TY - JOUR

T1 - Gut microbiota profile and selected plasma metabolites in type 1 diabetes without and with stratification by albuminuria

AU - Winther, Signe A.

AU - Henriksen, Peter

AU - Vogt, Josef K.

AU - Hansen, Tue H.

AU - Ahonen, Linda

AU - Suvitaival, Tommi

AU - Zobel, Emilie Hein

AU - Frimodt-Møller, Marie

AU - Hansen, Tine W.

AU - Hansen, Torben

AU - Parving, Hans-Henrik

AU - Legido-Quigley, Cristina

AU - Rossing, Peter

AU - Pedersen, Oluf

PY - 2020

Y1 - 2020

N2 - 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 (= 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 andl-citrulline than those with normo- or microalbuminuria and higher plasma levels of homocitrulline andl-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.

AB - 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 (= 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 andl-citrulline than those with normo- or microalbuminuria and higher plasma levels of homocitrulline andl-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.

KW - 16S RNA sequencing

KW - Diabetes

KW - Diabetic kidney disease

KW - Diabetic nephropathy

KW - Gut microbiota

KW - Metabolome

KW - Plasma metabolome

KW - Renal complications

KW - Targeted metabolites

KW - Type 1 diabetes

KW - INDOXYL SULFATE

KW - KIDNEY-DISEASE

KW - INTESTINAL MICROBIOTA

U2 - 10.1007/s00125-020-05260-y

DO - 10.1007/s00125-020-05260-y

M3 - Journal article

C2 - 32886190

VL - 63

SP - 2713

EP - 2724

JO - Diabetologia

JF - Diabetologia

SN - 0012-186X

ER -