Signe A Winther1,2, Peter Henriksen3, Josef K Vogt4, Tue H Hansen4, Linda Ahonen3,5, Tommi Suvitaival3, Emilie Hein Zobel3, Marie Frimodt-Møller3, Tine W Hansen3, Torben Hansen4, Hans-Henrik Parving6, Cristina Legido-Quigley3,7, Peter Rossing3,8, Oluf Pedersen9. 1. Steno Diabetes Center Copenhagen, Gentofte, Denmark. signe.abitz.winther@regionh.dk. 2. Novo Nordisk A/S, Maaloev, Denmark. signe.abitz.winther@regionh.dk. 3. Steno Diabetes Center Copenhagen, Gentofte, Denmark. 4. The Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark. 5. Biosyntia ApS, Copenhagen, Denmark. 6. Department of Endocrinology, Rigshospitalet, Copenhagen, Denmark. 7. Institute of Pharmaceutical Science, King's College London, London, UK. 8. University of Copenhagen, Copenhagen, Denmark. 9. The Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark. oluf@sund.ku.dk.
Abstract
AIMS/HYPOTHESIS: Abnormal gut microbiota and blood metabolome profiles have been reported both in children and adults with uncomplicated type 1 diabetes as well as in adults with type 1 diabetes and advanced stages of diabetic nephropathy. In this study we aimed to investigate the gut microbiota and a panel of targeted plasma metabolites in individuals with type 1 diabetes of long duration without and with different levels of albuminuria. METHODS: In a cross-sectional study we included 161 individuals with type 1 diabetes and 50 healthy control individuals. Individuals with type 1 diabetes were categorised into three groups according to historically measured albuminuria: (1) normoalbuminuria (<3.39 mg/mmol); (2) microalbuminuria (3.39-33.79 mg/mmol); and (3) macroalbuminuria (≥33.90 mg/mmol). From faecal samples, the gut microbiota composition at genus level was characterised by 16S rRNA gene amplicon sequencing and in plasma a targeted profile of 31 metabolites was analysed with ultra HPLC coupled to MS/MS. RESULTS: Study participants were aged 60 ± 11 years (mean ± SD) and 42% were women. The individuals with type 1 diabetes had had diabetes for a mean of 42 ± 15 years and had an eGFR of 75 ± 25 ml min-1 (1.73 m)-2. Measures of the gut microbial beta diversity differed significantly between healthy controls and individuals with type 1 diabetes, either with micro- or macroalbuminuria. Taxonomic analyses showed that 79 of 324 genera differed in relative abundance between individuals with type 1 diabetes and healthy controls and ten genera differed significantly among the three albuminuria groups with type 1 diabetes. For the measured plasma metabolites, 11 of 31 metabolites differed significantly between individuals with type 1 diabetes and healthy controls. When individuals with type 1 diabetes were stratified by the level of albuminuria, individuals with macroalbuminuria had higher plasma concentrations of indoxyl sulphate and L-citrulline than those with normo- or microalbuminuria and higher plasma levels of homocitrulline and L-kynurenine compared with individuals with normoalbuminuria. Whereas plasma concentrations of tryptophan were lower in individuals with macroalbuminuria compared with those with normoalbuminuria. CONCLUSIONS/ INTERPRETATION: We demonstrate that individuals with type 1 diabetes of long duration are characterised by aberrant profiles of gut microbiota and plasma metabolites. Moreover, individuals with type 1 diabetes with initial stages of diabetic nephropathy show different gut microbiota and plasma metabolite profiles depending on the level of albuminuria. Graphical abstract.
AIMS/HYPOTHESIS: Abnormal gut microbiota and blood metabolome profiles have been reported both in children and adults with uncomplicated type 1 diabetes as well as in adults with type 1 diabetes and advanced stages of diabetic nephropathy. In this study we aimed to investigate the gut microbiota and a panel of targeted plasma metabolites in individuals with type 1 diabetes of long duration without and with different levels of albuminuria. METHODS: In a cross-sectional study we included 161 individuals with type 1 diabetes and 50 healthy control individuals. Individuals with type 1 diabetes were categorised into three groups according to historically measured albuminuria: (1) normoalbuminuria (<3.39 mg/mmol); (2) microalbuminuria (3.39-33.79 mg/mmol); and (3) macroalbuminuria (≥33.90 mg/mmol). From faecal samples, the gut microbiota composition at genus level was characterised by 16S rRNA gene amplicon sequencing and in plasma a targeted profile of 31 metabolites was analysed with ultra HPLC coupled to MS/MS. RESULTS: Study participants were aged 60 ± 11 years (mean ± SD) and 42% were women. The individuals with type 1 diabetes had had diabetes for a mean of 42 ± 15 years and had an eGFR of 75 ± 25 ml min-1 (1.73 m)-2. Measures of the gut microbial beta diversity differed significantly between healthy controls and individuals with type 1 diabetes, either with micro- or macroalbuminuria. Taxonomic analyses showed that 79 of 324 genera differed in relative abundance between individuals with type 1 diabetes and healthy controls and ten genera differed significantly among the three albuminuria groups with type 1 diabetes. For the measured plasma metabolites, 11 of 31 metabolites differed significantly between individuals with type 1 diabetes and healthy controls. When individuals with type 1 diabetes were stratified by the level of albuminuria, individuals with macroalbuminuria had higher plasma concentrations of indoxyl sulphate and L-citrulline than those with normo- or microalbuminuria and higher plasma levels of homocitrulline and L-kynurenine compared with individuals with normoalbuminuria. Whereas plasma concentrations of tryptophan were lower in individuals with macroalbuminuria compared with those with normoalbuminuria. CONCLUSIONS/ INTERPRETATION: We demonstrate that individuals with type 1 diabetes of long duration are characterised by aberrant profiles of gut microbiota and plasma metabolites. Moreover, individuals with type 1 diabetes with initial stages of diabetic nephropathy show different gut microbiota and plasma metabolite profiles depending on the level of albuminuria. Graphical abstract.
Authors: Ninna H Tougaard; Marie Frimodt-Møller; Hanne Salmenkari; Elisabeth B Stougaard; Andressa D Zawadzki; Ismo M Mattila; Tine W Hansen; Cristina Legido-Quigley; Sohvi Hörkkö; Carol Forsblom; Per-Henrik Groop; Markku Lehto; Peter Rossing Journal: J Clin Med Date: 2022-06-21 Impact factor: 4.964
Authors: Jukka Hintikka; Sanna Lensu; Elina Mäkinen; Sira Karvinen; Marjaana Honkanen; Jere Lindén; Tim Garrels; Satu Pekkala; Leo Lahti Journal: Int J Environ Res Public Health Date: 2021-04-12 Impact factor: 3.390