, \{Ana M\} and Cristina Menni",

note = "Funding Information: Acknowledgments. The authors thank all the participants of TwinsUK for contributing and supporting their research and all participants of KORA for their long-term commitment to the KORA study, the staff for data collection and research data management, and the members of the KORA Study Group (https://www.helmholtz-munich.de/en/epi/cohort/kora) who are responsible for the design and conduct of the study. Finally, the authors thank Caroline Le Roy (Department of Twin Research \& Genetic Epidemiology, King{\textquoteright}s College, London) for the helpful discussion. Data collection in the KORA study is done in cooperation with the University Hospital of Augsburg. Funding. This research was funded by the Chronic Disease Research Foundation, and in part by the Wellcome Trust (grant no. 212904/Z/18/Z) and by DiabetesUK (19/0006053). TwinsUK receives funding from the Wellcome Trust, the European Commission H2020 grants SYSCID (contract \#733100), the National Institute for Health Research (NIHR) Clinical Research Facility, and the Biomedical Research Centre based at Guy{\textquoteright}s and St Thomas{\textquoteright} NHS Foundation Trust in partnership with King{\textquoteright}s College London, the Chronic Disease Research Foundation, the UKRI Medical Research Council (MRC)/British Heart Foundation Ancestry and Biological Informative Markers for Stratification of Hypertension (AIM-HY, MR/M016560/1). This work was also supported by UKRI grant MR/ W026813/1 to C.M. and A.M.V. The KORA study was initiated and financed by the Helmholtz Zentrum M€unchen–German Research Center for Environmental Health, which is funded by the German Federal Ministry of Education and Research (BMBF) and by the State of Bavaria. Stool sample collection and metabo-lomics analysis in KORA FF4 was supported by iMED, a research alliance within the Helmholtz Association, Germany. C.M., L.P., and A.N. are funded by the Chronic Disease Research Foundation. A.M.V. is supported by the National Institute for Health Research Nottingham Biomedical Research Centre. Duality of Interest. This study received support from Zoe Ltd. T.D.S. is a cofounder and shareholder of Zoe Ltd. A.M.V., P.W.F., F.A., and N.S. are consultants to Zoe Ltd. K.W. and G.A.M. are employees of Metabolon Inc. No other potential conflicts of interest relevant to this article were reported. Author Contributions. A.N., F.T., Q.D., A.V., C.C., H.G., F.A., and C.G. curated the data. A.N., F.T., Q.D., and C.M. performed the formal analyses. A.N., A.M.V., and C.M. wrote the manuscript. Q.D., P.L., A.V., C.C., T.B., J.L., H.G., N.W., F.A., K.W., A.-F.B., G.A.M., N.S., M.F., A.P., P.W.F., V.B., T.D.S., J.T.B., and C.G. contributed reagents/materials/analysis tools. T.D.S. and C.M. conceived and designed the experiments. All of the authors revised the manuscript. C.M. is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Publisher Copyright: {\textcopyright} 2023, American Diabetes Association Inc. All rights reserved.",

year = "2023",

month = dec,

doi = "10.2337/db23-0170",

language = "English",

volume = "72",

pages = "1870--1880",

journal = "Diabetes",

issn = "1939-327X",

publisher = "American Diabetes Association Inc.",

number = "12",

}

Nogal, A, Tettamanzi, F, Dong, Q, Louca, P , Visconti, A , Christiansen, C, Breuninger, T, Linseisen, J, Grallert, H, Wawro, N, Asnicar, F, Wong, K, Baleanu, A-F, Michelotti, GA, Segata, N, Falchi, M, Peters, A, Franks, PW, Bagnardi, V, Spector, TD , Bell, JT, Gieger, C, Valdes, AM & Menni, C 2023, 'A Fecal Metabolite Signature of Impaired Fasting Glucose: results from two independent population-based cohorts', Diabetes, vol. 72, no. 12, pp. 1870-1880. https://doi.org/10.2337/db23-0170

TY - JOUR

T1 - A Fecal Metabolite Signature of Impaired Fasting Glucose

T2 - results from two independent population-based cohorts

AU - Nogal, Ana

AU - Tettamanzi, Francesca

AU - Dong, Qiuling

AU - Louca, Panayiotis

AU - Visconti, Alessia

AU - Christiansen, Colette

AU - Breuninger, Taylor

AU - Linseisen, Jakob

AU - Grallert, Harald

AU - Wawro, Nina

AU - Asnicar, Francesco

AU - Wong, Kari

AU - Baleanu, Andrei-Florin

AU - Michelotti, Gregory A

AU - Segata, Nicola

AU - Falchi, Mario

AU - Peters, Annette

AU - Franks, Paul W

AU - Bagnardi, Vincenzo

AU - Spector, Tim D

AU - Bell, Jordana T

AU - Gieger, Christian

AU - Valdes, Ana M

AU - Menni, Cristina

N1 - Funding Information: Acknowledgments. The authors thank all the participants of TwinsUK for contributing and supporting their research and all participants of KORA for their long-term commitment to the KORA study, the staff for data collection and research data management, and the members of the KORA Study Group (https://www.helmholtz-munich.de/en/epi/cohort/kora) who are responsible for the design and conduct of the study. Finally, the authors thank Caroline Le Roy (Department of Twin Research & Genetic Epidemiology, King’s College, London) for the helpful discussion. Data collection in the KORA study is done in cooperation with the University Hospital of Augsburg. Funding. This research was funded by the Chronic Disease Research Foundation, and in part by the Wellcome Trust (grant no. 212904/Z/18/Z) and by DiabetesUK (19/0006053). TwinsUK receives funding from the Wellcome Trust, the European Commission H2020 grants SYSCID (contract #733100), the National Institute for Health Research (NIHR) Clinical Research Facility, and the Biomedical Research Centre based at Guy’s and St Thomas’ NHS Foundation Trust in partnership with King’s College London, the Chronic Disease Research Foundation, the UKRI Medical Research Council (MRC)/British Heart Foundation Ancestry and Biological Informative Markers for Stratification of Hypertension (AIM-HY, MR/M016560/1). This work was also supported by UKRI grant MR/ W026813/1 to C.M. and A.M.V. The KORA study was initiated and financed by the Helmholtz Zentrum M€unchen–German Research Center for Environmental Health, which is funded by the German Federal Ministry of Education and Research (BMBF) and by the State of Bavaria. Stool sample collection and metabo-lomics analysis in KORA FF4 was supported by iMED, a research alliance within the Helmholtz Association, Germany. C.M., L.P., and A.N. are funded by the Chronic Disease Research Foundation. A.M.V. is supported by the National Institute for Health Research Nottingham Biomedical Research Centre. Duality of Interest. This study received support from Zoe Ltd. T.D.S. is a cofounder and shareholder of Zoe Ltd. A.M.V., P.W.F., F.A., and N.S. are consultants to Zoe Ltd. K.W. and G.A.M. are employees of Metabolon Inc. No other potential conflicts of interest relevant to this article were reported. Author Contributions. A.N., F.T., Q.D., A.V., C.C., H.G., F.A., and C.G. curated the data. A.N., F.T., Q.D., and C.M. performed the formal analyses. A.N., A.M.V., and C.M. wrote the manuscript. Q.D., P.L., A.V., C.C., T.B., J.L., H.G., N.W., F.A., K.W., A.-F.B., G.A.M., N.S., M.F., A.P., P.W.F., V.B., T.D.S., J.T.B., and C.G. contributed reagents/materials/analysis tools. T.D.S. and C.M. conceived and designed the experiments. All of the authors revised the manuscript. C.M. is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Publisher Copyright: © 2023, American Diabetes Association Inc. All rights reserved.

PY - 2023/12

Y1 - 2023/12

N2 - Prediabetes is a metabolic condition associated with gut mi-crobiome composition, although mechanisms remain elu-sive. We searched for fecal metabolites, a readout of gut microbiome function, associated with impaired fasting glucose (IFG) in 142 individuals with IFG and 1,105 healthy individuals from the UK Adult Twin Registry (TwinsUK). We used the Cooperative Health Research in the Region of Augsburg (KORA) cohort (318 IFG individuals, 689 healthy individuals) to replicate our findings. We linearly combined eight IFG-positively associated metabolites (1-methylxantine, nicoti-nate, glucuronate, uridine, cholesterol, serine, caffeine, and protoporphyrin IX) into an IFG-metabolite score, which was significantly associated with higher odds ratios (ORs) for IFG (TwinsUK: OR 3.9 [95% CI 3.02–5.02], P < 0.0001, KORA: OR 1.3 [95% CI 1.16–1.52], P < 0.0001) and incident type 2 diabetes (T2D; TwinsUK: hazard ratio 4 [95% CI 1.97–8], P = 0.0002). Although these are host-produced me-tabolites, we found that the gut microbiome is strongly associated with their fecal levels (area under the curve >70%). Abundances of Faecalibacillus intestinalis, Dorea formicigenerans, Ruminococcus torques, and Dorea sp. AF24-7LB were positively associated with IFG, and such associations were partially mediated by 1-methylxanthine and nicotinate (variance accounted for mean 14.4% [SD 5.1], P < 0.05). Our results suggest that the gut microbiome is linked to prediabetes not only via the production of microbial metabolites but also by affecting intestinal absorption/excretion of host-produced metabolites and xenobiotics, which are correlated with the risk of IFG. Fecal metabolites enable modeling of another mechanism of gut microbiome effect on prediabetes and T2D onset.

AB - Prediabetes is a metabolic condition associated with gut mi-crobiome composition, although mechanisms remain elu-sive. We searched for fecal metabolites, a readout of gut microbiome function, associated with impaired fasting glucose (IFG) in 142 individuals with IFG and 1,105 healthy individuals from the UK Adult Twin Registry (TwinsUK). We used the Cooperative Health Research in the Region of Augsburg (KORA) cohort (318 IFG individuals, 689 healthy individuals) to replicate our findings. We linearly combined eight IFG-positively associated metabolites (1-methylxantine, nicoti-nate, glucuronate, uridine, cholesterol, serine, caffeine, and protoporphyrin IX) into an IFG-metabolite score, which was significantly associated with higher odds ratios (ORs) for IFG (TwinsUK: OR 3.9 [95% CI 3.02–5.02], P < 0.0001, KORA: OR 1.3 [95% CI 1.16–1.52], P < 0.0001) and incident type 2 diabetes (T2D; TwinsUK: hazard ratio 4 [95% CI 1.97–8], P = 0.0002). Although these are host-produced me-tabolites, we found that the gut microbiome is strongly associated with their fecal levels (area under the curve >70%). Abundances of Faecalibacillus intestinalis, Dorea formicigenerans, Ruminococcus torques, and Dorea sp. AF24-7LB were positively associated with IFG, and such associations were partially mediated by 1-methylxanthine and nicotinate (variance accounted for mean 14.4% [SD 5.1], P < 0.05). Our results suggest that the gut microbiome is linked to prediabetes not only via the production of microbial metabolites but also by affecting intestinal absorption/excretion of host-produced metabolites and xenobiotics, which are correlated with the risk of IFG. Fecal metabolites enable modeling of another mechanism of gut microbiome effect on prediabetes and T2D onset.

UR - https://www.scopus.com/pages/publications/85178291423

U2 - 10.2337/db23-0170

DO - 10.2337/db23-0170

M3 - Article

C2 - 37699401

SN - 1939-327X

VL - 72

SP - 1870

EP - 1880

JO - Diabetes

JF - Diabetes

IS - 12

ER -

A Fecal Metabolite Signature of Impaired Fasting Glucose: results from two independent population-based cohorts

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