Camila Alvarez-Silva1, Alireza Kashani1,2, Tue Haldor Hansen1,3, Nishal Kumar Pinna4, Ranjit Mohan Anjana5, Anirban Dutta4, Shruti Saxena6, Julie Støy7, Ulla Kampmann7, Trine Nielsen2, Torben Jørgensen8, Visvanathan Gnanaprakash5, Rameshkumar Gnanavadivel5, Aswath Sukumaran5, Coimbatore Subramanian Shanthi Rani5, Kristine Færch7, Venkatesan Radha5, Muthuswamy Balasubramanyam5, Gopinath Balakrish Nair6, Bhabatosh Das6, Henrik Vestergaard1, Torben Hansen1, Sharmila Shekhar Mande9, Viswanathan Mohan10, Manimozhiyan Arumugam11,12, Oluf Pedersen13. 1. Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Blegdamsvej 3B, DK-2200, Copenhagen N, Denmark. 2. Danish Academy of Diabetes, Odense University Hospital, DK-5000 Odense C, Kløvervænget 6, Odense, Denmark. 3. Department of Cardiology and Endocrinology, Slagelse Hospital, Slagelse, Denmark. 4. TCS Research, Tata Consultancy Services Limited, 54B Hadapsar Industrial Estate, Pune, 411013, India. 5. Madras Diabetes Research Foundation, No. 4, Conran Smith Road, Gopalapuram, Chennai, 600 086, India. 6. Molecular Genetics Laboratory, Infections and Immunology, Translational Health Science and Technology Institute, NCR Biotech Science Cluster, Faridabad, 121001, India. 7. Steno Diabetes Center Aarhus, Aarhus Universitetshospital, Hedeager 3, 2. sal, Aarhus, 8200, Denmark. 8. Center for Clinical Research and Prevention, Bispebjerg and Frederiksberg Hospitals, University of Copenhagen, Copenhagen, Denmark. 9. TCS Research, Tata Consultancy Services Limited, 54B Hadapsar Industrial Estate, Pune, 411013, India. sharmila.mande@tcs.com. 10. Madras Diabetes Research Foundation, No. 4, Conran Smith Road, Gopalapuram, Chennai, 600 086, India. drmohans@diabetes.ind.in. 11. Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Blegdamsvej 3B, DK-2200, Copenhagen N, Denmark. arumugam@sund.ku.dk. 12. Faculty of Health Sciences, University of Southern Denmark, Odense, Denmark. arumugam@sund.ku.dk. 13. Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Blegdamsvej 3B, DK-2200, Copenhagen N, Denmark. oluf@sund.ku.dk.
Abstract
BACKGROUND: Type 2 diabetes (T2D), a multifactorial disease influenced by host genetics and environmental factors, is the most common endocrine disease. Several studies have shown that the gut microbiota as a close-up environmental mediator influences host physiology including metabolism. The aim of the present study is to examine the compositional and functional potential of the gut microbiota across individuals from Denmark and South India with a focus on T2D. Many earlier studies have investigated the microbiome aspects of T2D, and it has also been anticipated that such microbial associations would be dependent on diet and ethnic origin. However, there has been no large scale trans-ethnic microbiome study earlier in this direction aimed at evaluating any "universal" microbiome signature of T2D. METHODS: 16S ribosomal RNA gene amplicon sequencing was performed on stool samples from 279 Danish and 294 Indian study participants. Any differences between the gut microbiota of both populations were explored using diversity measures and negative binomial Wald tests. Study samples were stratified to discover global and country-specific microbial signatures for T2D and treatment with the anti-hyperglycemic drug, metformin. To identify taxonomical and functional signatures of the gut microbiota for T2D and metformin treatment, we used alpha and beta diversity measures and differential abundances analysis, comparing metformin-naive T2D patients, metformin-treated T2D patients, and normoglycemic individuals. RESULTS: Overall, the gut microbial communities of Danes and Indians are compositionally very different. By analyzing the combined study materials, we identify microbial taxonomic and functional signatures for T2D and metformin treatment. T2D patients have an increased relative abundance of two operational taxonomic units (OTUs) from the Lachnospiraceae family, and a decreased abundance of Subdoligranulum and Butyricicoccus. Studying each population per se, we identified T2D-related microbial changes at the taxonomic level within the Danish population only. Alpha diversity indices show that there is no significant difference between normoglycemic individuals and metformin-naive T2D patients, whereas microbial richness is significantly decreased in metformin-treated T2D patients compared to metformin-naive T2D patients and normoglycemic individuals. Enrichment of two OTUs from Bacteroides and depletion of Faecalibacterium constitute a trans-ethnic signature of metformin treatment. CONCLUSIONS: We demonstrate major compositional differences of the gut microbiota between Danish and South Indian individuals, some of which may relate to differences in ethnicity, lifestyle, and demography. By comparing metformin-naive T2D patients and normoglycemic individuals, we identify T2D-related microbiota changes in the Danish and Indian study samples. In the present trans-ethnic study, we confirm that metformin changes the taxonomic profile and functional potential of the gut microbiota.
BACKGROUND: Type 2 diabetes (T2D), a multifactorial disease influenced by host genetics and environmental factors, is the most common endocrine disease. Several studies have shown that the gut microbiota as a close-up environmental mediator influences host physiology including metabolism. The aim of the present study is to examine the compositional and functional potential of the gut microbiota across individuals from Denmark and South India with a focus on T2D. Many earlier studies have investigated the microbiome aspects of T2D, and it has also been anticipated that such microbial associations would be dependent on diet and ethnic origin. However, there has been no large scale trans-ethnic microbiome study earlier in this direction aimed at evaluating any "universal" microbiome signature of T2D. METHODS: 16S ribosomal RNA gene amplicon sequencing was performed on stool samples from 279 Danish and 294 Indian study participants. Any differences between the gut microbiota of both populations were explored using diversity measures and negative binomial Wald tests. Study samples were stratified to discover global and country-specific microbial signatures for T2D and treatment with the anti-hyperglycemic drug, metformin. To identify taxonomical and functional signatures of the gut microbiota for T2D and metformin treatment, we used alpha and beta diversity measures and differential abundances analysis, comparing metformin-naive T2D patients, metformin-treated T2D patients, and normoglycemic individuals. RESULTS: Overall, the gut microbial communities of Danes and Indians are compositionally very different. By analyzing the combined study materials, we identify microbial taxonomic and functional signatures for T2D and metformin treatment. T2D patients have an increased relative abundance of two operational taxonomic units (OTUs) from the Lachnospiraceae family, and a decreased abundance of Subdoligranulum and Butyricicoccus. Studying each population per se, we identified T2D-related microbial changes at the taxonomic level within the Danish population only. Alpha diversity indices show that there is no significant difference between normoglycemic individuals and metformin-naive T2D patients, whereas microbial richness is significantly decreased in metformin-treated T2D patients compared to metformin-naive T2D patients and normoglycemic individuals. Enrichment of two OTUs from Bacteroides and depletion of Faecalibacterium constitute a trans-ethnic signature of metformin treatment. CONCLUSIONS: We demonstrate major compositional differences of the gut microbiota between Danish and South Indian individuals, some of which may relate to differences in ethnicity, lifestyle, and demography. By comparing metformin-naive T2D patients and normoglycemic individuals, we identify T2D-related microbiota changes in the Danish and Indian study samples. In the present trans-ethnic study, we confirm that metformin changes the taxonomic profile and functional potential of the gut microbiota.
Entities:
Keywords:
Danes; Gut microbiota; Indians; Metformin; Populations; Trans-ethnic; Type 2 diabetes
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